CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
`
`
` APPLICATION NUMBER:
`
`
` 212477Orig1s000
`
` PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`RECOMMENDATION
`
`
`
`
`☒ Approval
`
`
`☐ Approval with Post-Marketing Commitment
`
`
`☐ Complete Response
`
`
`
`
`
` Drug Product Name
`
`
`
`
`
`
`
`NDA 212477
`
`
`
`
` Assessment # 2
`
`
` ledipasvir and sofosbuvir, LDV and SOF, (GS-5885 and
`
` GS-7977)
`
` Oral Pellets
` Dosage Form
` 33.75 mg /150 mg; 45 mg/200 mg
`
`
` Strength
`
`
` Route of Administration Oral
`
`
` Rx/OTC Dispensed
` Rx
` Gilead Sciences, Inc.
`
` Applicant
`
` US agent, if applicable
`Applicant’s Responsible Official: Linda Lintao, RAC,
`
` Associate Director, Regulatory Affairs
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Submission(s)
`
` Assessed
`
` eCTD 0007
`
` eCTD 0011
`
`
`
`
`
` Document Date
`
`
`
` Discipline(s) Affected
`
`
` 6/25/2019
`
` 8/01/2019
`
`
` Quality
`
` Quality
`
`QUALITY ASSESSMENT TEAM
`
`
`
`
`
`
`
`
`
` Discipline
`
` Drug Substance
`
` Drug Product
`
` Manufacturing
`
` Microbiology
` Biopharmaceutics
`
`
` Regulatory Business
`
` Process Manager
`Application Technical
`
` Lead
` Laboratory (OTR)
`
`
`Environmental
`
`
`
`
`
`
` Primary Assessment
`
` N/A
`
` George Lunn
`
` Nathan Davis
`
` N/A
` Mei Ou
`
`
`
`
`
`
` Secondary Assessment
`
`
` N/A
` Balajee Shanmugam
`
` Rapti Madurawe
`
` N/A
` 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
`
`
`
`
`
`
`
`
` 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 212477 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 22, 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: 90mg/400 mg per
` day (adults and pediatric patients >35 kg);
`
`
`
` 45mg/200 mg per day (pediatric patients 17-35 kg)
` and 33.75mg/150 mg per 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: Adequate
`
`
` 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 the NDA is recommended for
`
`
`
` approval from an OPF perspective.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`

`

`
`
`
` 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 08:46:21PM
`GUID: 51389ea30003450414230afb8c3e8114
`
`

`

`
`
`
` QUALITY ASSESSMENT
`
`
`BIOPHARMACEUTICS
`
`
`
`
`
`NDA: 212477 [505(b)(1)]
`
`
`
`
`
`Drug Product Name/Strength: Harvoni (ledipasvir/sofosbuvir, LDV/SOF) Oral
`
`
`
`
` Granules; 33.75 mg/150 mg, 45 mg/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)
`
` 06/25/2019 (Response to Biopharmaceutics Information Request)
`
`
` Primary Reviewer: Mei Ou, Ph.D.
` Secondary Reviewer: Elsbeth Chikhale, Ph.D.
`
`
`
`
`
`
`
`
`
`
` EXECUTIVE SUMMARY
`
`
`
` The proposed drug product, Harvoni (ledipasvir/sofosbuvir; LDV/SOF) Oral Granules,
` 33.75 mg/150 mg, 45 mg/200 mg, is an immediate-release dosage form. Each LDV/SOF
`
`
`
`
`
` oral granule unit has a diameter of approximately 2 mm and has a taste-masking
`
`
`
`
`
`
`
`coating. LDV/SOF oral granules are packaged into
`
` packets. The 33.75
`
`
`
`
`
`
` mg/150 mg strength contains 90 counts and the 45 mg/200 mg strength contains 120
` counts of LDV/SOF oral granules in each unit-dose packet. In the proposed labeling, the
`
`
`
`
` recommended dosage in pediatric patients 3 years
` is
` 33.75/150 mg to 90/400 mg per day with or without food.
`
`
`
`
` In the current NDA 212477 submissions, the Biopharmaceutics Review focuses on the
` evaluation of (1) the in vitro dissolution method as a quality control (QC) test and
`
`
`
`
` acceptance criteria 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 Drug Product:
`
`
`
` The Applicant proposed USP Apparatus II (Paddle), 75 rpm, 900 mL of 25 mM
` potassium phosphate buffer, pH 5.5, containing 1.0% polysorbate 80 and 0.005 mg/mL
`
`
` butylated hydroxytoluene (BHT), 37±0.5°C as the dissolution method for quality control
`(QC) and stability testing. The proposed dissolution method resulted in rapid dissolution
`
`
`
`
`
` for LDV (i.e., more than % dissolution in 30 minutes) and very rapid dissolution for
` SOF (i.e., more than % dissolution in minutes) and has limited discriminating
`
`
`
`ability toward
` . 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 a
`
`
`
`
`control strategy to ensure the integrity of the taste-masking coat.
`
`
`
`
`
`
`
`
`
`
`
`
`
` Page 1 of 22
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b)
`(4)
`
`

