CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`212480Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`RECOMMENDATION
`
`☒ Approval
`☐ Approval with Post-Marketing Commitment
`☐ Complete Response
`
`NDA 212480
`Assessment # 2
`
`sofosbuvir (GS-7977)
`Drug Product Name
`Oral Pellets
`Dosage Form
`150 mg, 200 mg
`Strength
`Route of Administration Oral
`Rx/OTC Dispensed
`Rx
`Applicant
`Gilead Sciences, Inc.
`US agent, if applicable
`Applicant’s Responsible Official: Linda Lintao, RAC,
`Associate Director, Regulatory Affairs
`
`
`
`
`Submission(s)
`Assessed
`eCTD 0010
`eCTD 0013
`
`
`
`Document Date
`
`Discipline(s) Affected
`
`7/9/2019
`8/01/2019
`
`Quality
`Quality
`
`Discipline
`Drug Substance
`Drug Product
`Manufacturing
`Microbiology
`Biopharmaceutics
`Regulatory Business
`Process Manager
`Application Technical
`Lead
`Laboratory (OTR)
`Environmental
`
`QUALITY ASSESSMENT TEAM
`Primary Assessment
`Secondary Assessment
`N/A
`N/A
`George Lunn
`Balajee Shanmugam
`Nathan Davis
`Rapti Madurawe
`N/A
`N/A
`Mei Ou
`Elsbeth Chikhale
`Shamika Brooks
`
`Erika Englund
`
`N/A
`George Lunn
`
`
`Balajee Shanmugam
`
`
`
`
`OPQ-XOPQ-TEM-0001v06 Page 1
`
`Effective Date: February 1, 2019
`
`
`
`

`

`QUALITY ASSESSMENT DATA SHEET
`IQA NDA Assessment Guide Reference
`
`
`1. RELATED/SUPPORTING DOCUMENTS, Other Documents and Consults
`
`Refer to Review #1
`
`
`EXECUTIVE SUMMARY
`IQA NDA Assessment Guide Reference
`
`
`I. RECOMMENDATIONS AND CONCLUSION ON APPROVABILITY
`From the Product Quality perspective, NDA 212480 is recommended for
`Approval. The NDA, as amended, has provided adequate CMC information
`to assure the identity, strength, purity, and quality of the proposed drug
`product. The manufacturing and testing facilities for this NDA are deemed
`acceptable and an overall “Approve” recommendation was entered into
`Panorama by the Office of Process and Facilities (OPF) on August 21, 2019.
`Therefore, this NDA is recommended for approval by the Office of
`Pharmaceutical Quality (OPQ).
`
`
`
`
`II. SUMMARY OF QUALITY ASSESSMENTS
`
`
`A. Product Overview
`
`Refer to Review #1
`
`
`
`
`Proposed
`Indication(s)
`including Intended
`Patient Population
`Duration of
`Treatment
`
`Maximum Daily Dose
`
`Alternative Methods
`of Administration
`
`Treatment of chronic hepatitis C in pediatric
`patients
`
`12-24 weeks
`
`The recommended doses are: 400 mg/day (adults
`and pediatric patients >35 kg); 200 mg/day (17-35
`kg) and 150 mg/day (pediatric patients at least 3
`years of age and < 17 kg).
`The oral pellets can be taken in the mouth without
`chewing, or with non-acidic food. The oral pellets
`can be administered with non-acidic food, such as
`
`

`

`pudding, chocolate syrup, mashed potato and ice
`cream.
`
`
`B. Quality Assessment Overview
`
`Drug Substance: Adequate
`Refer to Review #1
`
`
`Drug Product: Adequate
`Refer to Review #1
`
`
`
`Labeling: Adequate
`Refer to Review #1
`
`
`
` Manufacturing: Inadequate
`Refer to Review #1 for additional discussion.
`
`In Review #1, there were outstanding concerns regarding the packaging
`process due to the OAI facility status and missing commercial
`manufacturing equipment. The outcome of the
` (primary
`packaging) was OAI due, in part, to missing commercial manufacturing
`equipment per the FDA-483.
`
`An addendum to the original review (Review #2) was completed on
`8/21/2019. The final outcome of the PAI review and EIR review can be
`found in CMS WA # 283608. The final outcome is adequate after review
`of FDA-483 responses and the firm response to an RAI. The inspection
`final classification is VAI and therefore approve.
`
`
`
` Biopharmaceutics: Adequate
`Note, at the time that IQA #1 was finalized, the biopharmaceutics
`review #1 could not be archived in Panorama. This IQA includes
`both biopharmaceutics review #1, and the addendum to
`biopharmaceutics review #1, which recommended the NDA for
`approval.
`
`Biopharmaceutics Review #1 described a pending IR regarding the
`controls in place to assure the integrity of the taste masking coat at batch
`release and during the shelf life of the product. The pending IR also
`requested a risk mitigation strategy to assure the integrity of the taste
`masking coat, which could include a two-phase dissolution test.
`
`
`(b) (4)
`
`

