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The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, System Kosmetik Produktionsgesellschaft fur kosmetische Gmbh, FEI 3011408975, at Raiffeisenstr. 2, Munster, Bavaria, from February 16 to February 18, 2022.

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).

We reviewed your March 14, 2022, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigator 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. Your firm also failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.100(a) and 211.67(b)).

You failed to provide data to demonstrate that the manufacturing processes for your over-the-counter (OTC) drug products have been validated. During the inspection, you were unable to provide documentation to support that each OTC drug product manufactured met predetermined quality requirements consistently and reliably. Your firm also lacked qualification protocols, reports, or studies documenting that acceptance criteria established were met with a description of the activities executed to ensure the manufacturing processes in place are in a state of control.

Furthermore, with your lack of process validation, your batch records were inadequate because they did not include critical production information. For example, batch records for (b)(4), batch (b)(4), and (b)(4), batch (b)(4) lacked information on the (b)(4) process, such as (b)(4) times, (b)(4), and in-process checks or samples. During the inspection, you stated that all (b)(4) equipment have variable (b)(4) manually adjusted by operators during manufacturing and that the operating (b)(4) are not documented in your production records.

In your response you committed to hire a third party to assist in the process validation. You also indicated that you will revise your production records.

Your response is inadequate. You failed to provide a detailed process performance protocol for the validation of your different manufacturing processes and the actions to be implemented to identify all sources of variability.

Additionally, your firm lacked bulk hold time studies for drug products although you follow a bulk hold time of (b)(4). In your response, you committed to validate bulk hold times for drug products manufactured in your facility. Your response is inadequate because you failed to provide sufficient information on how you will establish time limitations for production phases to ensure the quality of your drug product. Furthermore, you did not include a retrospective evaluation of your manufacturing operations to determine the impact that the lack of bulk hold time studies may have had on the stability and quality atrributes of your drug products.

Your OTC drug products, including (b)(4) and (b)(4) products containing (b)(4) and (b)(4), are manufactured on the same equipment used to manufacture non-pharmaceutical products, such as ointments, (b)(4), and (b)(4) products which may contain (b)(4).

You identified (b)(4) as a worst-case substance for cleaning purposes. The safety data sheet for (b)(4) lists the substance as harmful if swallowed. Note that your drug products are for (b)(4) use and there is a risk of unintentional ingestion. The information provided about your cleaning validation program for drug products is insufficient.

It is unacceptable as a matter of CGMP to continue manufacturing drug products using the same equipment that you use to manufacture non-pharmaceutical products.

In response to this letter, provide the following:

    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; and     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.

Your firm lacks a process validation program. 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.

2. 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)).

You failed to demonstrate that your (b)(4) system can consistently meet the minimum USP monograph specifications and that you have appropriate microbial limits suitable for drug manufacturing. For example, during 2021, your firm’s (b)(4) testing results for (b)(4) exceeded the USP criteria. In addition, your firm does not have a specification for (b)(4) and does not perform (b)(4) testing on (b)(4).

It is essential that you design your (b)(4) system to consistently produce (b)(4) that is suitable for its intended use.

In your response, you stated your intention to outsource the supply of (b)(4) to ensure USP standards are met. Your response is inadequate because it did not include a risk assessment of the drug products manufactured and released using the unsuitable (b)(4) system.

In response to this letter, provide the following:

    o A (b)(4) system validation report. Also include the summary of any improvements made to system design and to the program for ongoing control and maintenance.

3. Your firm failed to conduct at least one test to verify the identity of each component of a drug product (21 CFR 211.84(d)(1)).

You failed to test incoming active pharmaceutical ingredients (API) used to manufacture your drug products to determine their identity. Instead, our investigator observed that your firm released (b)(4) API for use in manufacturing without an identification test for (b)(4). Identity testing is required for each component lot prior to use in drug product manufacturing, and you can only rely on a Certificate of Analysis (COA) for other component attributes through validation of the supplier's test results at appropriate intervals.

In your response, you stated that your firm does not have the equipment to perform an identification test on (b)(4). You also committed to performing reserve sample testing of used APIs by a third-party laboratory.

Your response is inadequate. You did not provide a comprehensive remediation of your materials system, an assessment of products already released and distributed, and a timeline of completion for the third-party testing.

In response to this letter, provide the following:

4. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

You failed to have adequate controls in place for your Fourier Transform Infrared Spectrometer (FTIR) system. For example, you did not establish unique usernames and passwords for each analyst. In addition, the audit trail function was disabled even though this Fourier Transform Infrared Spectrometer is routinely used for raw material and finished product testing.

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.

We acknowledge that you are using a consultant to audit your operation and assist in meeting FDA requirements. We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide the following:

A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.

B. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.

C. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

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. 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 any violations.

Failure to address any violations may also result in the FDA refusing admission of articles manufactured at System Kosmetik Produktionsgesellschaft fur kosmetische Gmbh, Raiffeisenstr. 2, 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 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 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.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3011408975 and ATTN: CO Rebecca Parrilla.

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

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