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WARNING LETTER

Aspire Pharmaceuticals, Inc. MARCS-CMS 630328 —


Delivery Method:
VIA UPS
Product:
Dietary Supplements

Recipient:
Recipient Name
Dr. Madhav Pai
Recipient Title
President & CEO
Aspire Pharmaceuticals, Inc.

41 Veronica Avenue
Somerset, NJ 08873-6800
United States

Issuing Office:
Division of Human and Animal Food Operations East II

United States


WARNING LETTER
CMS #630328

November 22, 2022

Dear Dr. Pai:

This is to advise you that the U.S. Food and Drug Administration (FDA) conducted a joint inspection of your dietary supplement and drug manufacturing facility, located at 37 & 41 Veronica Avenue, Somerset, NJ 08873-6800 on November 29 through 30, 2021; December 1 through 3, 6 through 9, 13 through 14, 17, 2021; and February 1 and 3, 2022. Based on our inspection and our. review of labeling collected during the inspection, we identified significant violations of the Federal Food, Drug, and Cosmetic Act (the Act). You may find the Act and the FDA's regulations through links on FDA's home page at http://www.fda.gov.

We received e-mail correspondences from you dated March 14, 2022, April 11, 2022, May 11, 2022, July 11, 2022, and August 11 , 2022, written in response to the Form FDA 483, lnspectional Observations, issued to you at the close of the inspection. We address your response below, in relation to each of the noted violations.

Dietary Supplement cGMP Violations

During the inspection, our investigators found significant violations of Title 21, Code of Federal Regulations (CFR), Part 111 (21 CFR Part 111), Current Good Manufacturing Practice (cGMP) in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements. These violations cause the dietary supplements manufactured at your facility to be adulterated within the meaning of section 402(g)(1) of the Act (21 U.S.C. § 342(g)(1)] because the dietary supplements have been prepared, packed, or held under conditions that do not meet cGMP requirements for dietary supplements.

Your significant violations of the cGMP requirements are as follows:

1. You failed to ensure that the tests or examinations that you use to determine whether the specifications are met are appropriate, scientifically valid methods, as required by 21 CFR 111.75(h)(1). Specifically:

a. Your finished product testing uses "(b)(4)" as a method to verify if finished product specifications for strength have been met for your (b)(4) Softgels - lot (b)(4), (b)(4) Mini Softgels - lot (b)(4), (b)(4) Softgels - lot (b)(4)(b)(4) Softgels - lot (b)(4), and (b)(4) Formula Softgels - lot (b)(4). Finished product testing using "(b)(4)" is not an appropriate, scientifically valid method to verify finished product specifications.

i. For your (b)(4) Softgels product: You use "(b)(4)" as a method to determine whether specifications are met for ingredients including, but not limited to, (b)(4).
ii. For your (b)(4) Mini Softgels product: You use "(b)(4)" as a method to determine whether specifications are met for each of the ingredients in the product. In addition, during the inspection, you stated that no testing for the strength of any ingredient has been conducted for this product.
iii. For your (b)(4) Softgels product: You use "(b)(4)" as a method to determine whether specifications are met for the ingredients (b)(4) extract and (b)(4) extract. Your specifications for this product, dated May 20, 2021, removed a test for the strength of (b)(4), a maker in the (b)(4) extract. The previous version of your specifications, dated November 6, 2020, included a test for (b)(4) to determine the amount of (b)(4) using your method, "MSIH-201 ," instead of "(b)(4)." During the inspection, you indicated the change to "(b)(4)" was at the request of the customer, as documented in your change control document dated May 18, 2021. You could not provide a basis for why removing this test and replacing it with "(b)(4)" would ensure the product met finished product specifications.
iv. For your (b)(4) Softgels product: You use "(b)(4)" as a method to determine whether specifications are met for the ingredients (b)(4).
v. For your (b)(4) Formula Softgel product: You use "(b)(4)" as a method to determine whether specifications are met for the ingredients (b)(4) (standardized to (b)(4)), (b)(4) Extract, (b)(4) Paste, (b)(4) Extract, (b)(4) Oil, (b)(4) (from (b)(4)), (b)(4) Extract, (b)(4)(b)(4) Extract (standardized to (b)(4)), and (b)(4) Extract (standardized to (b)(4)).

