Pharmaplast S.A.E.

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Pharmaplast S.A.E., FEI 3003767891, at Amria Free Zone, 30 Beside Lord International Factory Building, Alexandria from November 6 to November 10, 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 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).

We reviewed your December 11, 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 test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. 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)).

You failed to perform adequate identity testing for each component lot used in the production of your (b)(4) drug products, including ethanol, your active pharmaceutical ingredient (API). Additionally, your API, ethanol, is not tested for methanol content, and your procedures did not ensure that you test glycerin for presence of diethylene glycol (DEG) or ethylene glycol (EG). For example, you failed to test your incoming components for identity prior to manufacturing (b)(4) Gel, batch (b)(4). Component testing is fundamental to quality. Without adequate testing, you do not have scientific evidence that your incoming components conform to appropriate specifications before use in the manufacture of drug products.

In your response, you provide a corrective action and preventive action (CAPA) that states samples of your raw materials in your warehouse will be tested for conformance to the supplier’s certificate of analysis (COA). You also state that glycerin will be tested for DEG and EG.

Your response is inadequate because it fails to include a detailed plan for how raw materials will be tested such as test method and review of compendial requirements. Your proposed action plan does not include a strategy to implement corrective actions. Also, you do not provide a detailed plan to ensure that previously distributed drug products were manufactured with incoming components that meet the identity and impurity testing requirements.

You manufacture drugs that contain glycerin. The use of glycerin contaminated with diethylene glycol (DEG) has resulted in various lethal poisoning incidents in humans worldwide.

See FDA’s guidance document Testing of Glycerin for Diethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing glycerin at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/testing-glycerin-diethylene-glycol.

You manufacture drugs that contain ethanol. The use of ethanol contaminated with methanol has resulted in various lethal poisoning incidents in humans worldwide.

See FDA’s guidance document Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, Including During the Public Health Emergency (COVID-19) at: https://www.fda.gov/media/145262/download.

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.

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 strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.

Results of tests for DEG and EG in retain samples of all glycerin lots used to manufacture your drug products.

A full risk assessment for drug products that contain glycerin and are within expiry in the U.S. market. Take prompt corrective actions and preventive actions and detail your future actions to ensure appropriate selection of your suppliers, ongoing scrutiny of their supply chain, and appropriate incoming lot controls.

Limit test of methanol and test results for all (b)(4) batches released and distributed.

You failed to include all pieces of product-contact equipment used for manufacturing your drug and device products in your cleaning validation protocols and procedures. Your cleaning validation protocols and procedures did not include the transfer carriage vessels that are used for moving drug and chemical device component during manufacturing, creating a risk of cross contamination.

In your response, you provide a CAPA and cleaning validation for the transfer carriage vessel. Your CAPA contains a list of products evaluated for use of the transfer carriage vessel.

Your response is inadequate because the list of products provided in the CAPA contained products without “orders” and therefore lacks a complete evaluation of all possible uses of the transfer carriage vessel. You state that (b)(4) and (b)(4) finished products are the worst-case product to clean. Your response, however, does not provide information on products listed in your CAPA without “orders,” whether those products use the transfer carriage vessel, and what impact those products had on your worst-case product selection.

In response to this letter, provide:

A detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.

Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:

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 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.

A summary of updated standard operating procedures (SOPs) that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

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.

FDA placed your firm on Import Alert 66-40 on April 4, 2023.

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 continuing to refuse admission of articles manufactured at Pharmaplast S.A.E., Amria Free Zone, 30 Beside Lord International Factory Building, Alexandria 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 3003767891 and ATTN: Sarah Rhoades, Compliance Officer.