WARNING LETTER
Advanced Pharmaceutical Technology
MARCS-CMS 692576 —
March 14, 2025
Delivery Method:
VIA UPS
Reference #:
320-25-55
Product:
Drugs
Recipient:
Recipient Name
Mr. Frank M. Bardani
Recipient Title
President
Advanced Pharmaceutical Technology
132 South Central Avenue
Elmsford
,
NY
10523
United States
Issuing Office:
Center for Drug Evaluation and Research (CDER)
United States
Warning Letter
320-25-55
March 14, 2025
Dear Mr. Bardani:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Advanced Pharmaceutical Technology Inc., FEI 3009963974, at 132 South Central Avenue, Elmsford, from July 10 to August 1, 2024. The products you manufacture at this facility are combination products under section 503(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 353(g) as your products include drug and device constituent parts.
This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) requirements for combination products
1
. See Title 21 Code of Federal Regulations (CFR) part 4, 21 CFR parts 210 and 211 (drug CGMP), and 21 CFR part 820 (Quality System or QS Regulation).
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to drug CGMP requirements, 21 CFR parts 210 and 211, your combination products are adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).
In addition, information and records gathered during the course of the inspection reflect that your products,
(b)(4)
, are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans. Therefore, these products meet the definition of drug as defined in section 201(g)(1) of the FD&C Act [21 U.S.C. 321(g)(1)].
We reviewed your August 22, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence. We also acknowledge that you recently registered as a 503B Outsourcing Facility. However, you have been distributing your drug products in the United States since 2023, prior to registering as a 503B Outsourcing Facility.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all sterilization processes (21 CFR 211.113(b)).
You lacked appropriate controls to ensure the sterility of
(b)(4)
drug products that purport to be sterile. For example, you relied on the
(b)(4)
sterilization process without monitoring pre-sterilization bioburden. In addition, you failed to establish an adequate system, as was required by your standard operating procedure (SOP), for monitoring environmental conditions (including the frequency performed) to ensure your manufacturing areas were suitable for sterile drug production.
In your response, you state that you plan to test for bioburden, prior to release, and will reject lots that fail to meet appropriate specifications for endotoxin. You also state that environmental monitoring is not required because your drug products are
(b)(4)
sterilized, and that you tested product that was manufactured more than
(b)(4)
prior for microbial content and the samples showed no signs of positive cultures.
Your response is inadequate because you failed to include relevant details for pre-sterilization bioburden testing, including limits you have established, and the steps you will take in the event these limits are exceeded. In addition, appropriate environmental conditions for the manufacture of your drugs, including appropriate air quality, must be provided to protect products from microbiological contamination, even when
(b)(4)
sterilized, in order to minimize sterilization challenges and the byproducts of excessive bioburden.
It should be noted that although the sterility test is a critical final quality control for products that purport to be sterile, it cannot be solely relied upon as justification to release each drug product batch, as the test is only the last in a series of design and control provisions intended to protect the consumer from distribution of an unsafe batch. Sample sizes for sterility testing are typically small compared to the total number of units in a batch and may not detect issues that result in sporadic non-sterility. For example, inadequate
(b)(4)
sterilization validation studies or failure to consistently execute a
(b)(4)
sterilization cycle within its validated state may go undetected for substantial periods if your firm places too much reliance on the final quality control test for sterility to identify a sterility assurance problem. It is also essential to note that any positive sterility test result represents a serious CGMP issue that requires a comprehensive investigation into the cause and extent of the problem, and prompt review of the qualification status of your
(b)(4)
sterilization process.
This is a repeat violation from your 2019 and 2021 inspections.
2. Your firm failed to have, for each batch of controlled-release dosage form, appropriate laboratory determination of satisfactory conformance to the specifications for the rate of release of each active ingredient (21 CFR 211.167(c)).
You failed to provide adequate data demonstrating your drug products,
(b)(4)
, have a
(b)(4)
of the active ingredient. For example, you claim your
(b)(4)
lasts for up to
(b)(4)
and that your
(b)(4)
products have
(b)(4)
effect for
(b)(4)
. Your release and stability data for dissolution does not provide data that drug
(b)(4)
. Drug products should not be released without appropriate determination of conformance to final specifications and intended use. There is a lack of assurance of appropriate quality and that your drug will have the intended effect it purports to possess.