`

`
`On 08/01/2019, the Applicant responded that the FDA’s recommended
`two-stage dissolution method is not necessary because adequate
`formulation and manufacturing controls were developed, evaluated, and
`implemented to ensure the integrity of the taste-mask coating of the drug
`product at the time of batch release and during its shelf life. The
`biopharmaceutics reviewer found that the provided information/data for
`the formulation design, manufacturing controls, and results of the taste
`assessment and coating integrity tests, fully support the integrity of the
`taste-mask coating of the SOF pellets, and the information also
`demonstrates that the coating remains intact during storage. Therefore,
`based on the satisfactory justification and the overall information provided,
`this Reviewer agrees with the Applicant’s proposal of not using a two-
`stage dissolution method to control the quality of the proposed
`drug product. It is noted that the Applicant also proposes to continue
`testing the primary stability batches of the proposed drug product through
`their shelf life using the coating integrity test. The NDA is recommended
`for approval from a biopharmaceutics perspective.
`
`
`
`
`
` Microbiology (if applicable): Choose an item.
`N/A
`
`
`
`C. Risk Assessment
`Refer to Review #1
`
`
`
`D. List of Deficiencies for Complete Response
`
`
`
`1. Overall Quality Deficiencies (Deficiencies that affect multiple sub-
`disciplines)
`None
`
`
`2. Drug Substance Deficiencies
`None
`
`
`3. Drug Product Deficiencies
`None
`
`4. Labeling Deficiencies
`None
`
`
`5. Manufacturing Deficiencies
`None
`
`

`

`
`6. Biopharmaceutics Deficiencies
`None
`
`7. Microbiology Deficiencies
`None
`
`
`
`
`
`8. Other Deficiencies (Specify discipline, such as Environmental)
`None
`
`
`Application Technical Lead Name and Date:
`
`
`Erika E. Englund, Ph.D.
`
`8/22/2019
`
`

`

`Erika
`Englund
`
`Digitally signed by Erika Englund
`Date: 8/22/2019 08:47:47PM
`GUID: 51389ea30003450414230afb8c3e8114
`
`

