center for drug evaluation and research€¦ · (low substitute), magnesium stearate, hpmc,...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

211843Orig1s000

PRODUCT QUALITY REVIEW(S)

~Jil#_~ QUALITY ASSESSMENT Cf1JiliW NDA 211843: THIOLA EC (Tiopronin)

Delayed Release Tablets

OPQ Integrated Quality Review

Recommendation: Recommended for Approval

Drug Name/Dosage Form THIOLA EC (Tiopronin) Delayed Release Tablets

Strength 100-mg and 300-mg

Route of Administration Tablets for oral use

Indication Prevention of cystine (kidney) stone formation in patients with severe homozygous cystinuri ---~111J<4

Rx/OTC Dispensed Rx

Applicant Mission Pharmacal Company

licable Hurle Consultin Associates Ltd. Submissions (s) Reviewed NDA 211843, and all the submitted CMC amendments

Quality Review Team

DISCIPLINE REVIEWER BRANCH/DIVISION

Drug Substance Sharon Kelly ONDP/DNDAPI/NDBI

Drug Product, Labeling, and Andrei Ponta ONDP/DNDPI/NDPBI Environmental Assessment (EA)

Process and Facility Anitha Govada OPF/DP AI/P ABI

Biopharmaceutics Ou Mei ONDP/DB/BBI

Regulatory Business Process Grafton Adams OPRO DRBPMI/RBPMBI Manager

Laboratory (OTR) NIA

Application Technical Lead Mohan Sapru ONDP/DNDPI/NDPBI

OPQ-XOPQ- NDA 208370 Valsartan ER Tablets

~k9i=*=--==iQ=&-=-~~~-Q_U_A_L_I_T_Y_A_s_s_E_s_sME~_N_T~~~----'Qjj@~~

1. RELATED/SUPPORTING DOCUMENTS:

DOCUMENT APPLICATION NUMBER DESCRIPTION

Pre-NDA Meeting Minutes pNDA/ plND 135653 (dated NIA May 3, 2018).

DMF Type II DMF # r (b)(4~ Previously reviewed and found adequate

2. CONSULTS: None.

(Continued on next pages)

OPQ-XOPQ- NDA 211843 {TRIOLA EC (Tiopronin) Delayed Release Tablets} 2

~~=*=Jil==#-~~=-~~~Q_U_A_L_I_T_Y_A_s_s_E_ss_ME~N_T~~~----'rgj~ Executive Summary

I. Recommendations

A. Recommendation and Conclusion on Approvability

From Chemistry, Manufacturing and Controls (CMC)/quality perspective, NDA 211843 {TRIOLA EC (Tiopronin) Delayed Release Tablets}is recommended for approval. As part of this action, an expiration period of 18 months is granted for the proposed product when stored at controlled room temperature (25°C or 77°F) in the commercial packaging. Product excursions are permitted to 15-30°C (59-860F). The following comments, listed below in Section B, represent post-approval quality agreement between Mission Pharmacal Company and the OPQ and need to be included in the action letter:

B. Recommendation on Post-Marketing Commitments (PMCs), Agreements, and/or Risk Management Steps, if Applicable

Per your product quality-related Post-Marketing Commitment (PMC), you are reminded of your commitment to:

1. Provid CbH4l testing results for eight development/registration batches and six validation batches. Specifically, the eight development/registration batches are to be tested after ~24 months storage under long-term conditions. The six validation batches are to be manufactured June 2019 and are to be tested approximately one week after manufacturing as part of release testing. The agreed time frame for reporting the testing results is the 3rd quarter of 2019. These results are to be submitted to the NDA as an amendment.

2. Perform Cb><4Yt testing, as part of the stability protocol, for the validation batches with the six-month results to be made available around December 2019.

3. Submit all Cb><4Yt testing results, to set the fina (bl1' imit, as a Prior Approval Supplement (PAS) at the end of the 1st quarter of 2020.

II. Summary of Quality Assessments

The applicant, Mission Pharmacal Company (Mission), has sought U.S. marketing approval for enteric-coated TRIOLA EC (Tiopronin) Delayed Release Tablets under the provisions of Section 505(b )(2) of the Federal Food and Cosmetic Act. The proposed delayed release formulation is indicated for the prevention of cystine (kidney) stone formation_in_nati entl with,sev_ere.homozyg_ous c_v_stinu~i

intake, alkali and diet modificatio


~~=*=j==t~~=-~~~Q_U_A_L_I_T_Y_A_s_s_E_ss_ME~N_T~~~----'rgj@l~ Mission is not requesting exclusivity since Thiola EC Tablets have the same active ingredient i.e. , N-(2-mercaptopropionyl) glycine (tiopronin), which is present in currently available THI OLA® (tiopronin) tablets (NDA 019569). Based on the quality information provided, the overall product control strategy is adequate and the delayed release claim for the proposed formulation is acceptable.

A. Drug Substance (Tiopronin) Quality Summary

The drug substance N-(2-mercaptopropionyl) glycine i.e. , tiopronin is an active reducing agent which undergoes thiol-disulfide exchange with cystine to form a mixed disulfide of tiopronin-cysteine. For CMC information concerning the drug substance, the applicant has cross-referenced Type II DMI) Cb><4~, which was been previously reviewed and found to be adequate. The same DMF holder supplies the drug substance for manufacture of Mission's previously approved (immediate release) Thiola® (tiopronin) Tablets (NDA 019569). The drug substance release specification provided in this NDA matches the approved specification under NDA 019569. Specifically, the drug substance meets the compendia! USP requirements such as levels of metals, residue on ignition, and residual solvents and the requirements for non-compendia! analytical methods for assay, related substances, identification, and loss on drying. Method validation information provided in the NDA is adequate. Based on cross-referenced information in Type II DMF (bH 4Y,

and drug substance specification, which involves testing critical quality attributes, and batch analysis data provided in the NDA, the control strategy is adequate to assure the quality of the incoming drug substance.