b. You use FTIR for identity testing for some of the ingredients in your dietary supplement products. Your procedure, RMA-279, "Testing Procedure for Identification by IR in Raw Material" requires comparison of the sample spectrum to a "Reference Standard/Reference Sample or Monograph Spectrum." During the inspection, you informed our investigators that your firm uses a purchased reference standard if there is one commercially available. For many of the ingredients, you use a reference sample because there is no reference standard available. A reference sample is a previous lot of the material from the vendor or a sample provided from the vendor to be used as reference material. However, your laboratory does not require verification of the previous lot or that the provided material is appropriate for use as a standard. Identity testing using FTIR to compare the sample spectrum to an unverified reference sample is not an appropriate, scientifically valid method to verify that specifications are met. For example:

i. (b)(4): You used FTIR for identity testing of (b)(4) lot (b)(4). During the inspection, you stated this was a previously received lot and there was no work done to qualify the previously received lot as a reference standard. In addition, (b)(4) is received as a pre-blend of (b)(4) different ingredients. During the inspection, you stated that FTIR cannot determine if each of the ingredients is present in the product. Identity testing must be able to confirm the identity of each ingredient in the finished product. (b)(4) lot (b)(4) was ultimately used in the manufacturing of the finished dietary supplement (b)(4) Softgel lot (b)(4).
ii. (b)(4) Extract: You used FTIR for identity testing of (b)(4) Extract lot (b)(4). During the inspection, you stated this was a previously received lot and there was no work done to qualify the previously received lot as a reference standard. (b)(4) lot (b)(4) was ultimately used in the manufacturing of the finished dietary supplement (b)(4) Softgel lot (b)(4).
iii. (b)(4) Extract: You used FTIR for identity testing of (b)(4) Extract lot (b)(4). During the inspection, you stated this was a previously received lot and there was no work done to qualify the previously received lot as a reference standard. (b)(4) Extract lot (b)(4) was ultimately used in the manufacturing of the finished dietary supplement (b)(4) lot (b)(4).

c. You use the (b)(4) Test Method to test your dietary supplement products for compliance with microbial specifications. This system includes testing for:

  • Total aerobic plate count, procedure MICROSTP-001
  • Yeast and mold, procedure MICROSTP-002
  • Salmonella, procedure MICROSTP-003
  • Staphylococcus aureus, procedure MICROSTP-004
  • Escherichia coli, procedure MICROSTP-005
  • Enterobacteriaceae, procedure MICROSTP-006

However, you are not conducting suitability testing to demonstrate whether these methods are appropriate for testing all of your products. According to your (b)(4) Technical Report, dated April 8, 2019, you conducted suitability testing for ten products, but not for all products. The report also determined that two of the ten products, (b)(4), required modified preparation steps for neutralization, or else the test may not provide a valid result.

The ingredients and amount of ingredients unique to individual dietary supplement products may interfere with the ability of microbial tests to provide a reliable result. Without suitability testing to demonstrate that a product does not interfere with the test, the method may not be determined to be an appropriate, scientifically valid method to verify that specifications are met.

Your response dated April 11, 2022 states you will provide new documents and procedures, including Finished Product Dossiers for all the products identified during the inspection and Finished Product Specification and Report Forms. However, we are unable to evaluate the adequacy of your corrective actions because your submission did not include documentation that shows that you are implementing such corrections. For example, you provided only draft examples of your Finished Product Dossiers and Finished Product Specification and Report Forms for some of your dietary supplement products.

In addition, your response suggested exempting ingredients that do not have verification methods from finished product testing, however, you did not provide the required documentation for such exemptions. Note that, to exempt one or more product specifications from verification requirements under 21 CFR 111.75(d), you must document why any component and in-process testing, examination, or monitoring, and any other information, will ensure that such exempted product specification is met without verification through periodic testing of the finished batch, and your quality control personnel must review and approve the documentation that you provide.