`

`
`
`
`QUALITY ASSESSMENT
`
`
`BIOPHARMACEUTICS
`
`
`
`
`NDA: 212480 [505(b)(1)]
`Drug Product Name/Strength: Sovaldi (sofosbuvir; SOF) Oral Granules,
`150 mg and 200 mg
`Route of Administration: Oral
`Applicant Name: Gilead Sciences, Inc.
`Proposed Indication: Treatment of chronic hepatitis C in Pediatric patients 3 years of
`age and older
`Submission Dates:
`02/28/2019 (Original Submission)
`07/09/2019 (Response to Biopharmaceutics Information Request)
`Primary Reviewer: Mei Ou, Ph.D.
`Secondary Reviewer: Elsbeth Chikhale, Ph.D.
`
`
`
`EXECUTIVE SUMMARY
`
`The proposed drug product, Sovaldi (sofosbuvir; SOF) Oral Granules, 150 mg and 200
`mg, under NDA 212480, is an immediate-release dosage form. Each SOF oral granule
`has a diameter of approximately 2 mm and has a taste-masking
`
`
`coating. SOF oral granules are packaged into
`heat-sealed packets. The 150 mg strength contains 60 counts and the 200
`mg strength contains 80 counts of SOF oral granules in each unit-dose packet. In the
`proposed labeling, the recommended dosage in pediatric patients 3 years
` is 150 mg to 400 mg per day with or without food.
`
`
`
`
`In the current NDA 212480 submissions, the Biopharmaceutics Review focuses on the
`evaluation of (1) the in vitro dissolution method as a quality control (QC) test and
`acceptance criterion of the proposed drug product, (2) the in vitro dissolution profiles of
`the proposed drug product mixed with various soft food, (3) the need for in vitro bridging
`between the clinical formulation and the to-be-marketed/commercial formulation.
`
`In Vitro Dissolution Testing of the Finished Product:
`The Applicant proposed USP Apparatus II (Paddle), 75 rpm, 900 mL of 25 mM
`potassium phosphate buffer, pH 5.5, 37±0.5°C as the dissolution method for quality
`control (QC) and stability testing. The proposed dissolution method resulted in very
`rapid dissolution for SOF (i.e., more than % dissolution in minutes) and has limited
`discriminating ability toward
`
`of oral granules. The possibility of a 2 phase dissolution test that can ensure
`the integrity of the taste-masking coat is currently considered. The acceptability of the
`proposed dissolution method cannot be determined at this point due to an outstanding
`response to an information request (IR) regarding the control strategy to ensure the
`integrity of the taste masking coat.
`
`
`
`
`
`Page 1 of 15
`
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`Dissolution Acceptance Criterion:
`
`The originally proposed dissolution acceptance criterion of “Q= % in 30 minutes for
`
`SOF” is permissive and not acceptable. The acceptability of the dissolution acceptance
`
`criterion cannot be determined at this point due to an outstanding response to an IR.
`
`
` In Vitro Drug Release Profiles in Soft Food
`The stability of the drug product, including the integrity of the taste-masking
`coating, cannot be determined at this point due to an outstanding response to an IR.
`
`The Need for In Vitro Formulation Bridging:
`The to-be-marked formulation has silicon dioxide while the Phase 1/2 clinical
`formulation has no silicon dioxide. Both the clinical formulations and to-be-marketed
`formulations have very rapid and similar dissolution profiles. Therefore, a bridge is
`established between the clinical Phase 1/2 formulation and the to-be marketed
`formulation.
`
`
`
`
`
`RECOMMENDATION
`
`
`From the Biopharmaceutics perspective, NDA 212480 for the proposed Sovaldi
`(Sofosbuvir; SOF) Oral Granules, 150 mg and 200 mg, is PENDING at this point due to
`an outstanding response to an IR.
`
`
`
`
`
`
`
`
`Page 2 of 15
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`BIOPHARMACEUTICS REVIEW
`
`
`
`1. Drug Substance Solubility and Permeability
`
`
`
`The Applicant did not request an official BCS designation for SOF.
`
`The Applicant stated that the drug substance sofosbuvir (SOF), a weak acid with a pKa of
`9.3, is a BCS class 3 compound (high solubility and low permeability). The sink
`conditions of SOF can be achieved across the pH range of 2 to 6.8 (Table 1).
`
`Table 1: Solubility of Sofosbuvir (SOF) at 37ºC across in aqueous media
`
`Note:
`2Sink factor = Equilibrium Solubility / (Label Claim / 900 mL Dissolution Medium Volume).
`
`
`
`
`The Applicant provide permeability data of SOF in NDA 212477 and stated that the
`permeability of SOF was assessed in Caco-2 cell monolayers using 3 mM (1.6 mg/mL)
`SOF solutions. The apparent PA→B and PB→A permeability coefficients for SOF were 0.71
`× 10-6 cm/s and 4.11 × 10-6 cm/s, respectively, with an efflux ratio of 5.81. SOF is
`considered to have low apparent permeability with the potential for efflux. However,
`without the data of permeability marker drugs conducted in the same study, per FDA
`BCS guidance (December 2017), this Reviewer cannot conclude the permeability
`category of SOF.
`
`2. Chemical Stability of Drug Substance
`
`
`
`
`
`
`Page 3 of 15
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`
`3. In Vitro Dissolution Method
`The proposed dissolution method and acceptance criterion are summarized as below:
`
`
`USP Apparatus
`Rotation Speed
`Dissolution Media
`and Volume
`Temperature
`Proposed Acceptance
`Criteria
`
`II (paddle)
`75 rpm
`900 mL of 25 mM potassium phosphate
`buffer, pH 5.5
`37oC
`
`Q= % in 30 min
`
`
`Because SOF is bitter tasting and requires taste-masking and an age-appropriate
`formulation, a variety of dissolution methods (e.g., two-stage dissolution methods at
`various of dissolution media at pH
` were used to assess the potential of the
`coating systems for taste-masking in the oral cavity and sufficient SOF release in the
`stomach.
` is selected as taste-masking coating
`/agent. The
`Applicant claims
`
`
`
`
`
`. The target weight gain of
` range). The Applicant will be asked to provide
` is
`dissolution data to show the stability of the coating at pH
`
`
`
`
`
`
`
`Page 4 of 15
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`
`
`(b) (4)
`
`(b) (4)
`
`( ) ( )
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`The complete dissolution method development is submitted in report PDM-3086. The
`
`following dissolution parameters were evaluated during the dissolution method
`
`development:
`
`
`
`
`
`
`
`
`Page 5 of 15
`
`(b) (4)
`
`4 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`
`4. Dissolution Data and Acceptance Criterion
`Dissolution data profiles of clinical batches (200 mg, Lots ED1401D1, ED1501C1,
`ED1401C1) and primary registration batches (150 mg, Lots FJ1702B3, FJ1703B3, and
`FJ1704B3; 200 mg, FJ1702B4, FJ1703B4, and FJ1704B4) are presented in Figure 9
`below. The proposed drug product show very rapid dissolution (> % in minutes).
`
`
`
`
`Page 10 of 15
`
`(b)
`(4)
`
`(b)
`(4)
`
`
`
`
`
`(b) (4)
`
`