B. Drug Product {THIOLA EC (Tiopronin) Delayed Release Tablets} Quality Summary

B.1. Product Design, and Release Specification: Thiola enteric-coated tablets for oral administration are manufactured by Mission in a delayed release solid oral dosage form containing 100-mg or 300-mg of tiopronin. Thiola EC Tablets containing 100-mg of tiopronin have "Tl" imprinted on one side with red ink while as Thiola EC Tablets containing 300-mg of tiopronin have ''T3" imprinted on one side with red ink. Drug product design is based on immediate release Thiola (tiopronin) 100-mg oral tablets a~roved under NDA 019569. The current enteric-coated tablet formulation is develo ed

(b) (4~

(b)(4~

oth tablets use the same enteric coating formulation CbH4l The coating process is designed ;;:_-----=================---.1i>Jlll

The tablet passes through the stomach with minimal loss and dissolve when it enters the intestinal tract. The excipients used in the manufacture of 100-mg and 300-mg tablets are not novel excipients. In addition, none of the excipients used are of animal origin except Lactose Monohydrate, NF. The supplier of Lactose Monohydrate NF states that CbJ <4>

and used in the manufacture of this excipient complies with the "Committee for


~~=*=Jil==#-~~=-~~~Q_U_A_L_I_T_Y_A_s_s_E_ss_ME~N_T~~~----'rgj~ Proprietary Medicinal Products (CPMP) Note for Guidance on Minimizing the Risk of Transmitting Animal Spongiform Encephalopathy Agents Via Human and Veterinary Medicinal Products (EMEA/410/01 Rev.3)." The specifications and analytical procedures used to test the excipients i.e. , lactose, hydroxypropyl cellulose, hydroxypropyl cellulose (low substitute), magnesium stearate, HPMC, Eudragit L 100-55, talc and triethyl citrate comply with the respective compendia} monographs. The product release specification, involving testing of all the product critical quality attributes (CQAs), is adequate to ensure the consistent product quality. The non-compendia} analytical procedures used for testing the drug product have been validated according to ICH guidelines for accuracy, specificity, linearity, method repeatability, solution stability, and intermediate precision. Per 21 CFR Part 211.194(a)(2), the suitability of the compendia} test methods for their intended use has been verified under actual conditions used for testing the drug product. The applicant has provided batch analysis data for three batches of the 100-mg strength and five batches of the 300-mg strength, all of which meet the proposed product specification >T

41 is well characterized impurity that is controlled in the drug substance (NM'I[CbH4~ ) and drug product (NMT[~~%). Based on i,nput from the Pharmacology and Toxicology review team, the proposed limit of NM ~~lo fo ltif<

4

bll4

is acceptable due prior history of its levels in previously approved (immediate .__,___,_ ... release) Thiola® (tiopronin) Tablets. The applicant has performed a risk assessment screening for elemental impurities, per ICH Q3D, taking into account any potential contributions from the drug substance, excipients, manufacturing equipment and process, and leachables from the container closure system. Based on this assessment, the elemental impurities in the proposed product do not exceed the ICH Q3D-compliant permitted daily exposure (PDE) limits. Hence, no release testing for elemental impurities is required.

B.2 . .Mann facturime..Brieflv_ the..manufacturing__of_the tab 1 etjQvo lv__e (b) (41

(b)l4J

Based on the details provided in the submission, the proposed manufacturing process is b)llll

The in-process controls CbH

4Y in the

--------------------------------e and are are used to tightly contro theJnanufacturin2: nmcess.__Ih.e amount of__enteric coatin2:.

I . b 1 · d . (b)(4' so utton to e app ie I

CbH41

There are no discrepancies between_the executed and_intended .. batch_records. , _p___ l"d . d" c d CbH4l rocess va I atton stu ies per1orme

(b)(4) • th f: . d m e manu acturmg process are a equate. -----

B.3. Microbiological Aspects: The proposed drug product is a non-sterile tablet. The microbiological testing is included in release and stability specifications. Testing performed per USP <61> and <62> is adequate for the proposed product. Based on stability studies, all stability batches meet the product specification for microbiological testing. No evidence of microbial activity has been observed in any of the batches tested to date.

OPQ-XOPQ- NDA 211843 {THIOLA EC (Tiopronin) Delayed Release Tablets} 5

~k9i=*=--==iQ=&-=-~~~-Q_U_A_L_I_T_Y_A_s_s_E_s_sME~_N_T~~~----'Qjj@~~ B.4. Biopharmaceutics Aspects: The Biopharmaceutics review evaluated the: i) in vitro dissolution method and acceptance criterion for the proposed drug product, ii) biowaiver request for lower strength (100-mg) tablet, iii) in vitro alcohol dose dumping study, and iv) data to support the delayed release claim.

In Vitro Dissolution Testing of the Finished Product: The proposed two-stage dissolution method is suitable for a delayed release drug product, and the method has been sho~ to be discriminating with respect to the weight gain of enteric coatin CbH

41

___ Cb_H_4Y,Hence, the proposed dissolution method (with the dissolution conditions of

USP apparatus I (basket), 100 rpm per USP <711>: and acceptance criteria of Acid Stage: NMTrn~% in 2 hours, and Buffer Stage: NLT ~~Yo (Q) in 45 minutes) is deemed adequate for the routine quality control test of the finished drug product for batch release and stability testing.