In your response, you state that you estimated the therapeutic duration and that you will remove
(b)(4)
claims until you perform adequate studies. Your response is inadequate because you did not provide a retrospective assessment of your drug products on the U.S. market within expiry to identify and take appropriate action on any product quality or patient safety risks.
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)).
Your firm manufactures
(b)(4)
sterilized,
(b)(4)
. You lacked adequate scientific rationale to demonstrate that your drug manufacturing processes are appropriately validated, reproducible, and controlled to consistently yield drug products of uniform character and quality. For example, you increased the commercial production batch size and released drug product without appropriate validation. You also failed to include critical process parameters in your batch records.
In your response, you plan to revalidate manufacturing processes and include more detailed production steps. Your response is inadequate because you failed to provide a detailed plan or supportive documentation for adequately validating your drug production process.
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 include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluate batches to 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. 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.
This is a repeat violation from your 2019 and 2021 inspections.
4. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).
Contract Testing Laboratories
Your quality unit (QU) did not exercise its responsibility to oversee your contract testing laboratory to ensure the appropriate finish product testing was being conducted. For example, you failed to ensure your contract testing laboratory completed the method validation protocol for
(b)(4)
. The Method Validation Report did not identify potential impurities of
(b)(4)
referenced in the method validation protocol. You did not adequately ensure the executed test method was suitable to monitor all potential impurities.
In your response, you provided an impurity method that did not adequately identify and characterize the potential impurities of your drug products. Your response is inadequate because the method validation protocol should include all potential impurities with the scientific justification for which ones would be included in the test method. You did not commit to performing a retrospective assessment of all the product lots currently on the market within expiry once new method validations are completed.
In addition, your contract testing laboratory was conducting a single dissolution test point for your drug products without scientific justification that a single time point demonstrates a consistent drug absorption over an extended period of time.
Your response states that the
(b)(4)
label claims were removed. Your response is inadequate because you did not provide sufficient scientific justification to support inadequately testing your finished drug product.
Your firm’s quality systems are inadequate. See the FDA’s guidance document
Quality Systems Approach to Pharmaceutical CGMP Regulations
for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download.
Contract Manufacturing Organizations
Your firm utilizes a contract manufacturing organization (CMO) to manufacture your prescription sterile
(b)(4)
drug product,
(b)(4)
. You stated to our investigators that you received a batch of
(b)(4)
from
(b)(4)
. You received this drug product without performing an evaluation of
(b)(4)
. You do not have adequate procedures to ensure that the sterile
(b)(4)
produced for your firm met appropriate quality attributes.
In your response, you provide documentation indicating that the CMO of
(b)(4)
is
(b)(4)
and provided documentation of an audit performed at this facility. Your response is inadequate because your QU did not ensure the drug product was manufactured in accordance with CGMP requirements.
Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.
FDA sent an electronic request for records and other information pursuant to section 704(a)(4) of the FD&C Act, 21 U.S.C. 374(a)(4) to your CMO of
(b)(4)
Injection USP),
(b)(4)
. After multiple follow-up requests, your CMO failed to respond to these attempted communications or otherwise provide the requested records or other information. It is a prohibited act under section 301(e) of the FD&C Act (21 U.S.C. 331(e)) to refuse to permit access to or copying of any record as required by section 704(a). Because your CMO failed to respond to the section 704(a)(4) records requests and associated communication attempts, FDA placed all drugs and drug products manufactured by your CMO on Import Alert 66-79. Drugs manufactured by facilities on Import Alert 66-79 are subject to refusal of admission pursuant to section 801(a)(3) of the FD&C Act in that all drugs from their facility appear to be adulterated under section 501(j) because they have been manufactured, processed, packed, or held in any factory, warehouse, or establishment and the owner, operator or agent of such factory, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection.
You are responsible for the quality of your drugs regardless of agreements in place with your contract facilities. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity. See FDA’s guidance document
Contract Manufacturing Arrangements for Drugs: Quality Agreements
at https://www.fda.gov/media/86193/download.
