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

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 02, 2019, which constituted a complete response to our October 19, 2018, action letter.

We also acknowledge receipt of your amendment dated December 6, 2019, which was not reviewed for this action. You may incorporate applicable sections of the amendment by specific reference as part of your response to the deficiencies cited in this 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.

PRODUCT QUALITY

(A) The leachables have not been adequately quantified or characterized. Qualify all leachables above the Analytical Evaluation Threshold (AET) for the proposed cefazolin drug product and | provide supporting data to justify the safety of the

© stoppers.

The following are the specific deficiencies and recommendations to address our concerns regarding the leachable study:

1. ®® could not be detected by HC-GC-MS analysis when the pharmaceutical matrix was spiked ©® (MST study). 9

© it is not clear why

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the proposed analytical method can detect ©® in the

extractables study, but not in the MST samples. We are concerned about the accuracy of maximum reported levels of ©® for the neat extractable study samples. Evaluate the suitability of the proposed analytical method further and define the LOD and LOQ levels for ©® testing (both for neat samples and for the pharmaceutical matrix). Additionally, as appropriate, evaluate alternate analytical methodologies for detection and quantification of ©® in the leachable study samples. 2. The characterization data for ©® are inadequate. Comments regarding the characterization data in Annex 2 of your submission dated October 15, 2019 are listed below:

i. You have not provided comparative mass spec (or any other structure specific characterization data) with standards to confirm the structure of these two leachables. Re-evaluate the suitability of your proposed GC/MS method for qualification of these two leachables. Provide appropriate comparative characterization data for the standards and leachable study samples to confirm the structures of a. Submit the complete analytical method details, i.e., sample preparation, analytical conditions, raw characterization data, etc. for both analytical standards and leachable study samples. Additionally, provide the overlaid spectra of standards and samples with clear and legible peak patterns.

ii. The total ion chromatograms for leachable study samples and MST samples, in Fiaure 1. do not show anv clear peak between retention (©) 4)

time (RT)

wey

3. Establish the LOD and LOQ values for the reported leachables with the GC/MS and HS-CG/MS analytical methods to confirm that these methods . are

suitable to detect all leachables at the reported levels. (o) (4)

Clarify the spiked concentration (and % recovery) of the standards for the MST study. We recommend you spike the MST study samples with higher concentration of the standards and then provide overlay of total ion-

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chromatograms for MST samples and leachable study samples. List the studied concentration of MST samples in the total ion- chromatograms.

. The retention time for the leachable in the MST samples does not

characterization data to confirm the structure of eS

Please provide the complete mass spec data to confirm the identification of compound in the leachable study samples.

i i leachables were calculated.

7.

We acknowledge that you have provided additional mass spectra using

different — — _ GC-EI-QTOF and — MS

However, the data only confirm the molecular weight or fragmentation pattern of these chal) but not the structures. As recommended

previously in the information request dated September 24, 2019, obtain the analytical standard of Pang perform detailed characterization studies of analytical standards and leachable study samples

using various analytical technologies (i.e., HPLC, MS and NMR) to confirm the structure of as potential leachables. Provide complete analytical met etails (e.g., sample preparation, analytical

conditions, raw characterization data, etc.) for both analytical standards and

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NDA 211413 / Cefazolin for Injection

Page 4

leachable study samples. Also, provide the overlaid spectra of standards and samples with clear and legible peak pattern.

8. You proposed to apply the ICH Q3B limits to justify the safety of cefazolin

® (Annex 2, submission dated October 15, 2019).

(b) (4)

®®1CH Q3B limits do not apply. Provide appropriate data to justify the safety of these a.

NONCLINICAL

(B) You have not adequately qualified the safety of the identified leachables detected with your drug product.

The following are the specific deficiencies and recommendations to address our concerns regarding the leachable study:

1.

Your approach to rely on QSAR analysis to qualify the identified leachables is not adequate. Other than for mutagenicity, QSAR assessments for general toxicity endpoints (i.e., respiratory sensitization, hepatotoxicity, nephrotoxicity, etc.), while informative, are not adequate to support safety of the identified leachables. In the absence of any additional toxicity information for the identified leachables in the published literature or public toxicological databases, a safety qualification threshold of 5 mcg/day for leachables detected in parenteral products is recommended. For the identified leachables containing API fragments oy

®® you applied ICH Q3B qualification threshold of 0.15%. As noted in the product quality comments above, we

(b) (4)

®©® the ICH Q3B limits do not qualify the safety of the leachables 7

Given the lack of available toxicity information regarding the identified leachables, as indicated in our Complete Response letter dated October 19, 2018, and information request dated July 23, 2019, we recommend that you conduct a general toxicity study for any leachable that exceeds the safety qualification threshold of 5 mcg/day. For example, you may consider conducting a toxicity study of 14-day duration in one species, using isolated leachables or the API enriched with the identified leachables, administered in a Clinically relevant manner at leachable levels equivalent to or greater than what patients would be administered.

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An Ames test and in vitro mutagenicity and/or mammalian chromosomal aberration assay (i.e., Mouse Lymphoma Assay) are recommended to qualify leachables that exceed 120 mcg/day with identified structural alerts for genotoxic potential. Test the synthesized or isolated leachables to achieve the highest test concentrations recommended for an ICH-compliant bacterial mutagenicity assay according to the current testing guidelines for each genotoxicity assay. For QSAR analysis conducted to predict bacterial mutagenicity of leachables > 120 mcg/day, use the latest versions of the QSAR software and knowledge databases available and submit the complete QSAR reports.

Refer to FDA Guidance for Industry ‘S2(R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use’ (https://www.fda.gov/media/71980/download) and OECD Genetic Toxicology Guidance Document (https://www.oecd.org/chemicalsafety/testing/Genetic%20Toxicology%20Guid ance%20Document%20Aug%2031%202015.pdf) for additional information.

We acknowledge receipt of your Final GLP Report: 19-02803-G1: “14-Day Toxicity Study Via Intravenous Injection in Sprague Dawley Rats with 14-Day Recovery,” assessing the difference in the safety profiles of potential leachates from the stopper on December 6, 2019. This amendment was not reviewed as the report was provided late in the review cycle. As stated above, you may reference this submission in any resubmission to this NDA.

(b) (4)

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

' http:/Awww.fda.gov/Drugs/GuidanceComplianceRegulatory|nformation/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

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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 Cefazolin for Injection USP 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:

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. Cefazolin for Injection USP Include an updated estimate of use for Cefazolin for Injection USP marketed in other countries.

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(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

his resubmission a complete response to the deficiencies outlined in this letter. A partial 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 ‘ake 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 hat 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

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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 12/26/2019 11:44:58 AM

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