2. Your firm's quality control personnel failed to conduct a material review and make a disposition decision when the established specification was not met, as required by 21 CFR 111.113(a)(1).

Specifically, out of specification results were received for the following components and finished products:(b)(4) lot (b)(4), (b)(4) lot (b)(4)(b)(4) lot (b)(4) bulk softgels, (b)(4) raw material lot (b)(4)(b)(4) raw material lot (b)(4), and (b)(4) Suspension raw material lot (b)(4). For these components and finished products, your quality control unit failed to follow your procedure, "MICRO009: Laboratory Investigation of "Out of Specification" Results for Microbiological Testing," which outlines the appropriate steps when a microbial specification is not met during testing. Your procedure states, if laboratory testing results fail to meet the specification, "(b)(4)" and, "The (b)(4) (Attachment Ill)." You did not follow your procedure to conduct and document a laboratory investigation using Attachment Ill of your procedure; rather, you retested the samples until a passing result was obtained, and then reported the passing result without conducting an investigation for the initial failing results. No material review or disposition decision was performed by your firm in these examples where the dietary supplements or components failed to meet established specifications.

Your response dated April 11, 2022 states, "Investigations and Corrective Actions are completed. All microbiological testing is currently being sent out while improvements to the micro lab facility and procedures can be carried out to address the apparent contamination issues in the micro lab. (Status: Completed on time)." We are unable to evaluate the adequacy of your response because you did not provide documentation to support that you have made the proposed corrective actions.

Misbranded Dietary Supplements

In addition, your product (b)(4), is a misbranded dietary supplement within the meaning of section 403 of the Act [21 U.S.C. § 343] because it does not comply with the labeling requirements for dietary supplements. Specifically, we identified the following:

Your "(b)(4)" product is misbranded within the meaning of section 403(q)(1)(A) of the Act (21 U.S.C. § 343(q)(1)(A)] because the serving size declared on the label is incorrect. Specifically, the product's label declares serving size as 2. The directions state to take two (2) softgels daily divided between morning and evening, with food, or as recommended by a healthcare practitioner. Serving size should be one based on one softgel per eating occasion.

We also offer the following comments:

1. During the inspection, we observed that your quality control operations did not include reviewing and approving the results of required tests as required by 21 CFR 111.110(c). For example, your laboratory Data Reviewer did not review the electronic audit trail for your analytical testing. According to your response letter, dated April 11, 2022; training was provided to include guidelines for audit trail review and are being followed. You also provided an example of what the training consisted of; however, you did not include the names of the personnel who were retained. FDA will assess this observation during the next inspection in order to determine the effectiveness of the training on personnel.

2. Your (b)(4) Softgels Supplement Facts label declares "(b)(4)" but only lists one ingredient, that being (b)(4) fruit. We note a proprietary blend refers to more than one ingredient. (21 CFR 101.36(c)].

Human Drugs CGMP Violations

This section 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 acknowledge receipt of your response, dated March 11, 2022, and subsequent correspondence.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

1. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)).

Your quality control (QC) analysts routinely recorded raw data, such as sample weights, into unofficial notebooks during release testing. Our inspection found an analyst maintained two separate notebooks recording different sample weights for the same assay test. Your analyst admitted to altering the sample weights in the approved notebook so that calculations based on those results would meet your release specifications. At least (b)(4) batches of Aspire Daytime Mucus and Sinus soft gel bulk product failed to meet your firm's internal assay specification for the active ingredients. Your quality unit released these batches based on a review of inaccurate laboratory data.

In your response, you stated that you conducted an investigation, retested the (b)(4) batches that were released based on falsified data, and concluded that all (b)(4) batches met your firm's acceptance criteria after retesting.

Your response is inadequate because your quality unit failed to conduct a comprehensive retrospective investigation to determine the extent of breaches of data integrity found during the inspection. It also lacks a root cause investigation into the original assay results failing to meet your release specification when the actual sample weights documented in the unofficial composition notebook were used for the calculation. You failed to provide scientific justification to invalidate the original unexpected results and only report the favorable results.

