Adello Biologics, LLCTheragrastim

BLA 761082 COMPLETE RESPONSE

Adello Biologics, LLC

Attention: Joel Brittain, PhD

Senior Associate, Global Regulatory Affairs 20 New England Avenue

Piscataway, NJ 08854

Dear Dr. Brittain:

Please refer to your Biologics License Application (BLA) dated July 8, 2017, received July 10, 2017, and your amendments, submitted under section 351(k) of the Public Health Service Act for Theragrastim.!

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.

FACILITY INSPECTIONS

1. During a recent inspection of Adello Biologics manufacturing facility (FEI: 3011289655), our field investigator conveyed deficiencies to the representative of the facility. Satisfactory resolution of these deficiencies is required before this application may be approved.

PRODUCT QUALITY

Analytical Similarity

2. The analytical similarity data for CEX-HPLC indicate that the species contributing to charge variants are different for Theragrastim and US-licensed Neupogen and that charge variant levels in the proposed commercial Theragrastim lots are higher than in US-licensed Neupogen. Specifically, we note:

a. Commercial DS Theragrastim lots 20-17001, 20-17002, and 20-17003 and DP Theragrastim lots 170086, 170087, and 170088 have total charge impurity levels outside the US-licensed Neupogen quality range.

' Your proposed proprietary name, Releuko, and proposed proper name, filgrastim-ayow, are conditionally accepted until such time that the application is approved. In this document, we refer to your proposed biosimilar product by using the descriptor Theragrastim, which was the name Adello used to refer to this product during development.

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. In Theragrastim, the predominant charge variant species elutes as a shoulder to the main peak (RRT = 0.95). This species is absent in US-licensed Neupogen lots under non-stressed conditions but is enriched in both products under forced degradation conditions of oxidative stress, suggesting this species may be also present in US- licensed Neupogen but in levels undetectable under non-stress conditions.

. A basic variant species eluting at RRT = 1.17 is consistently present in Theragrastim lots but absent in US-licensed Neupogen lots.

. Results from a photostability study (Table 8 of report PTL-1192-R) showed high levels of charged variants eluting around RRT =1.10-1.15 in Theragrastim following one cycle of light exposure. These species are not seen in US-licensed Neupogen.

Without additional data and an appropriate justification, these differences preclude a determination that Theragrastim is highly similar to US-Neupogen. To address these differences, you should conduct a comparative analysis of individual charge species between Theragrastim and US-licensed Neupogen and address the differences in the levels and type of charge variants observed between these products. In addition, you should justify why these differences do not preclude a determination that Theragrastim is highly similar to US-licensed Neupogen. Provide data and information in your 351(k) BLA resubmission.

. RP-HPLC data included in your analytical similarity assessment was originally evaluated using the valley to valley integration method. This integration method resulted in an underestimation of the impurities in Theragrastim. You re-analyzed the RP-HPLC data using a baseline drop integration method and submitted the data in Table 2 of your response to our IR dated February 28, 2018. You proposed to exclude lots 45-15025, 30-15018 and 30-15019 from the analyses because they were formulated using ™4 You

also propose to exclude clinical lot 45-14042 proposed shelf life. We agree with your propo manufactured with ™® because yo However, we disagree with your lot 45-14042 because you did not provide evi

ecause you state that it was tested beyond the sal to exclude the referred three lots u proposed a strategy to control proposal to exclude from the analysis clinical lence that lot 45-14042 was within the RP-

(by (4)

HPLC US-licensed Neupogen quality range at release and within the proposed shelf life when RP-HPLC data are analyzed using the baseline drop peak integration method. The analytical similarity data for RP-HPLC indicate that the level of individual species contributing to total impurities is different in Theragrastim and US-licensed Neupogen and the total impurities by

RP-HPLC is higher in Theragrastim compares deficiencies, provide the following in your 35

to US-licensed Neupogen. To address these (k) BLA resubmission:

a. Data and information to support that the level of total impurities in lot 45-14042 are due to its age. The RP-HPLC data should be integrated using the baseline drop method.

. Conduct a comparative analysis of individual species between Theragrastim and US- licensed Neupogen and address the differences in the levels of individual and total impurities observed between these products. You should also justify why these differences do not preclude a determination that Theragrastim is highly similar to US- licensed Neupogen.