`

`QUALITY ASSESSMENT
`
`
`Figure 9: Dissolution of Sofosbuvir from Clinical and Primary Stability Batches
`
`
`
`
`
`
`
`
`
`
`
`
`Note: the dissolution condition is: USP Apparatus 2 Paddle, 75 rpm, 900 mL of 25 mM
`Potassium Phosphate buffer, pH 5.5 at 37°C. Mean profiles (n = 6 for ED1401D1,
`ED1501C1, ED1401C1; n = 12 all others).
`
`
`The dissolution data of six registration batches (150 mg, Lots FJ1702B3, FJ1703B3, and
`FJ1704B3; 200 mg, FJ1702B4, FJ1703B4, and FJ1704B4) in various stability conditions
`(sampling time at 10, 15, 20, 30, 45 and 60 minutes, n=12 at initial and n=6 at 3, 6 and 12
`months) showed that SOF has complete dissolution (100%) in minutes when stored up
`to 12 months at long-term stability condition (30oC/75%RH).
`
`The proposed dissolution acceptance criterion of “Q= % in 30 minutes for OF” is
`permissive and not acceptable. The data-driven acceptance criterion of “Q= % in 15
`minutes for SOF” was recommended on 06/13/2019. (see Appendix 1 Biopharmaceutics
`Information Request). In the response submitted on 07/09/2019, the Applicant wishes to
`retain the acceptance criterion of “Q= % in 30 minutes” for SOF.
`
`Due to an outstanding response to an information request (see Appendix 2
`Biopharmaceutics Information Request), the acceptability of the dissolution acceptance
`criterion cannot be determined at this point.
`
`
`5. Administration of Drug Product with Soft Food:
`One packet of 200 mg SOF oral granules was mixed into various soft foods to evaluate
`the chemical stability and dissolution. The soft foods included chocolate pudding,
`chocolate syrup, and ice cream and the dwell time prior to analysis was
`.
`
`
`Page 11 of 15
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`Based on the data presented in Table 2 below, SOF oral granules are chemically stable in
`
` with no SOF-related degradation products detected.
`all tested foods for
`
`
`
`Table 3: Chemical Stability of SOF in SOF Oral Granules from Lot FJ1704B Stored in
`
`Non-Acidic Soft Foods at Room Temperature
`
`
`As shown in Figure 10 below, SOF dissolution was not impacted by the tested food
`vehicles
`% dissolution in 10 minutes).
`
`
`Figure 10: Dissolution of SOF in SOF Oral Granules from Lot FJ1704B Stored in Non-
`Acidic Soft Foods at Room Temperature
`
`
`
`Note: the dissolution condition is: USP Apparatus 2 Paddle, 75 rpm, 900 mL of 25 mM
`Potassium Phosphate buffer, pH 5.5 at 37°C. SOF oral granule dose tested during dissolution
`was 200 mg.
`
`
`
`
`The acceptability of these data will be determined after the Applicant responds to the
`outstanding IR, because the integrity of the taste-masking coat needs to be assured while
`the drug product is in contact with food.
`
`6. In Vitro Formulation Bridging:
`Table 4 below shows that the to-be-marked formulation has silicon dioxide while the
`Phase 1/2 clinical formulation has no silicon dioxide. The dissolution data presented in
`
`Page 12 of 15
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`above Figure 9 show that the clinical batches (200 mg, Lots ED1401D1, ED1501C1,
`
`ED1401C1) and primary registration batches (150 mg, Lots FJ1702B3, FJ1703B3, and
`
`FJ1704B3; 200 mg, FJ1702B4, FJ1703B4, and FJ1704B4) have very rapid and similar
`
`dissolution profiles, establishing a bridge between the Phase 1/2 clinical formulation and
`
`the to-be-marketed formulation.
`
`
`Table 4: Clinical Development History of the Sofosbuvir Oral Granule Formulation
`
`
`Since the only difference of the proposed 150 mg and 200 mg strengths are the granule
`counts (e.g., 60 counts and 80 counts of SOF oral granules in each unit-dose packet)
`, in addition, the dissolution profile data are comparable
`across the proposed two strengths of SOF oral granules (Figure 9 above), bridging across
`the proposed strengths is considered established.
`
`
`
`
`
`
`
`
`
`
`Page 13 of 15
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`APPENDIX 1
`
`BIOPHARMACEUTICS INFORMATION REQUESTS and RESPONSES
`
`
`
`Biopharmaceutics 1st IR (conveyed on 06/13/2019):
`
`
`Based on the provided dissolution data of all registration batches (FJ1702B3, FJ1703B3,
`FJ1704B3, FJ1702B4, FJ1703B4, and FJ1704B4), FDA recommends that you implement
`a dissolution acceptance criterion of “Q= % in 15 minutes” for the proposed Sovaldi
`(sofosbuvir) Oral Granules, 150 mg and 200 mg. Update the dissolution acceptance
`criterion in the drug product release and stability specifications and other relevant
`sections of your NDA accordingly.
`
`Summary of Applicant’s Response to 1st IR (submitted on 07/09/2019):
`
`Application 212480 - Sequence 0010 - Response to FDA CMC Information Request
`dated 2019-06-13 received 2019-07-01
`
`The Applicant proposes to retain the acceptance criterion of “Q % in 30 minutes” for
`sofosbuvir per FDA guidance for industry (August 2018): Dissolution Testing and
`Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug Products
`Containing High Solubility Drug Substances.
`
`
`
`Page 14 of 15
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`APPENDIX 2
`
`BIOPHARMACEUTICS INFORMATION REQUESTS
`
`
`
`Biopharmaceutics 2nd IR (conveyed on 07/19/2019):
`
`
`We have a potential concern about the assurance of the integrity of the taste masking coat
`at drug product batch release and during the shelf life of your proposed drug product.
`a) Provide an overview of the controls that you have in place to assure the integrity
`of the taste masking coat at batch release and during the shelf life of your
`proposed drug product.
`b) Provide a risk mitigation strategy to assure the integrity of the taste masking coat
`at the batch release and during the shelf life of your proposed drug product. This
`strategy could include, for example, the following two-phase dissolution test at
`batch release, during stability studies, and/or to support post approval CMC
`changes:
`
`USP Apparatus
`Rotation Speed
`
`Dissolution Media
`and Volume
`
`Temperature
`
`Acceptance
`Criteria
`
`
`
`
`c) If available, provide data to show the integrity of the taste masking coat at pH
`
`The response to this IR is currently pending.
`
`
`
`
`Page 15 of 15
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`Mei
`Ou
`
`Elsbeth
`Chikhale
`
`Digitally signed by Mei Ou
`Date: 7/27/2019 07:27:34PM
`GUID: 54ca9d7000073c57d2eb7cc6e42c05bb
`
`Digitally signed by Elsbeth Chikhale
`Date: 7/27/2019 09:03:47PM
`GUID: 50743ccc000031928b54eba1769a5df9
`
`

