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WARNING LETTER

Teligent Pharma, Inc. MARCS-CMS 587592 —


Delivery Method:
UPS Next Day Air
Product:
Drugs

Recipient:
Recipient Name
Mr. Jason Grenfell-Gardner
Recipient Title
President and CEO
Teligent Pharma, Inc.

105 Lincoln Avenue
Buena, NJ 08310
United States

Issuing Office:
Division of Pharmaceutical Quality Operations I

United States

(973) 331-4900

Dear Mr. Grenfell-Gardner:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Teligent Pharma, Inc., FEI 1000526875, at 105 Lincoln Avenue, Buena, New Jersey, from April 22 to May 20, 2019.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 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).

In addition, our inspection revealed that you failed to submit NDA Field Alert Reports (FARs) to FDA as required by 21 CFR 314.81(b)(1)(ii) and section 505(k) of the FD&C Act, 21 U.S.C. 355(k).

We reviewed your June 4, 2019, 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 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).

Your investigations into out-of-specification (OOS) test results were inadequate. You failed to investigate OOS results in a timely manner, appropriately justify potential root causes, expand investigations to all potentially affected lots, implement corrective and preventive actions (CAPA), and evaluate CAPA effectiveness.

A. During release testing you obtained OOS individual impurity results for clobetasol propionate finished drug product lot 8922 in June 2017. Re-analysis of the original samples confirmed the OOS result. You then obtained passing results after (b)(4) your samples. Your investigation concluded, without adequate supporting evidence, that the root cause was "most likely due to lot-specific sample interaction with the (b)(4) during sample preparation." Despite the lack of supporting evidence, you released the lot.

Your 18-month stability interval sample for the same lot of clobetasol propionate also had failing results for an unknown impurity. As part of your investigation, you re-tested your samples and obtained a new impurity OOS result at a different retention time. The retest also failed the total related compounds specification. Your investigation into this failure concluded that, because the original OOS peak was not detected in the retest, it did not confirm the original OOS result. You further determined that the impurities were not product related and were most likely due to glassware contamination.

In addition to the failing result for the 18-month stability interval sample, clobetasol propionate lot 8922 also had an OOS result for related compounds at the 9-month interval. However, this failure was not investigated until December 2018, nine months later. You used the 12- and 18-month stability interval test results to invalidate the nine-month interval OOS result and concluded that the root cause was not product related, disregarding the ongoing investigation into OOS test result.

Although you could not adequately assign definite root causes for these OOS results, you failed to:

o Conduct hypothesis testing to confirm theoretical root causes.

o Expand the OOS investigation to manufacturing or other potentially affected lots.

o Identify the impurities detected to support your claim that they were not product-related.

Despite Clobetasol propionate lot 8922 failing for impurities at release testing and at two different stability intervals, you took no market action.

B. Your 24-month stability interval sample for flurandrenolide ointment, USP, lots 8071 and 8072, used to support process validation, had failing results for related compounds. You re-injected the original samples and conducted a retest. In both instances, you obtained failing results. Despite this confirmation, the investigation was closed with the unsupported conclusion that impurities were not detected upon retest. You failed to:

o Conduct a Phase 2 investigation specifically including an evaluation of your manufacturing operation.

o Expand the investigation to other potentially affected lots.

o Include all test results in your stability summary.

o Submit a timely Field Alert Report for this product failure.

o Implement CAPAs such as revising the expiration date.

In your response, you stated that you will train your employees and eliminate all potential sources of contamination. You also proposed to (b)(4).

While you acknowledged that your investigative process was not robust, your response lacked sufficient information to address your investigation process as a factor in the inadequate management of product quality issues. You also failed to include an updated SOP for OOS investigations.

In your response, provide:

• A comprehensive, independent assessment of your system for investigating deviations, atypical events, complaints, OOS results, and failures. Your CAPA plan should include, but not be limited to, improvements in investigations, root cause analysis, written procedures, and quality unit oversight. Also include your process for evaluating CAPA plan effectiveness.