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4. The characterization data of product-related species provided in your original 351(k) BLA were limited with regards to the spectra of species identified and were insufficient to establish a conclusive identification of individual species. For example, you did not provide data and information on whether product related species known to occur in therapeutic protein products such as sequence variants, formylate methionine species, succinimide species, norleucine species, acetylated species, and truncated species are present in Theragrastim. You explain that additional product-related species were not detected by the intact mass or peptide mass methods in ten-fold concentrated Theragrastim samples. However, it is unclear whether these species are absent in Theragrastim or whether the material used for the characterization studies was inadequate. In addition, it appears that your characterization data correspond to chromatography fractions, which may include various product-related species, instead of individual species eluting as single peaks in the chromatography methods. This information is needed to support the safety profile of your product and to support that the species present in Theragrastim are the species also identified in US-licensed Neupogen.

Provide characterization data of individual product-related species of Theragrastim, including low abundance species and determine whether they are product related substances or product-related impurities. You may consider using in your characterization studies, process intermediates or accelerated stability Theragrastim and US-license Neupogen samples containing higher levels of these species. The characterization data are needed to support analytical similarity and inform the control strategy for your product. Submit the data and information in your 351(k) BLA resubmission.

5. Table 16 of PTL-1192-R shows the RP-HPLC results of the comparative forced degradation study under oxidation conditions. We note that Theragrastim lot 3-FIN-2475 shows high levels of impurities eluting at RRT = 0.96-97 and RRT=0.97-0.99 compared to other Theragrastim and US-licensed Neupogen lots. You did not provide an explanation for these data and did not provide an evaluation of how these results may impact the comparative assessment. In your 351(k) BLA resubmission, provide an explanation for the results and a justification as to why they do not impact the comparative assessment of forced degradation under oxidation conditions. Furthermore, clarify whether RP-HPLC data from the forced degradation study under oxidation conditions were generated using the baseline drop integration method or the valley to valley integration method. If valley to valley integration was used, we request that you provide these data reanalyzed using the baseline drop integration method.

6. In Table 28 in PTL-1192-R showing mass balances for CEX-HPLC, the results for 3 hours of oxidative stress are listed to have mass balances significantly different than 100%. Notably, the Theragrastim samples are listed below 100% (at around 77%), while the US-licensed Neupogen lots are above 100% (at around 174-226%). Furthermore, it appears there might be errors in the data shown in table 28. In your 351(k) BLA resubmission, provide:

a. An updated table 28 with corrected values for mass balances, as needed.

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b. A justification for the use of data where the mass balance data provided are

significantly different from 100%, and for any data where Theragrastim has a different range of mass balance values than US-licensed Neupogen in the same studies. Clarify whether the area of the sample and standard used in the mass balance calculation is based on area under all peaks or only area under the main peak. Clarify the method of peak integration for mass balances.

Reference standard or materials

7. The reference standard (RS) program for Theragrastim is inadequate. Specifically,

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a. The qualification of your current Theragrastim in-house primary reference standard Lot

OM is inadequate because its potency and protein concentration were not accurately assigned. The potency and protein concentration of this RS was assigned based on release testing results from © This approach is inadequate because your potency and protein concentration release testing uses three replicates, which are insufficient for an accurate determination of potency and protein concentration for RS qualification. Potency and protein concentration of a RS should be determined using sufficient replicates and appropriate statistical methods to ensure an accurate and precise potency and protein concentration values are assigned to the RS. This determination is critical to prevent drift in potency of your product. You state that you qualified your in-house reference standard against a USP filgrastim reference standard Lot # FOL526. You also noted that in addition to USP filgrastim RS Lot # FOL526 and in-house © other reference standards were used duri development. These include Theragrastim lots

. It is unclear how these reference standards are related because you did not provide data and information to establish a bridge between the RS lot ® the RS used in the analytical similarity assessment, and the RSs used for release and stability testing of DS and DP lots during development. Provide these data and information.

. You indicate that stability testing of reference standard lot © js redundant with the stability program for © because they are the same drug substance material. For this reason, you used stability testing data from ce to support the stability of reference standard lot ® You also state that “retest of the RS will be performed a

While °@ lot was developed from ©@ "the container closure systems are

different. Section 3.2.5.5 Reference Standards or Materials, indicates that the container

closure system for is oy

and that the container closure for reference standard lot oes Oe

The RS

requalification approach used for "lot is inadequate because you did not

provide data and information to demonstrate that the stability data collected from DS lot ™® i; relevant to support that © remains stable over time.