`

`
`QUALITY ASSESSMENT
`
`
`BIOPHARMACEUTICS REVIEW ADDENDUM
`
`
`
`
`NDA: 212480 [505(b)(1)]
`Drug Product Name/Strength: Sovaldi (sofosbuvir; SOF) Oral Pellets,
`150 mg and 200 mg
`Route of Administration: Oral
`Applicant Name: Gilead Sciences, Inc.
`Proposed Indication: Treatment of chronic hepatitis C in Pediatric patients 3 years of
`age and older
`
`
`
`Submission Dates:
`02/28/2019 (Original Submission)
`07/09/2019 (Applicant’s Response to Biopharmaceutics Information Request)
`08/01/2019 (Applicant’s Response to Biopharmaceutics Information Request)
`Primary Reviewer: Mei Ou, Ph.D.
`Secondary Reviewers: Elsbeth Chikhale, Ph.D., and Angelica Dorantes, Ph.D.
`
`
`Addendum Summary:
`
`This review is an Addendum to the Original Biopharmaceutics review for NDA 212480
`for Sovaldi (sofosbuvir; SOF) Oral Pellets, 150 mg and 200 mg. The Original
`Biopharmaceutics review was archived in Panorama on 07/29/20191; however, the
`Biopharmaceutics recommendation was pending at that time because of the outstanding
`response to the Biopharmaceutics Information Request (IR) dated 07/19/20192.
`
`On 08/01/2019, the Applicant responded to the above IR3. In the response, the Applicant
`states that the FDA’s recommended two-stage dissolution method is not necessary
`because adequate formulation and manufacturing controls were developed, evaluated,
`and implemented to ensure the integrity of the taste-mask coating of the drug product at
`the time of batch release and during its shelf life. The Applicant states that the
`implemented controls will prevent the release/dissolution of SOF in the oral cavity when
`the product is ingested without chewing (SOF is a bitter tasting compound in the
`proposed oral granules product).
`
`Additionally, to further prevent the release/dissolution of SOF during its administration,
`the product’s labeling indicates the following; i) “Take SOVALDI
` within 30
`minutes of gently mixing with food and swallow the entire contents without chewing to
`avoid a bitter aftertaste”, and
`
`
`
`
`
`
`
`
`
`1 Biopharmaceutics Review for NDA 212480:
`http://panorama.fda.gov/PanoramaDocMgmt/webhooks/viewdownload?id=090026f88334eb17
`2 \\cdsesub1\evsprod\nda212480\0013\m1\us\112-other-correspondence\comments-advice-req-nda.pdf
`3 \\cdsesub1\evsprod\nda212480\0013\m1\us\111-information-amendment\quality.pdf
`
`Page 1 of 2
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`Reviewer’s Assessment:
`
`
`
`The provided information/data for the formulation design, manufacturing controls, and
`
`results of the taste assessment and coating integrity tests, fully support the integrity of the
`
`taste-mask coating of the SOF pellets, and the information also demonstrates that the coating
`remains intact during storage. It is noted that the Applicant also proposes to continue testing
`the primary stability batches of the proposed drug product through their shelf life using the
`coating integrity test.
`
`Overall, this Reviewer considers that the implemented manufacturing controls and labeling
`recommendations are adequate to prevent the release/dissolution of SOF in the oral cavity
`when the product is ingested without chewing. Therefore, based on the satisfactory
`justification and the overall information provided, this Reviewer agrees with the Applicant’s
`proposal of no using a two-stage dissolution method to control the quality of the proposed
`drug product.
`
`The following one-stage dissolution method and acceptance criterion are acceptable for the
`Quality Control of the proposed drug product at release and on stability:
`
`
`Medium and Volume
`
`USP Apparatus
`Rotation Speed
`
`II (Paddle)
`75 rpm
`900 mL of 25 mM potassium phosphate
`buffer, pH 5.5
`37 ± 0.5°C
`Temperature
`Acceptance Criterion Q = % in 30 minutes
`
`
`
`
`
`RECOMMENDATION
`
`From the Biopharmaceutics perspective, NDA 212480 for the proposed Sovaldi
`(sofosbuvir; SOF) Oral Pellets, 150 mg and 200 mg, is recommended for APROVAL.
`
`
`
`Page 2 of 2
`
`(b)
`(4)
`
`

`

`Mei
`Ou
`
`Angelica
`Dorantes
`
`Digitally signed by Mei Ou
`Date: 8/08/2019 09:46:09AM
`GUID: 54ca9d7000073c57d2eb7cc6e42c05bb
`
`Digitally signed by Angelica Dorantes
`Date: 8/08/2019 10:05:37AM
`GUID: 502d0913000029d59f1c87e0a380c7f7
`
`

`

`Erika
`Englund
`
`Digitally signed by Erika Englund
`Date: 8/22/2019 08:56:26PM
`GUID: 51389ea30003450414230afb8c3e8114
`
`48 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately
`following this page
`
`