`

`
`
`
`
` QUALITY ASSESSMENT
`
`
` Dissolution Acceptance Criteria:
`
`
`
`
`
`
` The originally proposed dissolution acceptance criterion for the proposed drug product is
`
` “Q= % in 30 minutes for both LDV and SOF”. The acceptability of the dissolution
`
`
`
`
` acceptance criterion cannot be determined at this point due to an outstanding response to
`
`
`
`
` an IR regarding the control strategy to ensure
`
`
`
` .
`
` 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 Phase 2/3 clinical formulation is the same as the proposed to-be-marketed
`formulation. The Phase 2/3 drug product batches and the to-be-marketed drug product
`
` batches have the same manufacturing process and manufacturing site. Therefore, studies
` to bridge clinical and to-be-marketed formulations are not needed.
`
`
`
`
`
`
`
`
`
` RECOMMENDATION
`
`
`
`
`
`
`
`
`
` From the Biopharmaceutics perspective, NDA 212477 for the proposed Harvoni
` (Ledipasvir/Sofosbuvir, LDV/SOF) Oral Granules, 33.75 mg/150 mg, 45 mg/200 mg, is
`
`
`
`
` PENDING at this point due to an outstanding response to and IR.
`
`
`
`
`
`
`
`
`
`
`
`
` Page 2 of 22
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
` QUALITY ASSESSMENT
`
`
` BIOPHARMACEUTICS REVIEW
`
`
`
`
` 1. Drug Substances Solubility and Permeability
`
`
`
` The Applicant did not request an official BCS designation for SOF or LDV.
`
`
`
`
`
`
` (1) The Applicant stated that the drug substance ledipasvir (LDV) is a BCS class 2
` compound (low solubility and high permeability). LDV has pH dependent solubility
`
`
`
` (Table 1 and Figure 1).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 1: Solubility of Ledipasvir (LDV) at 37ºC across the Physiologically pH Range
`
`
`
`
`
`
` Figure 1: Solubility of Ledipasvir (LDV) as a function of pH at Room Temperature
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Page 3 of 22
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`( ) ( )
`
`(b) (4)
`
`

`

`
`
`
`
` QUALITY ASSESSMENT
`
`
`
`
` The Applicant stated that the permeability of LDV was assessed in Caco-2 cell
`
` monolayers using 10 μM LDV solutions. The apparent apical to basolateral (PA→B) and
`
`
`basolateral to apical (PB→A) permeability coefficients for LDV were 1.76 × 10 -6 cm/s and
`
`
`
`
`
` 0.68 × 10 -6 cm/s, respectively, with an efflux ratio of 0.38. The Applicant stated that LDV
`
`
`
` has high apparent permeability with no efflux potential. 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 LDV.
`
`
`
`
` (2) The Applicant stated that the drug substance sofosbuvir (SOF) is a BCS class 3
` compound (high solubility and low permeability). SOF has pH-independent and high
`
`
`
`
` solubility over the physiological range from pH 2.0 to 6.8 (Table 2).
`
`
`
`
`
`
`
`
`
`
` Table 2: Solubility of Sofosbuvir (SOF) at 37ºC across the Physiologically pH Range
`
`
`
`
`
`
`
`
`
`
`
` The Applicant 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 Substances
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Page 4 of 22
`
`(b) (4)
`
`
`
`
`
`
`
`(b) (4)
`
`