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Therefore, your proposed © Jot is not adequately qualified to be used for release of commercial lots of Theragrastim. To address this deficiency, provide the following data and information in your 351(k) BLA resubmission:

a. Implement a adequately qualified in-house reference standard for release and stability testing of Theragrastim DS and DP (refer to item a above).The RS should be representative of production and clinical materials, and the material used in analytical similarity. As per ICH Q6B, your in-house reference standards should be calibrated against an international or national standard (if available) and be bridged with the RS used in the analytical similarity assessment and throughout development.

b. Describe the procedures used to determine the potency and protein concentration of the Theragrastim in-house reference standard.

c. Describe the procedures you use to declare the biological activity of Theragrastim in- house reference materials, e.g. the potency range within which a reference standard will be assigned a potency of 100%.

d. Provide data to support the stability of your in-house RS and a protocol for requalification of your in-house RS. The protocol should incorporate the considerations discussed above regarding qualification for potency and protein concentration.

e. Ifyou propose to qualify a RS other than © be aware that you will need to bridge the new RS, © and the RS lot used in analytical similarity and throughout development.

8. In Section 3.2.8.5 Reference Standards or Materials you describe the development of your current in-house reference standard lot © prepared from PPQ lot oO In that section, you also state that reference standard lot COG)

had been previously used during drug development. However, in section 2 of document PTL-1193-R “Qualification Report of Theragrastim In-House Primary Reference Standard Lot © vou state that the USP reference standard has been used during process development for release, stability, characterization and similarity, and in- process testing. The information provided in Document PTL-1193-R is inconsistent with information provided in Section 3.2.8.5 Reference Standards or Materials. To address these inconsistencies, provide the following information in your 351(k) BLA resubmission: a. Clarify whether reference standard lot Ls were used for release and stability testing of drug substance and/or drug product. If so, provide qualification data for each RS used for the control of DS and

DP and explain how content and potency were assigned for each reference material

used.

b. Clarify whether primary reference standard lot © has been used for release and stability testing of Theragrastim DS and/or DP. Provide a list of the lots tested using this RS material, as appropriate.

9. We note that in the description of the analytical methods used for in process, release and stability testing and characterization, you state that reference standard material could be USP

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RS, in-house RS or US-licensed Neupogen. As per ICH Q6B, reference standards should be representative of production and clinical lots. USP filgrastim reference standard and US- licensed Neupogen are not appropriate reference standards for Theragrastim because they are not representative of your production and clinical lots. For commercial manufacturing and control of Theragrastim, you should only use an adequately qualified Theragrastim reference standard that has been developed, characterized, and qualified in-house. In addition, you should revise your analytical method description and SOPs to only use an adequately qualified in-house reference material. Provide this information in your 351(k) BLA. resubmission.

Drug substance process description and validation

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Drug substance container closure system

Drug product

18. In 3.2.P.3.3, 3.2.P.3.4 and, 3.2.P.3.5 you use the terms specifications, acceptance criteria, and limits interchangeably to describe the acceptable ranges for Theragrastim DP in-process controls (IPC) critical process parameters (CPPs) and non-CPPs. Note that the disposition of lots that fail specifications acceptance criteria are different from the disposition of lots that fail alert or action limits. For example, lots failing specifications acceptance criteria should be rejected whereas lots failing action limits should trigger an investigation. Therefore, it is

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unclear what each of these terms mean and what actions will be taken when results fall outside the specifications acceptance criteria or limits. To address this deficiency, revise your 351(k) BLA to clearly define whether the ranges described for DP IPCs, CPPs and non-CPPS are specifications with acceptance criteria or whether they are limits. Specify the actions that are taken when acceptance criteria or action limits fail for IPCs, CPPs and non-CPPs. Indicate whether failure of acceptance criteria or action limits will trigger lot rejection or a deviation with product quality impact assessment and batch disposition evaluation. Ensure these terms are used consistently in your 351(k) BLA application.