`

`
`
`RECOMMENDATION
`
`☐ Approval
`☐ Approval with Post-Marketing Commitment
`☒ Complete Response
`
`NDA 212480
`Assessment # 1
`
`sofosbuvir (GS-7977)
`Drug Product Name
`Oral Pellets
`Dosage Form
`150 mg, 200 mg
`Strength
`Route of Administration Oral
`Rx/OTC Dispensed
`Rx
`Applicant
`Gilead Sciences, Inc.
`US agent, if applicable
`Applicant’s Responsible Official: Linda Lintao, RAC,
`Associate Director, Regulatory Affairs
`
`
`
`
`Submission(s)
`Assessed
`Original NDA
`eCTD 0003
`eCTD 0004
`eCTD 0005
`eCTD 0006
`eCTD 0007
`eCTD 0010
`eCTD 0012
`
`
`
`Document Date
`
`Discipline(s) Affected
`
`2/28/2019
`4/01/2019
`4/12/2019
`4/18/2019
`4/19/2019
`4/23/2019
`7/9/2019
`7/15/2019
`
`All
`Quality
`Quality
`Quality
`Quality
`General Correspondence
`Quality
`Quality
`
`Discipline
`Drug Substance
`Drug Product
`Manufacturing
`Microbiology
`Biopharmaceutics
`Regulatory Business
`Process Manager
`Application Technical
`Lead
`Laboratory (OTR)
`
`QUALITY ASSESSMENT TEAM
`Primary Assessment
`Secondary Assessment
`N/A
`N/A
`George Lunn
`Balajee Shanmugam
`Nathan Davis
`Rapti Madurawe
`N/A
`N/A
`Mei Ou
`Elsbeth Chikhale
`Luz Rivera
`
`Erika Englund
`
`N/A
`
`
`
`OPQ-XOPQ-TEM-0001v06 Page 1
`
`Effective Date: February 1, 2019
`
`
`
`