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.

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 establish sufficient specifications and analytical testing procedures for critical quality attributes for the drugs that you manufacture. You lacked specifications and failed to test for the 4-aminophenol impurity in acetaminophen-containing drug products.

For example, at least three acetaminophen-containing solid oral dosage form drug products lacked the specification and testing procedure for 4-aminophenol content.

In your response, you stated that your drug products do not have a specific USP monograph, and therefore there was not a method for testing for impurities. You also committed to developing, validating, and implementing an analytical method to detect and quantify impurities by September 2022. 

Your response is inadequate. Regardless of whether a drug product has a USP monograph, you are responsible for ensuring you have scientifically sound specifications and test methods used to determine drug quality and purity prior to release. The 4-aminophenol impurity is a known impurity of acetaminophen and should be controlled and established as a condition of release of acetaminophen-containing drug products. FDA is also concerned that you plan to continue manufacturing and releasing the same drug products without testing for the 4-aminophenol impurity prior to implementing an analytical testing method. for this impurity. You have not implemented interim controls to ensure product quality and to mitigate the risk to patients.

In response to this letter, provide:

  • A list of chemical and microbial test methods and specifications used to analyze each batch of your drug products before a batch disposition decision, and the associated procedures, including but not limited to 4-aminophenol content for all acetaminophen containing drug products.
  • An assessment to ensure complete and appropriate specifications are established for batch release and stability studies for all drug products manufactured by your firm.
  • Your detailed plan for retrospective testing of all drug product batches that were insufficiently tested and remain within expiry. Determine whether each batch conforms to all appropriate specifications, including but not limited to 4-aminophenol impurity content.
  • A risk assessment on marketed finished drug product batches containing acetaminophen that were not tested for the 4-aminophenol impurity.
  • Interim controls established prior to completing the development, validation, and implementation of the test method to detect the 4-aminophenol impurity.

3. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

During this ·inspection, FDA investigators observed that your firm performed multiple single "trial" injections of test samples on high performance liquid chromatography (HPLC) systems without any scientific justification.

Your response stated that your firm's standard operating procedures (SOPs) for liquid chromatographic analysis and gas chromatographic analysis allow "trial" injections of the standard solution only to verify the resolution of HPLC and gas chromatography (GC) systems, and the "trial" injections must be a part of the sample set sequence. Your investigation report PE-22-0005 confirmed that "trial" injections were performed using test samples instead of standards.

Your response is inadequate. The inspection documented that your HPLC audit trail records showed that these "trial" injections were not part of the sample set sequence, which is contrary to the statement in your firm's response to the Form FDA 483 observations. In addition, these standalone sample "trial" injections were made before your official reinjections of the content uniformity samples in a sample set sequence, which is contrary to the statement in your retrospective investigation PE-22-0005.

The injection of trial samples is not acceptable, in part, because all data from analysis of product samples must be retained and reviewed (21 CFR 211 .22, 211.165, 211.192, and 211.194). Therefore, FDA considers it a violative practice to perform a trial injection. FDA also considers it a violative practice to use an actual sample in test, preparation, or equilibration runs as a means of disguising testing into compliance.

Reinjecting to obtain favorable results

Your firm lacked adequate documentation of all calculations and rationale for additional laboratory testing when unexpected content uniformity results for acetaminophen in batches (b)(4) were obtained during a process validation study for Aspire Mucus and Pain Relief soft gel drug product. Your analyst noticed differences in the peak shapes, reinjected the samples the next day, and used favorable reinjection results to invalidate the original results. Your response indicated that the laboratory manager was informed of the unexpected test results and authorized the reinjection of the samples. However, neither the inspection nor your firm's response included evidence to support that statement.

In your response, you indicated that a retrospective investigation PE-22-0005 was initiated for the unexpected content uniformity results for batch (b)(4) and (b)(4) in Aspire Mucus and Pain Relief soft gel process validation. Your investigation, initiated four months after the event, concluded that the initial results were invalidated because the analyst forgot to add the check standard.