Biowaiver for Lower Strength: The biowaiver request for the proposed Thiola entericcoated 100-mg tablets is granted per CFR 320.22(d)(2) based on the supportive data, including: (a) acceptable relative bioavailability/bioequivalence (BA/BE) results of the proposed higher strength (300-mg) tablets (refer to the Office of Clinical Pharmacology review), (b) proportionality in composition of the proposed two strengths (100-mg and 300-mg), ( c) utilization of the same manufacturing process and manufacturing site for the proposed two strengths, ( d) the comparable dissolution profiles of the proposed two strengths, and ( e) the PK linearity in the range of 100-mg and 300-mg dose.

In Vitro Alcohol Dose Dumping: The in vitro alcohol dose dumping of the proposed enteric-coated tablets was observed particularly with 20% and 40% of alcohol. The increased dissolution in the presence of alcohol was observed for both the 100-mg and 300-mg tablets. These findings have been shared with the Office of Clinical Pharmacology (OCP) review team who will determine the need for in vivo study and provide the labeling language regarding alcohol consumption.

Delayed-Release Claim: The delayed release claim of the proposed Thiola enteric-coating tablets is supported by the following considerations:

(b)(4l • The proposed product formulation involves the use of enteric coating

(b)(4~ ----

• The two-stage in yitro dissolution data demonstrate that the proposed drug product has no more tha r><4~/o drug release in acid stage for 2 hours, and immediate and complete drug release in buffer stage.

• The proposed Thiola enteric-coating tablets show delayed T max compared to the Thiola immediate release (IR) tablets.

B.5. Container Clos re_system: C9nsists of a 100-cc white, high density polyethylene (HDPE) bottle with CbH

4> closure and heat-seal inner liner. Stability data from

the stability/qualification batches lends additional support to the suitability of the container closure system for providing adequate protection to the drug product over the proposed shelf-life. The applicant has cross referenced the bottle and closure information


~~=*=Jil==#-~~=-~~~Q_U_A_L_I_T_Y_A_s_s_E_ss_ME~N_T~~~----'rgj~ to DMFi ___ Cb_n_~~and D~, which have been previously reviewed and found adequate.

B.6. Stability, Storage Conditions and Expiration Date: Based on stability studies, the applicant has demonstrated stability for the proposed product for a period of: a) 18 months under long-term storage conditions (25°C ± 2°C/60% RH ± 5% RH; b) 12 months under intermediate conditions (30°C ± 2°C/65% RH ± 5% RH), and c) 6 months under accelerated storage conditions (40°C ± 2°C/75% RH ± 5% RH). As demonstrated by photostability studies, the proposed product is not sensitive to light. Taken together, the product stability data support a shelf-life period of 18 months for 100-mg and 300 mg Thiola EC Tablets containing when stored at 25°C (77°F) in white 100 cc HDPE bottles

"th (b)(41 1 d h 1 . 1. P d . . d w1 c osure an a eat-sea mner mer. ro uct excursions are perm1tte

to 15-30°C (59-86°F).

C. Assessment of Manufacturing Facilities: The office of Process and Facilities has recommended an overall approval for all the currently listed manufacturing facilities concerning this NDA.

D. Environmental Assessment: The applicant has claimed categorical exclusion from the environmental assessment requirements under 21 CFR Part 25 .31 (b) on the basis that the estimated concentration of tiopronin at the point of entry into the aquatic environment


~~=*=Jil==#-~~=-~~~Q_U_A_L_I_T_Y_A_s_s_E_ss_ME~N_T~~~----'rgj~ will be well below 1 part per billion. There are no in vivo estrogenic, androgenic, or thyroid activities known to be caused by tiopronin.

E. Any Special Product Quality Labeling Recommendations:

The following recommendations have been communicated to the applicant:

THIOLA EC_(.tiooroninL Delayed

(6Jlll

(b)(.iJ

(b)(4

• Replace the proprietary name Eudragit with methacrylic acid: ethyl acrylate copolymer in the physician's insert.

• As part of the bottle labeling, include a space for the lot number, the expiration date, and the bar code. <6>1.iJ

F. Life Cycle Knowledge Information

See Final Risk Assessment on the next page.


~~=*=j==t~~=-~~~Q_U_A_L_I_T_Y_A_s_s_E_ss_ME~N_T~~~----'rgj@l~ Final Risk Assessment

NDA 211843 {THI OLA EC (Tiopronin) Delayed Release Tablets}

Attribute/ Factors Initial Risk Miti2ation Final Risk Lifecycle CQA lmpactinl! Risk Approach Evaluation Considerations

CQAs Ranking I Comments

' . ssay, • ormu at1on w ccep e A F Lo A tabl

Stability • Container (L) closure

• Impurity exceeding

specification • Process

parameters • Scale/

equipment/ site

Solid state • Formulation Mode- Acceptable NIA Polymorph •Raw rate ic form) materials (M)

• Process parameters

• Scale/ equipment/ site

Content • Formulation Moder- Acceptable Any proposed changes Uniformity • Particle size ate (M) to formulation ,

• Segregation manufacturing, or the

•Raw control strategy will

materials need to be evaluated

• Process for possible impact on

parameters content uniformity or

• Scale/ delayed release

equipment/ properties of the

site proposed product.