Unapproved Drugs
Your
(b)(4)
products,
(b)(4)
, as well as your
(b)(4)
injection product are listed in FDA’s electronic Drug Registration and Listing System (eDRLS) as “Export Only.” However, information obtained during the inspection of your firm indicates that your firm plans to distribute these products commercially in the United States. Please be advised that, based on review of the product labeling collected during the inspection of your firm and the labeling that your firm submitted to FDA’s eDRLS, these products are new drugs within the meaning of section 201(p) of the FD&C Act and require FDA premarket approval under section 505 of the FD&C Act [21 U.S.C. 355]. Distribution of an unapproved new drug in the United States is prohibited under section 301(d) of the FD&C Act [21 U.S.C. 331(d)].
We encourage you to contact FDA’s Office of New Drugs at ONDCommunications@fda.hhs.gov for assistance with the application process for your unapproved drug products.
503B Registration
Under section 503B(b) of the FD&C Act, a compounder can register as an outsourcing facility with FDA. Drug products compounded by or under the direct supervision of a licensed pharmacist in an outsourcing facility qualify for exemptions from the drug approval requirements in section 505 of the FD&C Act [21 U.S.C. § 355(a)], the requirement in section 502(f)(1) of the FD&C Act [21 U.S.C. § 352(f)(1)] that labeling bear adequate directions for use, and the Drug Supply Chain Security Act requirements in section 582 of the FD&C Act [21 U.S.C. § 360eee-1] if the conditions in section 503B of the FD&C Act are met. However, outsourcing facilities must comply with other applicable provisions of the FD&C Act, including section 501(a)(2)(B) [21 U.S.C. § 351(a)(2)(B)], regarding CGMP requirements.
2,3
Drugs Manufactured for Importation into the United States
Drug products imported into the United States must comply with all applicable requirements under the FD&C Act and the corresponding regulations set forth in Title 21 of the Code of Federal Regulations. These requirements include compliance with labeling requirements, firm registration and drug listing, and adherence to CGMP. Facilities that manufacture drug products and drug components intended for importation into the United States are subject to inspection by the FDA to determine compliance with these regulatory standards. For drugs requiring NDA or ANDA approval, the application must be submitted to and approved by the FDA’s Center for Drug Evaluation and Research (CDER) prior to importation, as required by section 505(a) of the FD&C Act and 21 CFR part 314.
Drugs Manufactured for Exportation out of the United States
Drug products exported from the United States under section 802 of the FD&C Act, must comply with applicable requirements under the FD&C Act, including those specified in section 802(f) [21 U.S.C. § 382(f)]. Under this provision, a drug may not be exported if it is not “manufactured, processed, packaged, and held in substantial conformity with current good manufacturing practice requirements.” Furthermore, a drug is considered adulterated under section 501(a)(2)(B) of the FD&C Act [21 U.S.C. § 351(a)(2)(B)] if the methods, facilities, or controls used in its manufacture, processing, packaging, or holding do not conform to CGMP standards.
We therefore encourage you to review your manufacturing processes to ensure that unapproved new drugs intended for export comply with CGMP requirements. Non-compliance with these requirements prevents your ability to export these drugs under section 802(f) of the FD&C Act [21 U.S.C. § 382(f)].
Repeat Violations at Facility
In previous inspections from September 10 to 27, 2019, and August 5 to 23, 2021, FDA cited similar CGMP violations. You proposed specific remediation for these violations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
CGMP Consultant Recommended
Because you failed to correct repeat violations, you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements.
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 any violations and for preventing their recurrence or the occurrence of other violations.
Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.
Failure to address violations may also cause FDA to withhold issuance of Export Certificates. 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 address any violations.
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 3009963974 and ATTN: Kevin Maguire.
Sincerely,
/S/
Jill P. Furman
Director
Office of Compliance
Center for Drug Evaluation and Research
_______________
1
The terms combination product and drug are used interchangeably in this letter.
2
We remind you that there are conditions, other than those discussed in this letter, that must be satisfied to qualify for the exemptions in section 503B of the FD&C Act.
3
For additional information, please see FDA’s “Information for Outsourcing Facilities” webpage, available at https://www.fda.gov/drugs/human-drug-compounding/information-outsourcing-facilities. Furthermore, FDA’s Compounding Quality Center Of Excellence (CQCOE) supports outsourcing facilities’ efforts to improve the quality of drugs they produce through training, research and engagement activities with FDA and other supporting stakeholders. For additional information on the CQCOE, please visit https://www.fda.gov/drugs/human-drug-compounding/compounding-quality-center-excellence.
Content current as of:
03/18/2025
Regulated Product(s)
Drugs