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WARNING LETTER

DermaPharm A/S MARCS-CMS 596662 —


Delivery Method:
VIA UPS
Product:
Drugs

Recipient:
Recipient Name
Mr. Brian Mollcrup
Recipient Title
Chairman of the Board and Owner
DermaPharm A/S

Europavej 10
8990 Farup
Denmark

Issuing Office:
Center for Drug Evaluation and Research | CDER

10903 New Hampshire Avenue
Silver Spring, MD 20993
United States


March 10, 2020

Warning Letter 320-20-29

Dear Mr. Mollerup:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, DermaPharm A/S, FEI 3005947959, at Europavej 10, Farup, Denmark from September 16 to 19, 2019.

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 product is adulterated within the meaning or section 501 (a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your October 24, 2019, 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 investigator observed specific violations including, but not limited to the following.

1. 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)).

Your firm failed to test your over-the-counter (OTC) (b)(4) drug product, (b)(4), for the identity and strength of the active ingredient prior to release for distribution. We note that this drug product is labeled for use on children. Testing is essential to ensure that the drug products you manufacture conform to all pre-determined quality attributes appropriate for their intended use. Because you lacked adequate testing of each batch of your drug products, you do not know whether they conform to all appropriate finished product specifications and are suitable for release to consumers.

In your response, you stated that finished product testing of the (b)(4) will include an "assay/potency of (b)(4)" for any future release.

Your response is inadequate. You failed to address previously released batches of this finished drug product, including testing reserve samples for batches in commercial distribution in the United States.

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 plan to remediate and evaluate the effectiveness of your laboratory system.

• 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.

• 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 within expiry as of the date of this letter.

• 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.

2. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier's test analyses at appropriate intervals (21 CFR 211.84(d)(1) and (2)).

Your firm receives raw material, "(b)(4)" as a component for use in production of (b)(4). This raw material is a (b)(4) containing (b)(4), the active ingredient in your finished drug product. Though you receive this raw material with a certificate of analysis from your supplier, you have not performed appropriate incoming analysis of component lots upon receipt, including confirming the identity prior to use in production of your finished drug product. You also relied on your supplier's Certificate of Analysis without establishing the reliability of your component supplier's test analyses at appropriate intervals.

During the inspection, you stated that raw materials are sampled by the quality unit but are not fully tested, and that only an appearance test is performed. You further stated that, because the supplier of this component is ·qualified, you did not perform incoming testing of this material.

In response to this letter, provide:

• A comprehensive 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.

• 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 you intend to accept any results from your supplier's Certificates of Analysis 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.

3. 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 did not validate the process used to manufacture your drug product, (b)(4), prior to distribution. During the inspection, you told our investigator that there are (b)(4) batch sizes for the production of (b)(4), approximately at (b)(4), and that neither batch size has been validated.

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 validation studies determine whether an initial state of control has been established. Successful process validation 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.

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/media/71021/download

In your response to this letter, provide:

• 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 performance qualification (PPQ), and ongoing monitoring of both intra-batch and inter-batch
variation to ensure a continuing state of control.

• A timeline for performing PPQ for each of your marketed drug products. Include your process performance protocol(s) and written procedures to qualify equipment and facilities.

• A detailed program for designing, validating, maintaining. controlling, and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and interbatch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.

CGMP consultant recommended

Based upon the nature of the violations we 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. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and that the consultant evaluates the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm's compliance status with FDA.

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.

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 these violations and for preventing their recurrence or the occurrence of other violations.

FDA placed your firm on Import Alert 66-40 on March 9, 2020.

Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.

Failure to correct these violations may also result in the FDA continuing to refuse admission of articles manufactured at DermaPharm A/S, Farup, Denmark 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 may be subject to refusal of 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).

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 CDER-OC-OMO-Communications@fda.hhs.gov or mail your reply to:

Rebecca Dombrowski
Compliance Officer
U.S. Food and Drug Administration
White Oak Building 51, Room 4235
10903 New Hampshire A venue
Silver Spring, MD 20993
USA

Please identify your response with FEI 3005947959.

Sincerely,
/S/

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