`

`
`
`
`
` QUALITY ASSESSMENT
`
`
`
`
` 3. In Vitro Dissolution Method
`
`
`
` The proposed dissolution method and acceptance criteria 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,
`
`
`
`
`
` containing 1.0% polysorbate 80 and 0.005 mg/mL
` butylated hydroxytoluene (BHT)
`
`
` 37oC
`
`
`
` Q= % in 30 min for both LDV and SOF
`
`
`
`
` Because SOF is bitter tasting, the Applicant
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` therefore; the
`
`Applicant will be asked to provide dissolution data to show the stability of the coating at
`
`
`pH
`
`
`
` Page 5 of 22
`
`
`
`
`
`(b)
`(4)
`
`(b) (4)
`
`2 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
` QUALITY ASSESSMENT
`
`
`
` The complete dissolution method development is submitted in report PDM-3099. The
`
` following dissolution parameters were evaluated during the dissolution method
`
`
`
` development:
`
`
`
`
`
`
` Page 8 of 22
`
`
`
`
`
`(b) (4)
`
`8 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`
`
`
`
`
`
` QUALITY ASSESSMENT
`
`
`
` 4. Dissolution Data and Acceptance Criteria
`
`
`
`
` Dissolution data profiles of the proposed drug product (the clinical and primary stability
`
`
` ) are presented in the following Figure 15. Ledipasvir (LDV) showed more than
`
`
`
`batches
`
`% dissolution
` ofosbuvir (SOF) showed more than
`
`% dissolution in 30 minutes, and S
`
`
` in minutes. Note that this Reviewer considers that the small difference in amount of
` mg/mL showed in Figure 16 below versus the proposed 0.005
`antioxidant BHT (
`
`
`
` mg/mL) will not affect the dissolution profiles of drug product.
`
` Figure 15: Dissolution of Ledipasvir (top) and Sofosbuvir (bottom) from Clinical and
`
`
` Primary Stability Batches
`
`
`
`
`
`
`
` Note:
`
` (1) Batch EL1601C2 (11.25 mg/50 mg, 30 counts of LDV/SOF oral granules) has same
`
`
` formulation with to-be-marked formulation and was used in Phase 1 BA study GS-US-337-2091;
`
`
`
`
`
`
`
`
`
`
`
` Page 17 of 22
`
`(b) (4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
` QUALITY ASSESSMENT
`
`
`(2) Batch EL1602D1 (11.25 mg/50 mg, 30 counts LDV/SOF oral granules) has same formulation
`
` with to-be-marked formulation and was used in Phase 2/3 safety and efficacy study GS-US-337­
`
`
` 1116 and taste assessment study GS-US-337-4565;
`
`
`
` (3) Batches EL1701D1, EL1702D1, EL1703D1 (33.75 mg/150 mg, 90 counts LDV/SOF oral
` granules) are three registration batches;
`
`
` (4) Batches L1701D2, EL1702D2, EL1703D2 (45 mg/200 mg, 120 counts LDV/SOF oral
` granules) are three registration batches;
`
`
`
` (5) Dissolution test condition (the proposed dissolution method) is: USP Apparatus 2 (paddle), 75
` rpm, 1.0% w/v polysorbate 80 with
`
`
`
`
` mg/mL BHT in 25 mM potassium phosphate, pH 5.5,
` 900 mL, at 37°C, for both LDV and SOF.
`
`The dissolution data of six registration batches (33.75 mg/150 mg, batches EL1701D1,
`
`
` EL1702D1, EL1703D1 and 45 mg/200 mg, batches L1701D2, EL1702D2, EL1703D2) in
`various stability conditions (sampling time at 10, 15, 20, 30, 45 and 60 minutes, n=6)
`
`
`
`
` showed that LDV has a mean dissolution > 93% in 30 minutes, SOF has a mean
` dissolution > 93% in 15 minutes when stored up to 12 months at long-term stability
`
`
`
`
`condition (30oC/75%RH).
`
`
`
` The proposed dissolution acceptance criterion is: Q= % in 30 minutes for both LDV and
`
` SOF. Considering the BCS Class 2 for LDV, the proposed criterion of “Q= % in 30
`
`
`
`
`
`
`
`
` minutes for LDV” may be acceptable. However, because of the BCS Class 3 for SOF,
` this Reviewer recommended a data-driven acceptance criterion of “Q= % in 15 minutes