OPQ-XOPQ- NDA 211 843 {TRIOLA EC (Tiopronin) Delayed Release Tablets} 9

~ri=*=j==t~~=-~~~Q_U_A_L_I_T_Y_A_s_s_E_ss_ME~N_T~~~----'Qjj@~~ Attribute/ Factors Initial Risk Miti2ation Final Risk Lifecycle CQA lmpactin2 Risk Approach Evaluation Considerations

CQAs Ranking I Comments

Poor • Formulation Low (b)(4

Acceptable Adhesion • Process (L) Related parameters Delaminati • Scale/equip on (for ment/site multilayere d tablets

Alcohol • Formulation Low Acceptable NIA Dose • Process (L) Dumping parameters

• Scale/equip ment/site

Dissolution • Formulation Moder- Acceptable •Raw ate (M)

materials • Process

parameters • Scale/equip

ment/site • API sources

Microbial • Formulation Low .

Acceptable limits •Raw (L)

materials • Process

parameters Scale/equip ment/site

OPQ-XOPQ- NDA 211 843 {TRIOLA EC (Tiopronin) Delayed Release Tablets} 10

~k9i=*=--==~=&-=-~~~-Q_U_A_L_I_T_Y_A_s_s_E_s_sME~_N_T~~~----'QjJilj~~

OVERALL ASSESSMENT AND SIGNATURES: EXECUTIVE SUMMARY

From Chemistry, Manufacturing and Controls (CMC)!quality perspective, NDA 211843 {THIOLA EC (Tiopronin) Delayed Release Tablets} is recommended for approval. As part of this action, an expiration period of 18 months is granted for the proposed product when stored at controlled room temperature (25°C or 77°F) in the commercial packaging. Product excursions are permitted to 15-30°C (59-86°F).

Mohan Sanru. M.S .. Ph.D. Application Technical Lead (A TL)

CMC Lead for Cardiovascular and Renal Products ONDP/DNDPI/NDPB

Mohan K. Sapru -5

Oligttdys'91\ed byMot\anK.S~ptU·S ON:c=US,o=U.S. Go'Vttr'll"tlent,. cu=tliS, cu=l-DA. ou=f>ecp~ cn=Mot\an K. S~p<u-S,

0.9.2342..19200300.100.1.1=20Cl(pj8931 s Oatl!z 201 !.06.0S 11 :16:54 -0400'


QUALITY ASSESSMENT

LABELING I. Packa e Insert

(b) (41

Item Information Provided in NDA f~2.~~£~_'Im.~_(!:-~!?_~li~gJleyj~w_Ipol __ ~~~.? !_g!_~_ 2Q_L?7 (~)_G_)) ______________________________ Proprietary name and established name THIOLA EC (tiopronin) delayed release

tablets

Reviewer's Note ll>H'!)

I

I ------------------------------·------·------·-------·-------·---- ------------------------------------- ----- --- ----- ----Qp§~_g~.f P~2!P_~-~~-o(_~~-~~-~str:~_tj_o~------- Tablets, oral -------------------------------------------------------Controlled drug substance symbol Not Applicable

QQ§~_g-~_E_Q~~~-~ tr:~I_l_g!h~_{1~Q~li~g_R_~vj~_w_Jgol_~_I_ld -~J_ Cf_~_1Q_t_?}fa)_@)} ___________ Summary of the dosage form and strength Delayed Release Tablets: 100 mg and 300

mg

Reviewer's Note !l>H4j

I

I

Is the information accurate? D Yes ~No

OPQ-XOPQ-TEM-0001 v05 Page 1of6 Effective Date: October 15, 2017

(b) (4)

(b) (4)

(b) (4)

QUALITY ASSESSMENT

(b)(iij

Item Information Provided in NDA ffi:~f~~JQ_l-~1?.~UQgJleyJ~w_I9ol __ ~~d ~J-~FK~.Q_L?7 (~)_Q~}) _________________________________ _

Special instructions for product None preparation (e.g., reconstitution, mixing with food, diluting with compatible diluents)

Is the information accurate?~ Yes D No (b)(4J

Item Information Provided in NDA (Refer to Labeling Review Tool and 21 CFR 201.57(c)(4)) Available dosage forms Delayed Release Tablets

Reviewer's Note: L

Strernrths: in metric svstem 1 00 mg anct'"'300 mg Active moiety expression of strength Tiopronin with equivalence statement A description of the identifying Round white to off-white tablet. The 100 mg characteristics of the dosage forms, strength is imprinted with a red "Tl " on one side including shape, color, coating, and blank on the other side. The 400 mg strength scoring, and imprinting, when is imprinted with a red "T3" on one side and applicable. blank on the other side.

Is the information accurate?~ Yes D No

4. Section 11 Description

OPQ-XOPQ-TEM-0001v05 Page 2of6 Effective Date: October 15, 2017

QUALITY ASSESSMENT

(b)l4~

Item Information Provided in NDA (Refer to Labeling Review Tool and 21CFR201.57(c)(12), 21CFR201.lOO(b)(S)(iii), 21CFR314.94(a)(9)(iii). and 21CFR314.94(a)(9)(iv)) Proprietary name and established name THIOLA EC (tiopronin) delayed release

tablets

Reviewer's Note (I>)(~

I I

Dosage form and route of administration Delayed Release Tablets: 100 mg and 300 mg

Reviewer's Note (l>ll4J

I

I Active moiety expression of strength with Tiopronin equivalence statement (if annlicable) For parenteral, otic, and ophthalmic The drug product contains the following dosage forms, include the quantities of all USP/NF excipients: lactose monohydrate, inactive ingredients [see 21 CFR hydroxy-propyl cellulose, hydroxy-propyl 201.lOO(b)(S)(iii), 21 CFR cellulose (low substitute), magnesium 314.94(a)(9)(iii), and 21 CFR stearate, hydroxypropyl methylcellulose, 314.94(a)(9)(iv)], listed by USP/NF methacrylic acid: ethyl acrylate copolymer names (if any) in alphabetical order (USP (Eudragit E 100), talc, and triethyl citrate. <1091>)

