- Delivery Method:
- Via Email
Recipient NameDr. Wladyslaw Retter
Recipient TitleCEO and Managing Director
- Dr Retter Ec Wladyslaw Retter
Ul. Warszawska 17
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
Warning Letter 320-22-12
March 14, 2022
Dear Dr. Retter:
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 June 2, 2021, request for records and other information pursuant to section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for your facility, Dr Retter Ec Wladyslaw Retter, FEI 3014686302, at Ul. Warszawska 17, Warszawa, Mazowieckie 05075, Poland.
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 product is adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)).
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, and to follow all of your written production and process control procedures (21 CFR 211.100(a) and (b)).
You distributed a homeopathic drug product, (b)(4) cream, to the United States without adequate process validation data to demonstrate that your manufacturing process can produce a homeopathic drug product of its purported quality and safety.
Specifically, the documents you provided do not support that the drug product you manufacture is of the concentration specified on the drug product label. Based on our review of the batch manufacturing record and the product label for (b)(4), the concentration of the active ingredient, (b)(4), is (b)(4)%, which is approximately between (b)(4) C and (b)(4) C. However, the label on the product you distributed is (b)(4) C. This means that you are manufacturing a drug with approximately 4 C difference in dilution, or 100,000,000 times, the active concentration that the homeopathic drug is purported to possess on the label.
Furthermore, in response to our initial 704(a)(4) request for a validation protocol and report for (b)(4), you replied that the validation protocol did not exist. Also, the documents you provided indicate a discrepancy between the components’ (b)(4) temperature as recorded in the batch manufacturing record ((b)(4)°C to (b)(4)°C) and the temperature range stated in the manufacturing instructions ((b)(4)°C to (b)(4)°C).
Each significant step of a manufacturing process must be controlled to ensure that in-process materials and finished drugs meet their quality attributes and specifications. Unvalidated production processes increase the probability that your products will vary in strength, quality, and purity. Your failure to validate your drug manufacturing processes signifies that you cannot ensure consistency, which may result in variable levels of ingredients in finished drug products.
In 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 appropriate PPQ for each of your marketed drug products.
• Your process performance protocol(s) and written procedures for qualification of 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 inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facilities.
• An assessment of each drug product process to ensure that the labeled content is accurate, consistent with the concentration of active ingredient, and represents the correct order of magnitude.
2. 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)).
Based on the records and information you provided, you have not demonstrated that you conduct at least one test to verify the identity of each component of a drug product.
For example, your response to our initial 704(a)(4) request for information on identity testing for each lot of component indicates that you conduct an organoleptic examination or rely upon the certificate of analysis (COA) provided by the supplier. The documents provided indicate that you do not conduct a specific identity test for incoming raw materials.
You can rely on a supplier’s COA for quality attributes, provided you conduct at least one test to verify the identity of each component lot before use in drug product manufacturing, and provided you establish the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results.
For all drug products imported to the United States before and after our 704(a)(4) request, provide the following in response to this letter:
• 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 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’s manufacturer. Include your standard operating procedure 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 that 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 comprehensive review of your drug formulation, product label, and batch manufacturing records to determine that the correct active ingredient(s) is used.
3. Your firm failed to prepare batch production and control records that include documentation of the accomplishment of each significant step in the manufacture, processing, packing, or holding of the batch, for each batch of drug product (21 CFR 211.188(b)).
The batch records you provided in response to our request for records lacked adequate production details, including, but not limited to, identity of major equipment, duration of execution of each significant step, total duration of the batch manufacturing, and identification of person(s) performing each significant step in the drug manufacturing operation. This documentation is necessary to establish that manufacturing processes were consistently followed and are reproducible. Having incomplete records deprives you of traceability of actions necessary for investigational purposes.
In response to this letter, provide:
• Your master production and control records for your drug products, to demonstrate that they fully document each significant and validated manufacturing step.
• A complete assessment of documentation systems used throughout your manufacturing operations, to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices, to ensure you retain attributable, legible, complete, original, accurate, and contemporaneous records throughout your operation.
4. 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)).
Our review of the COAs you provided for batches shipped to the United States indicate that you have failed to establish appropriate specifications for microbiological testing of (b)(4). Your COA does not indicate that you test for total aerobic microbial count according to United States Pharmacopoeia (USP) General Chapter <61>, Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests, or an equivalent validated method. In addition, there is no justification for the limit of (b)(4)CFU/1G for yeast and mold that is specified in the COA. Under 21 CFR 211.160(b), laboratory controls shall include the establishment of scientifically sound and appropriate specifications to assure that the finished drug product conforms to the appropriate standards of identity, strength, quality, and purity. It is critical that you establish scientifically sound and appropriate specifications for total aerobic microbial count, as well as for yeast and mold count, because the product label indicates use on (b)(4).
In response to this letter, provide:
• A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your finished product testing. Your remediated program should include, but not be limited to, your commitment to using current USP compendial monograph specifications (as applicable).
• A list of 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 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.
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.
Your firm does not have an adequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.
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/files/drugs/published/Process-Validation—General-Principles-and-Practices.pdf.
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 if your firm intends to continue manufacturing drugs for the U.S. market. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance, and that the consultant evaluate the completion and efficacy of your CAPA 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.
The violations cited in this letter are not intended to be an all-inclusive list of violations that exist in connection with your products. 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 all products from your firm on Import Alert 66-40 on March 4, 2022. 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 Dr Retter Ec Wladyslaw Retter, Warszawa, Poland, 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.
If you believe you have complied with FDA regulations, include your reasoning and any supporting information for our consideration.
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3014686302 and ATTN: Ganesh N Joshi.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research