`
`
`
`for SOF” to the Applicant conveyed on 06/13/2019 (see Appendix 1 Biopharmaceutics
`
`
`
`Information Request). In the response submitted on 06/25/2019, 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
`
`
` criteria cannot be determined at this point.
`
`
`
` 5. Administration of Drug Product with Soft Food
` One packet of 45 mg/200 mg LDV/SOF (120 counts oral granules) were mixed into
`
`
`
` various soft foods to evaluate the chemical stability and dissolution. The soft foods
`
`
` included chocolate pudding, chocolate syrup, and vanilla ice cream.
`
`
`
`
` Based on the data presented in Table 3 below, the LDV/SOF oral granules are chemically
`
`
`with no significant degradation products detected.
`stable in all tested foods for
`
`
`
`
`
`
`
`
`
` Page 18 of 22
`
`
`
`
`
`(b) (4)
`
`(b)
`(4)
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`(b)
`(4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`
`
` QUALITY ASSESSMENT
`
`
` Table 3: Chemical Stability of LDV/SOF Oral Granules in Various Soft Foods
`
` (Lot JB1789)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` As shown in Table 4 below, the LDV/SOF oral granules
` after being left in soft food for
`
`
`
`
`
`
` % dissolution at 30 minutes
`
`
`
`
`
`
`
`
` Table 4: Dissolution of LDV/SOF Oral Granules in Various Soft Foods
`
` (Lot JB1789)
`
`
`
`
` 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:
`
`
`Per the Applicant (Table 5), the formulation used in Phase 2/3 clinical studies (GS-US­
` 337-1116 and GS-US-337-4565) are the same as the proposed to-be-marketed
`
`
` formulation. Also, the Phase 2/3 batches and the to-be-marketed batches have the same
` manufacturing process and manufacturing site. Therefore, studies to bridge the clinical
`
`
`and to-be-marketed formulations are not needed.
`
`
`
`
`
`
`
`
` Page 19 of 22
`
`
`
`
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
` QUALITY ASSESSMENT
`
`
` Table 5: Clinical Development History of the proposed LDV/SOF Oral Granules
`
`
`
`
`
`
`
`
` Since the only difference of the proposed 33.75 mg/150 mg and 45 mg/200 mg strengths
`
`
`
`
`
`
` are the granule counts (e.g., 90 counts and 120 counts of LDV/SOF oral granules in each
`
`
` , in addition, the dissolution profile data
` unit-dose packet)
`
` are comparable across the proposed two strengths of LDV/SOF oral granules (Figure 16
`
`
`above), bridging across the proposed strengths is considered established.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Page 20 of 22
`
`(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 6/13/2019):
`
`
`
`
`
`
` Based on the provided dissolution data of all registration batches (EL1701D1,
` EL1702D1, EL1703D1, EL1701D2, EL1702D2, and EL1703D2), FDA recommends that
`
`you implement a sofosbuvir dissolution acceptance criterion of “Q= % in 15 minutes”
`
`
`
`
`for the proposed drug product, Harvoni (ledipasvir/sofosbuvir) Oral Granules 33.75
`
`
` mg/150 mg and 45 mg/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 06/25/2019):
`
` Application 212477 - Sequence 0007 - Response to the Question Number 1 of FDA Email
`
`
`
` Request for Information dated 2019-06-13
`
`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 21 of 22
`
`(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 22 of 22
`
`
`
`
`
`
`
`
`
`( )
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`Mei
`Ou
`
`Elsbeth
`Chikhale
`
`Digitally signed by Mei Ou
`Date: 7/27/2019 07:24:35PM
`GUID: 54ca9d7000073c57d2eb7cc6e42c05bb
`
`Digitally signed by Elsbeth Chikhale
`Date: 7/27/2019 09:01:07PM
`GUID: 50743ccc000031928b54eba1769a5df9
`
`