Reviewer's Note: Applicant will be asked to replace Eudragit with methacrylic acid: ethy ~crvlate cooolvme11


QUALITY ASSESSMENT

Statement of being sterile (if aoolicable) Not aoolicable Pharmacological/ therapeutic class Reducing and cysteine binding thiol drug Chemical name, structural formula, CsH9N03S - 163.20 g/mol molecular weight If radioactive, statement of important Not applicable nuclear characteristics. Other important chemical or physical Soluble in water properties (such as pKa or pH)

Reviewer's Not (1>>14!

I

Is the information accurate?~ Yes D No CbHllY

Item Information Provided in NDA (Refer to Labeling Review Tool and 21 CFR 201.57(c)(l 7)) Strength of dosage form Delayed Release Tablets: 100 mg, 300 mg

- -Reviewer's Not (1>>14!

I Available units (e.g., bottles of 100 mg: bottles of 300 tablets 100 tablets) 300 mg: bottles of 90 tablets Identification of dosage forms, Round white to off-white tablet. The 100 mg e.g., shape, color, coating, strength is imprinted with a red "Tl " on one side and scoring, imprinting, NDC number blank on the other side. The 400 mg strength is

imprinted with a red "T3" on one side and blank on the other side.

Special handling (e.g., protect Not Applicable from light) Storage conditions USP controlled room temoerature Manufacturer/ distributor name Mission Pharmacal Company (21CFR201.l(h)(S))

Reviewer's Assessment of Packaee Insert: Adequate

Prescribing Information complies with all regulatory requirements from a CMC perspective.


QUALITY ASSESSMENT

However, some revisions have been identified and will be communicated to the Applicant as part of DCRP labeling negotiations.

II. Labels:

1. Bottle Label~

Item Information provided in the bottle label Proprietary name, established name (font THIOLA EC (tiopronin) delayed release size and prominence (21 CFR tablets 201.10(g)(2))

Reviewer's Note

I Dosage strernrth Como lies Net contents Complies ''Rx only" displayed prominently on the Complies main panel NDC number (21CFR207.35(b)(3)(i)) Como lies

(b)(41

(l>f<4J

I

Lot number and expiration date (21 CFR Reviewer's Note: Applicant will be asked .121 201.17) include a space for the lot number and the

expiration date Storage conditions Como lies Bar code (21 CFR 201.25) Reviewer's Note: A licant will be asked .!21

include the bar code Name of manufacturer/distributor Complies And others. if soace is available Not Aoolicable

Reviewer's Assessment of Labels: Adequate

The carton/container label complies with regulatory requirements from a CMC perspective, with the exception of the proprietary name. It bears the "Rx only" statement, the NDC number, name of manufacturer, net contents, strength, and the name (proprietary and established).


QUALITY ASSESSMENT

Revisions have been identified and will be communicated to the Applicant as part of DCRP labeling negotiations. The carton/container labeling is adequate assuming Applicant accepts edits.

List of Suggested Edits Communicated to Applicant:

3. Replace the proprietary name Eudragit with methacrylic acid: ethyl acrylate copolymer in the physician's insert.

4. As part of the bottle labeling, include a space for the lot number, the expiration date, and the bar code >rr

4

(bl\l

Overall Assessment and Recommendation: Adequate

Primary Labeling Reviewer Name and Date: Andrei Ponta, Ph.D. 6-May-2019


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QUALITY ASSESSMENT

BIOPHARMACEUTICS

NDA: 211843 [505(b)(2)] Drug Product Name/Strength: Thiola TM enteric-coated (EC) Tablets, 100 mg and

300mg Route of Administration: Oral Applicant Name: Mission Pharmacal Company Proposed Indication: For the prevention of cystine (kidney) stone formation in patients with severe homozygous cystinuria Submission Dates: 08/31/2018, 01/15/2019, 02/28/2019, 03/14/2018, 05/0712019 Primary Reviewer: Mei Ou, Ph.D. Secondary Reviewer: Jing Li, Ph.D.

REVIEW SUMMARY

The proposed drug product, Thiola TM EC Tablets, 100 mg and 300 mg, is an entericcoated tablet for oral administration, indicated for the prevention of cystine (kidney) stone formation in patients with severe homozygous cystinuria <6><41

(6) (41

high fluid intake, alkali and diet modificatio (b1<41

____ Cb_ 11_<4>The listed drug (LD) product of this 505(b)(2) application is Thiola® (tiopronin) 100 mg Immediate-Release tablets, which was approved under NDA 019569 on 08/11/1988.

This Biopharmaceutics Review focuses on the evaluation of: i) the in vitro dissolution method and acceptance criterion of the proposed drug product, ii) the in vitro alcohol dose dumping study, iii) the biowaiver request for lower strength (100 mg) drug product ' . iv) data to support the delayed release claim.

In Vitro Dissolution Testing of the Finished Product: The proposed two-stage dissolution method is suitable for a delayed release drug__product, and the method is shown to be discriminating with respect to the weight gai <6><

45

(b)(41 Th c h d d" 1 . h d . --------------- ere1ore, t e propose isso ution met o is

acceptable for the routine quality control (QC) test of the finished drug product for batch release and stability testing.