19. In your response to our IR dated February 12, 2018, you explain that visual inspection is performed on all Theragrastim DP vials and syringes manufactured in a lot. Your proposed rejection limits for visual inspection are OF) for particulate matter rejects and © for overall rejects. These limits were not exceeded for any of the PPQ and PV lots. However, you do not explain the actions you will follow if visual inspection failures are above for particulate matter rejects or above | for overall rejects. Likewise, you do not explain the actions you will follow if the lot fails AQL inspection. In your 351(k) BLA resubmission, explain your control strategy for particulate matter by visual inspection including a description of the conditions that would result in rejection of the lot.

20. To comply with 21 CFR 610.14, you propose to test DP identity by SDS-PAGE after the primary container closure labeling activities have been completed. This is not sufficient because SDS-PAGE does not assess a unique characteristic of your product. This limitation is not overcome by including a rhG-CSF reference standard because showing that the RS and the Theragrastim have the same apparent molecular weight does not unequivocally demonstrate the identity of Theragrastim. To address this deficiency, implement a suitable identity assay, to comply with 21 CFR610.14, such as peptide mapping and include the assay results in the CoA. Provide data and information to support the identity assay in the 351(k) BLA resubmission.

21. Theragrastim DP is manufactured at a CMO, © where other products may also be manufactured. Therefore, having an identity test that unequivocally distinguishes Theragrastim from other products manufactured at the facility is critical. To address this deficiency, implement identity testing for incoming Theragrastim DS at!) that evaluates a unique characteristic of your product. Include the information in your 351(k) resubmission.

22. In the initial steps of the DP manufacturing process |

Provide the information in your 351(k) BLA resubmission.

23. In Figure 4, section 3.2.P.3.3 Description of Manufacturing Process and Process Controls you describe the DP manufacturing process and in process parameters and controls for each

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step of the manufacturing process.

To address this deficiency, implement an upper limit for OM and provide the information in your 351(k) BLA resubmission.

Stability protocols

24. We identified the following deficiencies regarding your annual stability testing protocol for IP, DS, and DP:

a.

You propose to test for stability of IP, DS, and DP every 6 months. This testing program does not allow adequate monitoring of the stability of your product. ICH QS5C recommends testing at least every three months the first year, every six months the second year and annually thereafter. In your 351(k) BLA resubmission, provide revised stability protocols that include the 3 months and 6 months testing timepoints.

‘You propose to monitor pH and concentration yearly. Testing for concentration and pH does not allow adequate monitoring of the stability of your product. Revise your protocol to monitor pH and concentration for IP, DS and DP in all stability timepoints recommended in ICHQSC. Provide the revised stability protocol in your 351(k) BLA resubmission

Testing for Theragrastim protein concentration at DS release is performed using UV absorbance-based method STM-0078 whereas testing for DS stability testing is performed using RP-HPLC based method STM-0076. Clarify whether you intend to use two different methods to monitor protein concentration at release and during stability. Explain how you plan to compare protein assay results at release with stability results when using methods with different read outs, and provide information and scientific justification in your 351(k) BLA resubmission to support the use of the two different protein concentration methods for release and stability testing.

The DP annual stability protocol does not include testing for extractable volume for vials and syringes. This testing is needed to ensure that your product meets label claim over the shelf life. Include extractable volume and deliverable volume in the annual stability protocol. You are not expected to test for this attribute in all stability timepoints. However, you should provide a justification for the testing points selected. Provide the revised stability protocol and justification in your 351(k) BLA resubmission.

Analytical methods

25. You describe updates to several analytical methods; however, no data or information were provided to describe the nature of the changes and to assess their impact on assay performance and testing results. To address this deficiency, in your 351(k) BLA

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resubmission, provide the following information regarding all analytical methods used for control of DS and DP:

a. Date of full validation.

b. The change history of the method and an assessment of the changes on the validation status of the analytical method, with a justification as to why the change was determined to be acceptable.

c. The version of the analytical procedure proposed to test commercial material and how

it differs from the version provided in the 351(k) application.