`

`Environmental
`
`George Lunn
`
`Balajee Shanmugam
`
`
`
`QUALITY ASSESSMENT DATA SHEET
`IQA NDA Assessment Guide Reference
`
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`A. DMFs:
`
`DMF #
`
`Type
`
`Holder
`
`
`
`II
`
`
`Variable
`
`III
`
`
`
`
`
`Item
`Referenced
`
`Status
`
`Date
`Assessment
`Completed
`
`Comments
`
`Refer to
`referenced
`NDA 204671
`Refer to DP
`review
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`B. OTHER DOCUMENTS: IND, RLD, RS, Approved NDA
`
`Document
`
`Application Number
`
`Description
`
`NDA
`NDA
`
`IND
`IND
`
`
`
`2. CONSULTS
`
`204671
`205834
`
`106739
`115268
`
`Sovaldi (Sofosbuvir tablet)
`Harvoni (Ledipasvir and
`sofosbuvir tablet)
`Sofosbuvir
`Ledipasvir/sofosbuvir
`
`Discipline
`
`Status
`
`Recommendation
`
`Date
`
`Assessor
`
`Biostatistics
`Pharmacology/Toxicology
`CDRH-ODE
`CDRH-OC
`Clinical
`Other
`
`
`NA
`
`NA
`NA
`
`NA
`
`
`Refer to DP review
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`EXECUTIVE SUMMARY
`IQA NDA Assessment Guide Reference
`
`
`I. RECOMMENDATIONS AND CONCLUSION ON APPROVABILITY
`From the Product Quality perspective, NDA 212480 is recommended for a
`Complete Response. The NDA, as amended, has not provided adequate
`CMC information to assure the identity, strength, purity, and quality of the
`proposed drug product. The manufacturing and testing facilities for this NDA
`are not deemed acceptable and an overall “Withhold” recommendation was
`entered into Panorama by the Office of Process and Facilities (OPF) on July
`26, 2019. Therefore, this NDA is recommended for a complete response by
`the Office of Pharmaceutical Quality (OPQ).
`
`The response to the biopharmaceutics IR, and the evaluation of
`responses to the observations from the inspection are pending. An
`addendum to this review will be completed upon receipt and evaluation of
`these pending items.
`
`
`
`II. SUMMARY OF QUALITY ASSESSMENTS
`
`
`A. Product Overview
`
`The proposed drug product in this NDA is white oral pellets. Each pellet
`has a taste masking coat and contains
` mg of sofosbuvir with 2mm X
`2mm dimensions. Note that in this NDA and in the corresponding reviews,
`the product is referred to as mini-tablets, granules and oral pellets. All
`three of these terms were used to describe the same product. Per the
`4/11/2019 e mail communication from Jibril Abdus-Samad in OPPQ, the
`dosage form name should be oral pellets.
`
`The product will be available in two strengths:
`
`
` 150 mg per packet (60 pellets per packet)
` 200 mg per packet (80 pellets per packet)
`
`
`The oral pellets are supplied in unit-dose packets and the entire of
`contents are mixed with non-acidic food such as pudding, chocolate
`syrup, mashed potato and ice cream. The stability of the product in these
`non-acidic foods were evaluated.
`
`Note that a new strength of the tablets is also currently under review as
`NDA 204671 Supplement 14.
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`Proposed
`Indication(s)
`including Intended
`Patient Population
`Duration of
`Treatment
`
`Maximum Daily Dose
`
`Alternative Methods
`of Administration
`
`Treatment of chronic hepatitis C in pediatric
`patients
`
`12-24 weeks
`
`The recommended doses are: 400 mg/day (adults
`and pediatric patients >35 kg); 200 mg/day (17-35
`kg) and 150 mg/day (pediatric patients at least 3
`years of age and < 17 kg).
`The oral pellets can be taken in the mouth without
`chewing, or with non-acidic food. The oral pellets
`can be administered with non-acidic food, such as
`pudding, chocolate syrup, mashed potato and ice
`cream.
`
`
`B. Quality Assessment Overview
`
`Drug Substance: Adequate