The final approved in vitro dissolution method and acceptance criteria for the finished drug product are presented below:

1 The meeting minutes of a Type B meeting cross-referenced to NOA 019569 dated 04/06/2017: https· //darrts fda goy//darrts/facesNiewQocu ment?docu mentld=090140af8043924b& afrRed jrect=l?Z??l 5411028

.22B.

Page 1of19

QUALITY ASSESSMENT

USP Annaratus I ffiasket) Rotation Speed 100 rpm Dissolution Media and Acid Stage for 2 hours: 0.1 N HCl, 900 mL Volume Buffer Stage: 50 mM potassium phosphate, pH 6.8,

900mL Temnerature 37°C±0.5°C Acceptance Criteria Acid Stage: NMTM<~l% in 2 hours

Buffer Stage: NLTr~~% (0) in 45 minutes

In Vitro Alcohol Dose Dumping: The in vitro alcohol dose dumping of the proposed enteric coating tablets was observed at the presence of20% and 40% of alcohol in O.lN HCl. The Office of Clinical Pharmacology (OCP) was informed, and OCP will determine the need for in vivo study and provide the labeling language regarding alcohol consumption.

Biowaiver for Lower Strength: The biowaiver request for the proposed Thiola ™ enteric-coated (EC) Tablets, 100 mg, is granted per CFR 320.22(d)(2), based on the supportive data and information of (i) the acceptable relative bioavailability/bioequivalence (BA/BE) results of the proposed higher strength (300 mg) tablets (refer to OCP review), (ii) the proportionality in composition of the proposed two strengths (100 mg and 300 mg), (iii) the same manufacturing process and manufacturing site for the proposed two strengths, (iv) the comparable dissolution profiles of the proposed two strengths, and (v) the PK linearity in the range of 100 mg and 300 mg dose.

Nevertheless, to meet the need of the patients too young to swallow tablets, the Clinical Division and OCP requested the Applicant to conduct an in vivo bioavailability study using crushed enteric coating tablets compared to the proposed Thiola EC Tablets to support the use of the crushed EC tablets. The protocol and study will be under the purview of the Office of Clinical Pharmacology and Clinical.

Page 2of19

QUALITY ASSESSMENT

Delayed-Release Claim: The delayed release claim of the proposed Thiola enteric-coating tablets is supported by the following information:

(b) (41 - The proposed drug product contains enteric coatin - The two-stage in vitro dissolution data demonstrated that the proposed drug product

has no more tha 't6><4l% drug release in acid stage for 2 hours, and immediate and complete drug release in buffer stage.

- The proposed Thiola enteric-coating tablets showed delayed Tmax compared to the Thiola immediate release (IR) tablets.

RECOMMENDATION

From the Biopharmaceutics perspective, NDA 211843 for Thiola™ enteric-coated (EC) Tablets, 100 mg and 300 mg, is recommended for APPROVAL.

Page 3of19

QUALITY ASSESSMENT

BIOPHARMACEUTICS REVIEW

1. Drue Substance Solubility Per the Applicant, the drug substance, Tiopronin (pKa = 3.672), can dissolve in the buffer solutions, however, tiopronin belongs to a class of compounds called "acidic thiols" which at high concentrations can significantly reduce the pH of buffer solutions. Therefore, the Applicant did not conduct the equilibrium solubility test for the drug substance by dissolving the solid compound in chemical equilibrium with a saturated solution of the compound.

To determine the solubility of the drug substance, the Applicant dissolved 36 mg tiopronin in 15 mL of buffers with pH range from 1.0 to 7.5 to get a 2.4 mg/mL solution, which equals to a 600 mg dose product in 250 mL of buffer. As the data presented in the Table 1 and 2, the average percent recoveries for tiopronin obtained ranged from 99.88% to 100.57% with no degradation product identified by a validated assay.

This Reviewer considered the solubility data acceptable, and the drug substance, Tiopronin, is considered to have high solubility. No permeability data is provided for review. Since the proposed drug product is an enteric coating tablets, BCS designation is not applicable to the drug product.

Table 1: Tiopronin Solubility in pH 1.0 to 7.5 Buffers (from 36 mg tiopronin in 15 mL buffers to get a 2.4 mg/mL solution)

Buffer Solution pl-I

Sample Solu11on pH

Difference: pH of Buffer - pH of Sample Solution

Tiopronin Concentration (mg/ml )

pl-I: 1.00 pl-I: 2.67 pl-I: 3.67 pl-I: 4.67 pH : 7.5 Mydrochlorlc Phthalate Phthalate Phthalate Phosphate Acid Buffer Buffer Buffer Buffer Buffer

(50 mM) 50 mM) (50 mM) (50 mM) (100 mM)

1.00

0

2.4

2.62

0.05

2.4

3.40

0.27

2.4

4.11

0.56

2.4

7.11

0.39

2.4

Table 2: The Recoveries of Tiopronin from pH 1.0 to 7.5 Buffers Theoretical Measured

Sample Concentration Concentration % Recovery Average% Samples Weight/mg (mglmL) (mg/mL) ofTiopronln Recovery

pH 1.00

Sampl• 1 36.63 2 .44 2.46 100.57

Sample 2 36.84 2.46 2.47 100.43

Somple 3 36.80 2.45 2.47 100.71 100.57

pH 2.67

s ample 1 37.06 2 .47 2.48 100.58

Sample 2 36.68 2 .45 2.44 99.92

Sample 3 36.92 2 .46 2.48 100.60 100.37

pH 3.67

Sample 1 36.78 2 .45 2.46 100.30

Sample 2 36.95 2 .46 2.48 100.48

Sample 3 36.50 2 .43 2.44 100.43 100.40

pH 4.67

Sample 1 36.89 2 .46 2.47 100.64

Sample 2 36.67 2 .44 2.46 100.57

Sample 3 36.86 2.45 2.46 100.30 100.50

pH 7.50

Sample 1 36.58 2.44 2.44 100.06

Sample 2 36.77 2 .45 2.44 99.65

Sample 3 36.47 2 .43 2.43 99.93 99.88

Page 4of19

QUALITY ASSESSMENT

2. In Vitro Dissolution Method The proposed enteric-coated tablets are designed to have minimal drug release in the acidic environment of the stomach, but dissolve quickly in the intestine and upper bowel. Therefore, a two-stage dissolution method was developed to describe the in vitro dissolution kinetics.