• A retrospective, independent review of all invalidated OOS (in-process and finished testing) results for products currently on the U.S. market within expiry. Assess whether the scientific justification and evidence for each invalidated OOS result was conclusive. For investigations that establish laboratory root cause, ensure that other laboratory methods vulnerable to the same root cause are identified for remediation. For those laboratory investigations where a root cause was not determined, include your assessment of the manufacturing operations.

• A thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, raw materials, process capability, deviation history, batch failure history) for any OOS results with inconclusive or no root cause identified.

2. Your firm failed to follow an adequate written testing program designed to assess the stability characteristics of drug products to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

On multiple occasions you failed to test stability samples within the timeframes stipulated in your procedures. For example:

• You tested the three-month long term stability sample of Triamcinolone Acetonide Cream USP, 0.1%, lot 9660 on February 1, 2018. However, results were not generated until October 1, 2018, eight months from the test date.

• You pulled six-month accelerated condition samples of LOPROX (ciclopirox), 0.77% suspension for assay of validation lots 6017, 6018, and 6019 on June 13, 2017. Although the assay test was performed on June 28, 2017, the results were not generated until January 16, 2018, approximately six months from the test date.

On both occasions the results were failing. Due to the delay in generating and reviewing the results, you were unable to investigate the OOS results in a timely manner.

In your response, you committed to (b)(4) to your firm’s stability testing program.

Your response is inadequate because you did not provide an updated stability SOP and you failed to include appropriate details on how you will ensure compliance with your stability SOP.

In your response provide:

• A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your CAPA plan should include, but not be limited to:

o A remediated SOP describing your stability program

o A comprehensive monitoring system that ensures compliance with your updated stability SOP

• A comprehensive evaluation of your stability program, including sample pull and actual test dates, and date results were generated, reviewed and approved by your Quality Unit (QU) to determine your adherence to the stability testing commitments. Also assess the impact of not identifying OOS in a timely manner for products that remain in the market.

3. Your firm failed to follow adequate written procedures describing the handling of all written and oral complaints regarding a drug product including the review by the quality control unit of any complaint involving the possible failure of a drug product to meet any of its specifications and, for such drug products, a determination as to the need for an investigation in accordance with 21 CFR 211.192. (21 CFR 211.198(a)).

Your quality unit failed to follow your complaint procedures. Product quality complaints were not adequately reviewed, approved, and closed by your quality unit within the time limits specified in your procedure. For example, our investigator found that 75 of 127 (over half) complaints received during 2018/2019 remained open for more than 30 days. At least six complaint investigations were open for more than 150 days.

Between January 2016 and May 2019, you recorded approximately 397 customer complaints related to container closure issues (e.g., approximately 60%), product separation, lack of effect and adverse events. Your quality unit failed to adequately review these complaints, identify trends, and implement effective CAPAs. During the inspection you explained that these lapses in quality system performance were due to underperforming staff, who had since been dismissed. In your response, you attributed these and other quality related issues to under staffing of the quality unit as your business expanded.

Your response is inadequate because you failed to appropriately address your quality unit not performing their required duties. Your firm must provide the quality unit with the appropriate authority, sufficient resources, and staff to carry out its responsibilities to consistently ensure drug quality.

In your response, provide:

• A comprehensive assessment with CAPA to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:

o A determination of whether procedures used by your firm are robust and appropriate

o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices

o A complete and final review of each lot and its related information before the QU disposition decision

o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products

• An independent assessment and remediation plan for your complaint handling program. Provide a report that evaluates all CAPA implemented. Include an evaluation of staff competencies, root cause analysis, CAPA effectiveness, regular reviews of investigation trends, improvements to the CAPA program when needed, and review of decisions made by the quality unit to ensure they are scientifically based and supported by executive management.

• An independent, retrospective review of all complaints and associated investigations for batches within expiry. This review should focus on the completeness of the investigations and analysis of complaint or reserve samples, particularly for investigations involving more than one complaint.

4. 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)).

You failed to evaluate changes to your manufacturing process to assess impact to the product and ensure consistent manufacturing operations and drug quality. After receiving a failing result for specific gravity during the testing of Triamcinolone Acetonide Lotion USP, 0.1% validation lot (b)(4), your technical services department suggested a change (b)(4) used in your manufacturing process. You failed to adequately evaluate this change prior to implementation. After you implemented this change, six of (b)(4) lots failed specific gravity specifications. In addition, since this change was made you also rejected three lots due to OOS results attributed to mixing issues.

