HQ Specialty Pharma CorporationCefazolin for Injection USP, 2 g/vial

NDA 211413 COMPLETE RESPONSE

HQ Specialty Pharma Corporation Attention: Stephanie Boffa

Vice President Regulatory

120 Route 17 North, Suite 130 Paramus, NJ 07652

Dear Ms. Boffa:

Please refer to your new drug application (NDA) dated and received on December 21, 2017, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Cefazolin for Injection USP, 2 g/vial.

We acknowledge receipt of your amendment dated July 09, 2020, which constituted a complete response to our December 26, 2019, action letter.

We have completed our review of this application, as amended, and have determined that we cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address these issues.

NONCLINICAL

Unless otherwise justified, nonclinical studies conducted to qualify the safety of leachables should be designed such that the identified leachables are administered in a clinically relevant manner at levels that are equivalent to or greater than what patients would be administered when incorporating interspecies allometric scaling. The information provided in your complete response does not adequately qualify the safety of the identified leachables with your drug product. Specifically:

1. The 14-day toxicity study in rats does not achieve clinically relevant leachables exposures, with animals receiving <_™ of the leachables/day when compared with the maximum estimated daily leachables exposure in patients. While the evaluation of analyzed concentrations in leachable study TE190276 in comparison with the 14-day toxicity study TE192771 based on the GC/MS analysis is informative, it does not address the observed differences in daily exposures to the animals versus maximum estimated daily exposures in humans when accounting for interspecies allometric scaling.

2. You have proposed an acceptable intake of’ mcg/day for the identified

™® leachables (Toxicological Assessment Annex 5). As previously communicated to you, while it is recognized that PQRI-

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PODP has proposed higher qualification threshold levels for leachables, the FDA recommends 5 mcg/day as the qualification threshold for non-genotoxic

leachables. a)

3. You applied ©® on the PQRI limit of __mcg/day to calculate acceptable intake for the © that would allow for sufficient safety margins. However, this approach is not considered adequate as the application ©® has not been considered for regulatory decisions on the qualification of leachables (or impurities) for safety.

4. You applied ©®to estimate that the total exposure of the API and

related leachables to the rats during the 14-day toxicity study is approximately times higher than what a patient would receive following administration of 8 g in a single day and proposed a change in labeling |

©® Given the unknown toxicity of the identified leachables, it cannot be assumed that lower daily doses of API and related leachables over the 14-day study in rat would adequately address the safety concerns of the higher leachables exposures associated with an 8 g dose in a single day.

5. The surrogates chosen for use in your read-across analysis with worst-case scenario substances (submitted December 8, 2020), do not contain sufficient toxicology information to qualify the identified leachables for safety. The

© surrogates included in the read-across assessment are not considered acceptable and there are insufficient toxicity data available for to predict any potential leachables toxicity. Because the ] cannot be fully characterized, there is considerable uncertainty regarding the structural similarity of the chosen surrogate compounds (i.e., active pharmaceutical ingredient [API] and which further limits the utility of the read-across approach.

(4)

Information needed to resolve the deficiencies

Given the absence of sufficient toxicity information surrounding the identified leachables, and the feasibility issues precluding adequate structural characterization of the ©@ ‘you will need to conduct an additional general toxicity study, in an appropriate animal species, for any leachable that exceeds the safety qualification threshold of 5 mcg/day. Such a study should be designed to achieve leachables exposures that are clinically relevant. The potential challenges of the API masking potential toxicity associated with the leachables exposure are acknowledged, but we believe it is feasible to design a nonclinical study that will allow for an adequate safety assessment of the leachables and/or identify any leachables-related shifts in the toxicity profile associated with the API. For example, you may consider conducting a toxicity study of 14-day duration in a larger animal species that would allow for a larger volume of the drug product containing leachables from the ©@ rubber stopper to be administered. As indicated in the teleconference held on November 30, 2020, we strongly recommend that you submit a draft study protocol for the Agency to review and provide feedback prior to initiating any additional nonclinical studies. Providing a draft protocol for comment will help you to design a study that can best

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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inform on the safety of the identified leachables when administered at clinically relevant exposures.

Submit a leachables assessment plan and/or justification that the leachables in the drug product to be administered to the animals are qualitatively and quantitatively similar to the identified leachables described in Study Report TE190276. If any additional leachables are characterized on further testing, or if there are any revised structures and/or identification of any new structures of leachables compared with those identified in your previous leachables assessment (TE 190276), plan to conduct additional (Q)SAR evaluation(s) for bacterial mutagenicity. A follow-up Ames test (bacterial reverse mutation assay) is recommended to qualify leachables that exceed

120 mcg/day with identified structural alerts for genotoxic potential.

PRESCRIBING INFORMATION

We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the PLR Requirements for Prescribing Information’ and Pregnancy and Lactation Labeling Final Rule? websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) - a checklist of important format items from labeling regulations and guidances.

If you revise labeling, use the SRPI checklist to ensure that the Prescribing Information conforms with format items in regulations and guidances. Your response must include updated content of labeling [21 CFR 314.50(I)(1)(i)] in structured product labeling (SPL) format as described at FDA.gov.3

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.

(1) Describe in detail any significant changes or findings in the safety profile.

(2) When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:

1 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm08415 9.htm 2 http://www. fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm09330 7.htm 3 http://www. fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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e Present new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission.

e Present tabulations of the new safety data combined with the original application data.

e Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above.

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in Clinical trials.

(3) Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.

(4) Provide case report forms and narrative summaries for each patient who died during a Clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

(5) Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data.

(6) Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

(7) Provide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug marketed in other countries.

(8) Provide English translations of current approved foreign labeling not previously submitted.

OTHER

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 314.110. If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under

21 CFR 314.65. You may also request an extension of time in which to resubmit the application.

A resubmission must fully address all the deficiencies listed in this letter and should be clearly marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider this resubmission a complete response to the deficiencies outlined in this letter. A partial

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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response to this letter will not be processed as a resubmission and will not start a new review cycle.

You may request a meeting or teleconference with us to discuss what steps you need to take before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.

The drug product may not be legally marketed until you have been notified in writing that this application is approved.

If you have any questions, call Jacquelyn Rosenberger, PharmD, RAC, Regulatory Project Manager, at (301) 796-9179.

Sincerely, {See appended electronic signature page}

Sumathi Nambiar, MD, MPH

Director

Division of Anti-Infectives

Office of Infectious Diseases

Center for Drug Evaluation and Research

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

SUMATHI NAMBIAR 01/08/2021 08:44:20 AM

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