The proposed dissolution method and acceptance criteria in the original submission dated 08/31/2018 are summarized as:

Dissolution Media and Volume

I Basket lOOr m Acid Stage for 2 hours: 0.1 N HCl, 900 rnL Buffer Stage for 45 minutes: 50 mM potassium

hos hate H 6.8 900 rnL ._T=-e=c:..;e:..:.r:::at;.:::ur:..:e;...._ ___ -1-=3:...:.7_0 c::::c±=0::..: . .::..5°-'c:::...._-r'(b)(41 ___________ --1

Originally Proposed Acid Stage: NMT1

~in 2 hours Acee tance Criteria Buffer Sta e: NLT <4>Yo in 45 minutes

The dissolution conditions of USP apparatus I (basket), 100 rpm, are selected per USP <711>, which is acceptable.

Therefore, a pH 6.8 buffer was selected as the buffer stage medium following the acid stage (2 hours in O. lN HCl), which is acceptable.

Page 5of19

QUALITY ASSESSMENT

Table 3: Dissolution Results of Thiola EC 100-mg tablet (batch 65X16, prepared by the proposed manufacturer Mission) in buffered dissolution media at pH I CbH41 6.8

I ~~ pH 6.8 Buffer

Time/Stage % Dissolved % RSD Mean

2 Hour 0.1N HCI 1.4 58.7 3.8

2.7 4.4

4.6

2.4

4.3

5.4

2.6

1.8

6.3 1.2

8.7

45 Minutes in Buffer 100.5 2.8 96.0

93.6 93.6

92.7 94.5

92.8

98.9

95.3 96.4

98.6

96.5

98.8

EC = Enteric-coated: RSD = Relative standard deviation .

Table 4: Dissolution Results of Thiola EC 300-mg tablet (batch 66X16, prepared by the proposed manufacturer Mission) in buffered dissolution media at H CbH41 6.8

Time/Stage

2 Hour 0.1N HCI

45 Minutes in Buffer

pH 6.8 Buffer

% Dissolved % RSD Mean

1.5 35.2 1.3

0.9

2.0 1.8

2.1

0.9 1.1

1.6

1.3

1.3

0.9 0.6

92.2

96.8

3.7 93.8

94.5

96.4 91.8

89.0 88.3

93.1

98.1

98.3

96.5

90.7

EC= Enterlc-coated: RSD = Relative standard deviation.

Page 6of19

(b)(4

QUALITY ASSESSMENT

Because the discriminating ability was not evaluated in the 08/31/2018 submission, the supportive testing/data were requested in the 1st Biopharmaceutics Information Request (IR) that was conveyed to the Applicant on 11/08/2018 (see Appendix 1, Biopharmaceutics 1st IR).

In the response submitted on 01/15/2019, the Applicant conducted tests to demonstrate the discriminating ability of the E!£posed dissolution method, by using the early dev_elonment hatches.__with !blT

41formulations__and '(l,?~~in Cb>C4Y--Cb)C

41

CbH4> compared to tarn:et 100 mg_table and target 300 mg table __ _

------------ The results are profiled in Figure 1 by this Reviewer. The proposed dissolution method i cons.ide~fi~ discriminating with respect to significant changes in coating weight ga ------

Additionally, the same proposed dissolution method has been used in formulation development to evaluate the tablet coating. As the data presented in Table 5 and 6, the dissoluf n method can,_differentiate the,_dnrn release of..nronosed table ts...at coircllg weight gamso

(b)(4)

Page 7of19

QUALITY ASSESSMENT

(b)(4~

Table 5: Dissolution Results for Different Weight Gain Coated ---------Table ts (100 mg, batch 34X16)

----------"'---' ....__ ____ ," ______ (b) (4)

(b)(4~

Table 6: Dissolution Results for Different Weight Gains o Coated Tablets (300 mg, batch 35X16) _____ _

----------"---' (b)(4~

The same proposed dissolutioUJilethod can_also generate diffeLent dissolution_data_for_t~tt41 formulations with and withou

~--------------------as the data presented in Table 7.

Table 7: Dissolution Results for 300 51X16), Without and Wit

(b)(4l

Coated..Ta&-J-~s (batch

Average % Dissolved (b) (41

Overall, the discriminating ability of the dissolution method has been demonstrated. The proposed dissolution method is acceptable as a quality control (QC) method for the proposed drug product.

Page 8of19

QUALITY ASSESSMENT

3. Dissolution Data and Acceptance Criteria The dissolution data in 08/31/2018 submission only had three time points (30, 45 and 60 minutes in buffer stage), the complete dissolution data with more sampling time at buffer stage were requested, and the advice on selection of the dissolution acceptance criteria was provided on 11/08/2018 (see Appendix 1, Bio pharmaceutics 1st IR).