`

`
`
`
` QUALITY ASSESSMENT
`
`
`BIOPHARMACEUTICS REVIEW ADDENDUM
`
`
`
`
`
`
`NDA: 212477 [505(b)(1)]
`
`
`
`
`
`Drug Product Name/Strength: Harvoni (ledipasvir/sofosbuvir, LDV/SOF) Oral
`
`
`
`
` Pellets; 33.75 mg/150 mg, 45 mg/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)
`
`
`
`06/25/2019 (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 212477
`
`
`
`
` for Harvoni (ledipasvir/sofosbuvir; LDV/SOF) Oral Pellets, 33.75 mg/150 mg, 45
` mg/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 07/19/2019)2.
`
`
`
` On 08/01/2019, the Applicant responded 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 at the time of batch
`
`
`
` release and during the product’s 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 the bitter tasting compound in the proposed LDV/SOF
`
`
`
` oral granules product).
`
`
`
`
`
` Additionally, to further prevent the release/dissolution of SOF during its administration,
` the product’s labeling indicates the following; i) “Take HARVONI granules 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 212477:
` http://panorama.fda.gov/PanoramaDocMgmt/webhooks/viewdownload?id=090026f88334eae3
`
`
` 2 \\cdsesub1\evsprod\nda212477\0011\m1\us\112-other-correspondence\comments-advice-req-nda.pdf
`
` 3 \\cdsesub1\evsprod\nda212477\0011\m1\us\111-information-amendment\quality.pdf
`
`
`
`
`
`
`
` Page 1 of 2
`
`
`(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 criteria are acceptable for the
`
`
`
`
`
`
`
` Quality Control of the proposed drug product at release and on stability:
`
`
`
`
`
`
`
`
`
` USP Apparatus
`
` Rotation Speed
`
`
`
` Medium and Volume
`
`
`
` Temperature
`
`
`
` Acceptance Criteria
`
`
`
`
`
` II (Paddle)
`
`
` 75 rpm
`
` 900 mL of 25 mM potassium phosphate buffer, pH
` 5.5, containing 1.0% polysorbate 80 and 0.005 mg/mL
`
`
`
` butylated hydroxytoluene (BHT)
`
`
`
`
` 37 ± 0.5°C
` Q = % in 30 minutes for both Ledipasvir (LDV) and
`
`
` Sofosbuvir (SOF)
`
`
`
`
`
`
`
`
`
` RECOMMENDATION
`
`
`
`
`
`
` From the Biopharmaceutics perspective, NDA 212477 for the proposed Harvoni (Ledipasvir/
` Sofosbuvir, LDV/SOF) Oral Pellets, 33.75 mg/150 mg, 45 mg/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 09:44:28AM
`GUID: 54ca9d7000073c57d2eb7cc6e42c05bb
`
`Digitally signed by Angelica Dorantes
`Date: 8/08/2019 10:04:33AM
`GUID: 502d0913000029d59f1c87e0a380c7f7
`
`64 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`Erika
`Englund
`
`Digitally signed by Erika Englund
`Date: 8/22/2019 08:57:55PM
`GUID: 51389ea30003450414230afb8c3e8114
`
`