Update the relevant sections of your 351(k) BLA with the proposed commercial

version of each analytical method.

a

Control strategy

26. Your proposed release and stability specifications are inadequate to support consistent product quality. Revise your release and stability specifications for drug substance (DS) and drug product (DP) to address the following deficiencies:

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Shipping validation

30. To support DP shipping validation, you performed simulated shipping studies with Theragrastim DP packaged in vials and syringes and the results for those studies were submitted in your 351(k) BLA submission. In addition, you propose to conduct shipping performance qualification studies. However, your submission lacks an adequate shipping performance qualification protocol or data from real time shipping studies using the proposed modes of transportation, and the shipping conditions that will be used for shipping of commercial product. To address this deficiency, provide results from real time shipping qualification studies in your 351(k) BLA resubmission. Alternatively, submit a shipping

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performance qualification protocol. This protocol should include, but not limited to, the following information:

a. Assessment of the qualification of the shipping container to maintain the product temperature when exposed to worst-case conditions of temperatures (e.g., different climatic zones and seasons) and to the maximum storage and transport duration that the product may encounter during shipping, using minimum and maximum shipping loads for each shipping container.

b. Description of the batches used in the study and criteria of selection. For shipping container qualification, representative mock-filled (e.g., water) container closure systems may be used, as appropriate.

c. Assessment of product quality of the fully packaged batch before and after shipping to evaluate the effect of shipping conditions.

d. Pre-defined acceptance criteria for evaluation of product quality and to support shipping container qualification.

Drug product container closure system

31. In section 3.2.P.2.6 you describe the leachable studies you performed on DP aged in vials and in syringes. You state that vas detected al ppm from aged vials and syringes after 24 hr extraction. » You did not provide information to demonstrate that the levels of @ detected in these studies do not impact product quality and stability of the drug product stored at long-term conditions up to the proposed expiry date. Likewise, you did not assess the impact on product quality and stability of ©® known to leach from syringes. To address these deficiencies, provide the following information in your 351(k) BLA resubmission:

a. Specify the maximum levels of: aa present in the container closures system.

b. Provide a risk assessment for the impact of © on the quality, stability and safety of your drug product.

c. Provide a justification for why the levels of © detected in the leachables studies are acceptable.

d. Describe your strategy to control the levels of © that could leach into your product from the container closure system.

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32. In section 3.2.P.2.6 you state that contract laboratory) performed an assessment of all product contact materials and equipment used in the manufacturing process of Theragrastim at Adello and at . You provided a summary of the result in assessment Report CMO-0034 Theragrastim. The report identified five high risk materials used in the manufacture of Theragrastim based on the lack of extractable data and the direct, long-term contact of these materials with the product. You explain that these high-risk materials were used in extractable studies and refer to report CMO-0039 for the study results. However, report CMO-0039 could not be located in your 351 (k) BLA submission. In your 351(k) BLA resubmission, provide the results of the studies you performed to assess the risk on product quality and safety of leachates from these materials.

Stability

34. You request a shelf life of 24 months for the Theragrastim DP vial presentations when stored at 5°C. To support the proposed shelf life, you submitted stability data for up to 36 months from one vial lot of the 300j1g/1.0 mL strength and two vial lots of the 480u1.g/1.6 mL strength. These data are insufficient to support the requested 24-month shelf life for the Theragrastim DP vial presentations. In your 351(k) BLA resubmission, provide stability data under the recommended storage conditions of 5°C for at least one additional vial lot of the 300g/1.0 mL strength. Alternatively, provide data to support that the stability and rate of degradation of Theragrastim DP in the 4801g/1.6 mL strength vial presentation are informative of those of Theragrastim DP in the 300j1g/1.0 mL strength vial presentation.

Microbiology

35. The end of the fermentation production does not include a bacterial purity test to monitor for possible contamination. Include a bacterial purity test at the end of each production bioreactor) and provide bacterial purity acceptance criterion.

36. Critical manufacturing steps of Theragrastim drug substance are not routinely monitored for bioburden and endotoxin to verify continued microbial control of the process. Additional monitoring samples proposed in BLA Amendment 0033 were not updated & in the BLA. Include in the BLA resubmission bioburden and endotoxin monit

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In addition, include a

description of the test methods and test method qualification.