Your response is inadequate. Your above conclusion is not supported by the chromatography data available. For example, there were two sample sets run on October 11, 2021 : the first set (without the check standard) was aborted in the middle of the run; and the second set (with the check standard) was completed and generated higher peak area counts for the two content uniformity samples. Your firm's conclusion contradicts the analyst's notebook ((b)(4)) comments which attributed the higher results to the different peak shapes compared to the rest of the samples analyzed in the same sample set.

Failure to investigate above limit results for purified water

Our review of your (b)(4) system audit trail report noted multiple results for total microbial testing of your purified water system were above limit. No investigation was performed. You also failed to follow your SOP MICRO009 and SOP QA025 which require an out of specification (OOS) investigation to be initiated when obtaining out of limit microbial test and purified water results, respectively. Purified water is used as one of the components in your OTC drug products.

In your response, you stated that your in-house testing was for information only and you sent the purified water samples to an outside testing laboratory for microbial release testing during the period of January 21, 2021, to July 9, 2021. You also stated that you suspended all internal microbiological laboratory operations until personnel and resources are in place to ensure compliance with all regulatory requirements.

Your response is inadequate:

  • Samples to your external laboratory were sent only after you obtained the in-house out of limit results.
  • You lack evidence to support that a protocol was in place for the testing of your samples later claimed to be for information only.
  • You failed to address the in-house test failures from September to November 2021.
  • Your retrospective investigation was performed in March 2022, approximately one year after the first out of limit result was obtained.

Your firm remains responsible for investigating all out of limit test results in a timely manner.

In response to this letter, provide:

  • A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for products currently in the U.S. market and within expiry as of the date of this letter and a report summarizing the findings of the analysis, including the following for each OOS:

    o Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.
    o For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.
    o For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, - complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.

  • A comprehensive review and remediation plan for your OOS result investigation systems. The CAPA should include but not be limited to addressing the following:

    o Quality unit oversight of laboratory investigations
    o Identification of adverse laboratory control trends
    o Resolution of causes of laboratory variation
    o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
    o Adequately scoping of each investigation and its CAPA
    o Revised OOS investigation procedures with these and other remediations

Data Integrity Remediation

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 strongly recommend that you retain a consultant highly qualified in data integrity assessment to assist in your remediation. In response to this letter, provide the following:

1. comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:

a) A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
b) Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
c) An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility's operations in which you discovered data integrity lapses.
d) A comprehensive retrospective evaluation of the nature of the (testing/manufacturing/other] data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses.

2. 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.

3. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include:

a) A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate including analytical data, manufacturing records, and all data submitted to FDA.
b) A comprehensive description of the root causes of your data integrity lapses including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
c) Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding batches to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
d) Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company's data.
e) A status report for any of the above activities already underway or completed.

This letter is not intended to be an all-inclusive statement of violations that may 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. It is your responsibility to ensure that your firm complies with all requirements of federal law, including FDA regulations.

This letter notifies you of our concerns and provides you an opportunity to address them. Failure to adequately address this matter may result in legal action including, without limitation, seizure and injunction.

Please notify FDA in writing, within 15 working days of receipt of this letter, of the specific steps you have taken to address any violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective actions within 15 working days, state the reason for the delay and the time within which you will do so. If you believe that your products are not in violation of the Act, include your reasoning and any supporting information for our consideration.

Your written response should be sent to Compliance Officer Melissa B. Libby at U.S. Food & Drug Administration, 10 Waterview Blvd., 3rd Floor, Parsippany, NJ 07054. An emailed response is also acceptable. Files greater than 100 megabytes may be submitted as smaller files in separate emails. If you have questions regarding this letter, please contact Melissa Libby by telephone at (973) 331-4997 or by email at melissa.libby@fda.hhs.gov.

Sincerely,
/S/

Randy F. Pack
District Director/Program Division Director
Baltimore District Office
Human & Animal Food East, Division 2
Office of Regulatory Affairs
U.S. Food and Drug Administration

 
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