`

`
`
`RECOMMENDATION
`
`
`
`
`☐ Approval
`
`
`☐ Approval with Post-Marketing Commitment
`
`
`☒ Complete Response
`
`
`
`
`
` Drug Product Name
`
`
`
`
`
`
`
`NDA 212477
`
`
`
`
` Assessment # 1
`
`
` ledipasvir and sofosbuvir, LDV and SOF, (GS-5885 and
`
` GS-7977)
`
` Oral Pellets
` Dosage Form
` 33.75 mg /150 mg; 45 mg/200 mg
`
`
` Strength
`
`
` Route of Administration Oral
`
`
` Rx/OTC Dispensed
` Rx
` Gilead Sciences, Inc.
`
` Applicant
`
` US agent, if applicable
`Applicant’s Responsible Official: Linda Lintao, RAC,
`
` Associate Director, Regulatory Affairs
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Submission(s)
`
` Assessed
`
` Original NDA
`
` eCTD 0002
`
` eCTD 0004
`
` eCTD 0005
`
` eCTD 0006
`
` eCTD 0007
`
` eCTD 0010
`
`
`
`
`
`
`
` Discipline
`
` Drug Substance
`
` Drug Product
`
` Manufacturing
`
` Microbiology
` Biopharmaceutics
`
`
` Regulatory Business
`
` Process Manager
`
`
`
` Document Date
`
`
`
` Discipline(s) Affected
`
`
` 2/28/2019
`
` 3/18/2019
`
` 4/18/2019
`
` 4/19/2019
`
` 4/23/2019
`
` 6/25/2019
`
` 7/15/2019
`
` All
`
`
` Labeling
`
` Quality
`
` Quality
`
` Quality
`
` Quality
`
` Quality
`
`QUALITY ASSESSMENT TEAM
`
`
`
`
`
`
`
`
` Primary Assessment
`
` N/A
`
` George Lunn
`
` Nathan Davis
`
` N/A
` Mei Ou
`
`
`
`
`
`
` Secondary Assessment
`
`
` N/A
` Balajee Shanmugam
`
` Rapti Madurawe
`
` N/A
` Elsbeth Chikhale
`
`
` Luz Rivera
`
`
`
` OPQ-XOPQ-TEM-0001v06 Page 1
`
`
`
`
`
`
`
` Effective Date: February 1, 2019
`
`
`
`
`
`

`

`Application Technical
`
` Lead
` Laboratory (OTR)
`
`
`Environmental
`
`
`
`
`
` Erika Englund
`
` N/A
`
` George Lunn
`
`
`
` Balajee Shanmugam
`
`
`
`
`
` QUALITY ASSESSMENT DATA SHEET
`
`
`
`
`
`
`
` 1. RELATED/SUPPORTING DOCUMENTS
`
` A. DMFs:
`
`
`
`
`
`
`
`
`
` DMF #
`
`
`
` Type
`
`Holde
`
` r
`
`Item
` Referenced
`
`
`
`Status
`
` Date
`
`
` Assessment
`
` Completed
`
`
`
` Comments
`
`
`
`
`
` II
`
`
`
`
` Variable
`
`III (if
` applicable)
`
`
`
`
`
`
`
` Refer to
`
` referenced
`
` NDA 205834
`
`and NDA
`
` 204671
` Refer to DP
`
`
` review
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` B. OTHER DOCUMENTS: IND, RLD, RS, Approved NDA
`
`
`
`
`
`
`
`
`
`
`
` Document
`
`
`
` Application Number
`
`
`
` Description
`
`
` NDA
`
` NDA
`
`
` IND
`
` IND
`
` IND
`
`
`
`2. CONSULTS
`
`
`
`
`
` 204671
`
` 205834
`
`
` 106739
`
` 115268
`
` 108214
`
`
`
`Sovaldi (Sofosbuvir tablet)
`
` Harvoni (Ledipasvir and
`
` sofosbuvir tablet)
`
` Sofosbuvir
` Ledipasvir/sofosbuvir
`
` Ledipasvir
`
`
`
`
`
` 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 212477 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 orange oral pellets. Each pellet
` taste masking coat and weighs approximately mg,
` has a
`
`
`
`
`
` with 2 mm X 2 mm 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 of ledipasvir/sofosb