37. Maximum hold times for thi are not sorted by microbial data. Yd The microbial study inc! in the BLA was not representative of the commercial process and therefore does not support the proposed hold times. Provide microbial data to support the maximum hold times for . Alternatively, reduce the maximum hold times

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ADDITIONAL COMMENTS We have the following comments/recommendations that are not approvability issues: Application Organization

41. Overall, Module 3 of your original 351(k) BLA submission is not well prepared. There were many inconsistencies in the information and data provided in different sections of the BLA as well as missing information. For example, in your narratives you frequently refer to reports that were not included in the submission (e.g. refer to comment 10 above). In addition, reports are not adequately labeled to allow for an efficient review process. Further, tabular data has not been consistently rounded or there are discrepancies between the primary data and the results reported in the submission narratives. Conduct an evaluation of your application and revise the submission as appropriate. Clearly identify all revisions in your 351(k) BLA resubmission

Reference standard or materials

42. Based on the data provided in Section 3.2.8.5 Reference Standards or Materials, it appears that you have a one-tier reference material system. You should develop a two-tier in-house reference material system consisting of primary and working reference materials. Each subsequent working or primary reference material should be calibrated against an in-house primary material appropriately characterized that is representative of production and clinical materials and of material used in the analytical similarity assessment. Calibrating against a single primary reference material assures that the bioactivity determined for the test samples is consistent over time and limits the potential drift in product potency that may occur when each new standard is compared to the current working standard. In your 351(k) BLA resubmission, provide a timeline for development of a two-tier RS system. Incorporate the recommendations provided in previous comments in the implementation of the two-tier RS system. Note that in the absence of a suitable protocol for qualification of primary and secondary reference standard, qualification of a new RSs will require the submission of a Prior Approval Supplement.

Drug substance manufacturing

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Analytical methods

49. We note in PTL-0568-R for the validation report for CEX-HPLC method, you use Theragrastim DP syringe lot 350-16012. This lot number is not listed in your DP batch analysis section. We also note the impurity value by CEX-HPLC is higher than the other lots used and would not pass current specifications for purity by CEX-HPLC. In your 351(k) resubmission, provide the disposition of this lot, the CoA for this lot, how this lot was used, and explain why this lot was chosen for use in the method validation protocol.

Control strategy

In your 351(k) BLA resubmission,

a. Specify the actions that are taken when potency investigational limit is not met. b. Explain whether this limit applies to both release and stability specifications.

Cell Banks

51. Your original 351(k) BLA submission lacks a protocol for qualification of new MCB and ‘WCB. Submit a protocol for qualification of new MCB and WCB in your 351(k) BLA resubmission. Note that in the absence of a suitable protocol for qualification of new MCB and WCB, qualification of new cell banks will require the submission of a Prior Approval Supplement.

Stability 52. You propose to place one batch of Theragrastim DP from each presentation on stability every

year. Specify the strength(s) of the products you intend to place on annual stability and provide a justification for the selection of lots in your 351(k) BLA resubmission.

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Page 22 53. We note that you are using the ELISA kit from ® to measure host cell proteins (HCP) © "The HCP antiserum and other reagents in

the kit are critical reagents that when changed could affect the performance of the HCP ELISA. Therefore, you should have adequate control over these critical reagents. Be aware that when changes to the ® critical reagents occur you should requalify your method to ensure it performs as expected. In particular, you should qualify new lots of the HCP kit to confirm comparable antibody coverage using two dimensional (2D) SDS-PAGE and western blot or a similarly sensitive and discriminating assay. The best approach is that you develop an in-house HCP antiserum and qualify it as described above. In your 351(k) BLA resubmission, clarify your plans to address this issue.

Analytical Similarity

54. In Table 2 of PTL-1192-R, you describe the stress conditions evaluated in the comparative forced degradation study. You indicate that studies under oxidation conditions were performed for 0, 3, 6, and 24 hours of treatment. Your submission, however, includes results for only a 3-hour treatment timepoint for some analytical methods. You indicate that samples may be over-stressed and data are not interpretable. In your 351(k) BLA resubmission, provide an explanation as to why these data are not interpretable and an evaluation of whether the missing data impact the comparative degradation assessment of Theragrastim and US-licensed Neupogen.

55. Figures 38 and 39 in report PTL-0618-R (Rev 02) show the results of isoelectric focusing point for Theragrastim and US-licensed Neupogen lots. In Figure 39, we note the presence of a small peak to the left of the “Filgrastim peak” at approximately 6.05 minutes in lots for both products. This peak is absent in the results shown in Figure 38 in both Theragrastim and US-licensed Neupogen lots. In your 351(k) BLA resubmission, provide an explanation for the presence of the small peak at approximately 6.05 minutes and information on the identity of this peak.