`This NDA referenced NDA 204671 for all drug substance information.
`Some general information, sites of manufacture, specification, and
`stability data for the drug substances are provided in this NDA.
`Per an e mail from the drug substance branch chief, Su Tran, Ph.D., a
`separate drug substance review was not required for this NDA.
`
`
`Drug Product: Adequate
`The drug product consists of oral pellets that provide 150 mg or 200 mg
`sofosbuvir in unit-dose heat-sealed packets. Each pellet contains
`
`mg sofosbuvir, is about 2 mm in diameter, and has a taste masking
`coating. The 150 mg presentation contains 60 pellets and the 200 mg
`presentation contains 80 pellets. The inactive ingredients are lactose
`monohydrate, microcrystalline cellulose, croscarmellose sodium,
`hydroxypropyl cellulose,
`, colloidal silicon dioxide, and
`sodium stearyl fumarate. In addition, there is
`taste-masking coat
` The excipients are USP/NF
`compendial or comprised of USP/NF compendial materials. Pellets are
`mixed with food
` pudding, chocolate syrup, ice cream, and
`mashed potato) for consumption and are reasonably stable in that matrix.
`
` assay,
`The specification includes tests for appearance, identity,
`degradants, dose uniformity, dissolution, and microbial limits. Generally,
`the specification is conventional for this type of product and is similar to
`the specification for the adult 400 mg tablets. The assay limit of
`% through expiration is tighter than the more usual
`Tests for appearance, identity, uniformity, and microbial limits are
`reasonable. Degradants were observed for a batch made with an
`
`%.
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`%). The applicant agreed to reduce the
`elevated level of
` limit to %. The degradants are toxicologically qualified or are
`metabolites that do not require qualification. The limits for the specified
`degradants are higher than those specified for the original 400 mg tablets.
`A justification of these higher limits was provided by the applicant and
`accepted after some internal discussion. The analytical methods are
`comprehensively described, and full validation reports are provided.
`Satisfactory batch analyses are provided for 9 batches.
`
`The container-closure system is a
`
` pouch made of
`. The size is such that it can contain
`60 or 80 pellets. The pouch material conforms to the relevant 21 CFR
`regulations.
`
`Less than 12 months of long-term stability data were accepted in the initial
`submission because this product fulfills an unmet pediatric need.
`Eventually 12 months of long-term (30°C/75% RH) and 6 months of
`accelerated (40°C/75% RH) stability data were provided for 6 batches. A
`batch was tested in the light chamber. There are no out of specification
`results and no significant trends. No degradants are observed.
`
`The applicant claims an expiration dating period of 24 months with the
`storage statement “Store below 30°C”. This is reasonable.
`
`The applicant submitted a claim for a categorical exclusion from an
`environmental assessment in accordance with 21 CFR 25.31(b). This is
`acceptable.
`
`
`
`Labeling: Adequate
`Per the 4/11/19 e-mail from Jibril Abdus-Samad, OPPQ communicated
`that the correct terminology for the dosage form is “oral pellets”
`
`See labeling review. Labeling recommendations have been conveyed to
`the OND review team.
`
`
`
` Manufacturing: Inadequate
`The applicant plans to manufacture using
`
`
`
`
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`The applicant has addressed all of the previously outstanding concerns.
`However, the packaging process remains inadequate as equipment is
`