Deviations from a validated process increase the likelihood of variation that can lead to product quality failures.

We acknowledge your commitment to cease production of Triamcinolone Acetonide Lotion USP, 0.1 %, until you complete adequate process validation. However, your response is inadequate, as it lacked a retrospective risk analysis of drug products currently in the U.S. market within expiry affected by inadequate process validation.

When significant variability is observed in one or more stages of pharmaceutical production, it is essential for executive management to support and implement effective actions that proactively address the source(s) of the variation and provide for a continued state of control.

In your response, 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, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.

• A timeline for performing appropriate process performance qualification (PPQ) for Triamcinolone Acetonide Lotion USP, 0.1 %. Also perform an assessment of the adequacy of your PPQ for each of your marketed drug products. Based on this assessment, include a timeline for performing PPQ for each of your marketed drug products that were determined to be inadequate.

Field alert reporting violations

The NDA/ANDA Field Alert reporting requirements in 21 CFR 314.81(b)(1)(i) and (ii), effective since May 23, 1985, require holders of NDAs and ANDAs to submit information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug product to the appropriate FDA district office within three working days of receipt by the applicant. The intent of the 21 CFR 314.81(b)(1) regulation is to establish an early warning system so that significant problems are brought to the FDA’s attention by applicant holders in order to prevent potential safety hazards from drug products already in distribution and also to prevent potential safety hazards with drug products manufactured in the future. FARs must be submitted for confirmed and unconfirmed problems meeting the definition of the regulation within three working days of becoming aware of the problem.

In addition to the aforementioned CGMP violations, your firm is in violation of the Field Alert reporting requirements set forth in 21 CFR 314.81(b)(1)(ii). Three generic drug products: Flurandrenolide Ointment USP, 0.05%; Betamethasone Dipropionate USP, Lotion, 0.05%; and Triamcinolone Acetonide USP, Cream USP, 0.1% were not provided to FDA within three working days from date of discovery for OOS result failure. Specifically,

1) On May 21, 2019, an initial and final FAR (F19-2840) was submitted for Flurandrenolide Ointment 0.5 mg/1g tube Lots # 8071 and 8072 at 24 months (b)(4) RH). The discovery was initially made on February 7, 2019. The root cause was contamination of glassware and was not reported to the FDA until after an FDA investigation.

2) On May 21, 2019, an initial FAR (F19-2845) was submitted for Betamethasone Dipropionate Lotion, 0.05% for Lots # 10850, 10857, and 10881. The OOS result was due to a stability impurity failure at 9 months at (b)(4) RH. The observation was discovered on February 11, 2019 but was not submitted until May 21, 2019 after an FDA inspection.

3) On November 14, 2018, an initial and final FAR (F19-0564) was submitted for Triamcinolone Acetonide Cream, 0.1% (Lot # 9660) for an OOS stability for Assay and(b)(4). The assay and related compound testing were initiated on February 1, 2018. Results were generated on October 1, 2018; 9 months after the problem occurred.

We remain concerned with the continuing CGMP violations demonstrated at your facility and failure to report FAR related events within three days of becoming aware of a problem. Please include in your written response the corrective action you plan to take regarding distributed products manufactured at your facility that may be affected by the violations.

Repeat Violations at Facility

In a previous inspection, dated October 2017, FDA cited similar CGMP observations. You proposed specific remediation for these observations in your response.

Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

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 these violations and for preventing their recurrence or the occurrence of other violations.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.

FDA may also withhold approval of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer until the above violations are corrected. We may re-inspect to verify that you have completed your corrective actions.

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.

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.

Send your electronic reply to orapharm1_responses@fda.hhs.gov. Your notification should refer to Warning Letter CMS # 587592 and reference FEI 1000526875.

If you have any questions, contact Compliance Officer CDR Liatte K. Closs at Liatte.Closs@fda.hhs.gov.

 

Sincerely,

/S/

Diana Amador-Toro

Program Division Director/District Director

OPQO Division I/New Jersey District