56. You did not specify the presentation and strength of Theragrastim and US-licensed. Neupogen lots used in the comparative stability studies described in Report PTL-0618-R. In your 351(k) BLA resubmission, provide a summary table identifying presentation and strength of each lot used in the comparative stability studies and a rationale for the selection of lots included in the studies.

57. In PTL-1192-R, Figure 15 “Impurity Profiles by RP-HPLC of Theragrastim and Neupogen under Oxidation for 3 hrs” and Figure 16 “Comparative Charge Variant Profile of Theragrastim and Neupogen under Oxidation for 3 hrs”, you provide expanded chromatogram of the lots tested in the study. However, this expanded view does not allow comparative assessment of the results. In your 351(k) BLA resubmission, provide an overlay of the expanded chromatograms to allow for comparison of all peaks in the chromatographic profile observed after 3 hours of oxidative stress.

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58. Figure 20 in PTL-1192-R shows peptide mapping results of forced degradation studies under oxidative stress. Based on other peptide mapping data submitted in the original 351(k) BLA submission, some peak identities are incorrectly labeled (e.g. multiple G1 peaks are labeled). In your 351(k) BLA resubmission, provide an updated image with correctly labeled peaks.

Microbiology

59. Bioburden reduction filters are not in place to ensure microbial control at critical steps ¢ of the Theragrastim drug substance manufacturing process.

. Implement bioburden-reduction filtration Oo and include this information in the BLA resubmission.

60. The endotoxin test results for © <amples are reported per mg. It is not clear whether that refers to mg of unpurified protein or to mg of Theragrastim. Report endotoxin limits in EU/mL and readjust the reported endotoxin values accordingly.

61. Describe how bioburden control is maintained and controlled’ y

during routine operations.

62. Include a study protocol to demonstrate microbial control |

63. Provide summary shipping validation report to support shipping of the drug substance to the drug product manufacturing facility. Include temperature limits, results, and allowable excursions based on stability data.

64. Clarify whether in-process and/or release methods for bioburden and endotoxin are conducted at Adello and ® and provide method descriptions and qualification summary reports for each site as applicable.

65. Implement an in-process endotoxin monitoring test with an appropriate limit prior to sterile filtration and provide the information in the BLA resubmission.

66. Provide the number of vials and syringes that were tested for container closure integrity in the shipping simulation studies.

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

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(SRPI) — a checklist of important format items from labeling regulations and guidances. In addition, we encourage you to review the draft FDA Guidance for Industry, “Labeling for Biosimilar Products,” March 2016 at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM493439.pdf

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 601.14(b)] in structured product labeling (SPL) format as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm

CARTON AND CONTAINER LABELING

Submit draft carton and container labeling that are identical to the carton and immediate container labels submitted on February 28, 2018.

PROPRIETARY NAME

Please refer to correspondence dated, September 20, 2017, which addresses the proposed proprietary name, Releuko. This name was found acceptable pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to the application deficiencies.

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update. The safety update should include data from all nonclinical and clinical studies of the product under consideration regardless of indication, dosage form, or dose level.

1. Describe in detail any significant changes or findings in the safety profile and their relevance, if any, to whether there may be clinically meaningful differences between the proposed biosimilar product and the U.S.-licensed reference product.

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 clinical studies for the proposed indication using the same format as the original BLA submission.

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

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

3. Present a retabulation of the reasons for premature study discontinuation by incorporating

the drop-outs from the newly completed studies. Describe any new trends or patterns identified.

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4. Provide case report forms and narrative summaries for each patient who died during a clinical study or who did not complete a study 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, ut less serious, adverse events between the new data and the original BLA data.

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

7. Provide a summary of worldwide experience on the safety of this product, including adverse events known to be associated with the use of the product and immunogenicity. nclude an updated estimate of use for this product 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 601.3(b)). 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 601.3(c). 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 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 FDA Guidance for Industry, “Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants,” November 2015 at https://www.fda.gov/downloads/drugs/guidances/ucm345649.pdf.

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

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If you have any questions, contact Kris Kolibab, Senior Regulatory Project Manager, at (240) 402-0277.

Sincerely,

{See appended electronic signature page} Albert Deisseroth, MD, PhD

Supervisory Associate Division Director Division of Hematology Products

Office of Hematology and Oncology Products Center for Drug Evaluation and Research

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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

ALBERT B DEISSEROTH 05/10/2018

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