In the response submitted on 01/15/2019, the dissolution data of the proposed 100 mg tablet (batch# 13Xl 7) and the 300 mg tablet (pivotal BE batch# 02Xl 7) are provided (n=12), as presented in the following Table 8 and 9, and Figure 2.

Table 8: Dissolution data of the Proposed Thiola EC 100-mg tablets (batch 13Xl 7) using the proposed dissolution method

0.1 N Cumulative Percent Dissolution Data Obtained In Buffer

Vessel HCI !Minutes)

(Tablet) 2 Hours 5 10 15 20 30 45 60

1 0 .0 0.1 2.8 3.3 14.3 50.9 100.5 102.1

2 0 .0 0.2 1.4 4.9 18.4 70.5 98.8 98.6

3 0 .0 0.2 1.4 3.9 10.9 45.8 97.3 99.6

4 0 .0 0.2 1.4 7.1 18.5 54.1 103.2 101.5

5 0 .0 0.0 0.8 3.1 10.3 59.3 97.7 99.3

6 0 .0 0.3 1.7 4.1 13.6 51.2 101 .6 99.4

7 0.4 1.2 3.9 4.5 9.0 19.5 41.3 78.1

8 0 .0 0.2 1.6 4.8 17.3 59.9 97.1 96.7

9 0 .0 0.1 1.0 4.8 19.2 65.7 96.2 97.4

10 0 .0 0.0 1.3 3.8 11.2 45.4 92.8 95.3

11 0 .1 0.5 2.3 4 .9 14.3 44.3 97.9 98.1

12 0 .0 0.0 1.0 3.1 10.4 42.3 94.9 96.9 Avg 0 .0 0.3 1.7 4.4 13.9 50.7 93.3 96.9

Min 0 .0 0.0 0.8 3.1 9.0 19.5 41.3 78.1

Max 0.4 1.2 3.9 7.1 19.2 70.5 103.2 102.1

% RSD 278.1 129.3 50.6 25.2 26.3 26.1 17.8 6.4

Note: Summary statistics were computed using 4 decimal places for percent dissolution.

Avg= Average dissolution; EC= Enteric-coated; HCI = Hydrochloric acid; Max = Maximum dissolution; Min = Minimum dissolution; RSD = Relative standard deviation.

Note: the average data included the outlier unit 7, confirmed by this Reviewer.

Table 9: Dissolution data of the proposed Thiola EC 300-mg tablets (pivotal BE batch 02Xl 7) by using the proposed dissolution method

0.1 N Cumulative Percent Dissolution Data Obtained In Buffer

Vessel HCI (Minutes)

(Tablet) 2 Hours 5 10 15 20 30 45 60

1 3.1 4.3 6.6 12.6 32.6 59.2 90.8 99.6

2 3.2 4.3 7.4 11.0 22.2 52.7 85.9 101.1

3 2.2 3.3 5.9 12.0 27.1 52.4 83.7 97.2

4 3.5 4.9 9.0 16.3 34.2 59.9 91.3 102.6

5 2.7 3.8 6.1 11.7 27.0 54.5 87.2 99.9 6 2.7 3.6 6.9 13.0 27.8 56.9 90.7 102.0

7 1.7 2.6 4.9 10.5 23.8 52.5 78.8 92.2

8 1.6 2.6 5.1 16.0 32.4 61.3 86.6 96.9

9 1.6 2.6 4.3 10.0 20.6 47.4 77.9 91 .2

10 1.2 2.1 4.3 9.9 24.2 54.7 83.5 99.4

11 2.7 3.8 6.3 12.8 26.7 58.5 87.4 99.1

12 1.7 2.7 4.2 7.7 17.5 50.6 84.5 98.3

Avg 2.3 3.4 5.9 12.0 26.3 55.1 85.7 98.3

Min 1.2 2.1 4.2 7.7 17.5 47.4 77.9 91 .2

Max 3.5 4.9 9.0 16.3 34.2 61.3 91 .3 102.6

% RSD 32.3 25.6 24.5 20.6 19.2 7.6 5.0 3.6

Note: Summary statistics were computed using 4 decimal places for percent dissolution.

Avg = Average dissolution; EC = Enteric-coated; HCI = Hydrochloric acid; Max = Maximum dissolution; Min = Minimum dissolution; RSD = Relative standard deviation.

Page 9of19

QUALITY ASSESSMENT

Figure 2: Comparative dissolution profiles of the proposed Thiola EC 100-mg tablets (batch 13Xl 7) and 300-mg tablets (pivotal BE batch 02Xl 7), obtained in buffer stage

100.0

90.0

80.0

70.0

"O 60.0 Q)

..2 50.0 0

"' "' 40.0 0 ~ 0 30.0

20.0

10 .0

0.0 0 20 40

Time (Minutes)

60 80

..,.__ Batch 13X17 - 100 mg Tablets

-+-Batch 02X17 - 300 mg Tablets

Note: this Reviewer calculated the similarity factor ([2) between the 100 and 300 mg tablets is 56.8.

Dissolution data of 8 registration batches (100 mg tablets, batch# OlXl 7, 12Xl 7, 13Xl 7; 300 mg tablets, pivotal BE 02Xl 7, batch# 14Xl 7, 15Xl 7, 34Xl 7-C, 35Xl 7-C) at 2 hours in acid stage, and single time point of 45 minutes in buffer stage were provided at various stability conditions (e.g., long-term 25±2°C/60±5% RH, up to 12 months; intermediate 30±2°C/65±5% RH, up to 12 months; and accelerated 40±2°C/75±5% RH, up to 6 months).

One batch of the product (300 mg, batch# 15Xl 7) was observed to have mean dissolution >rr4~ in buffer stage at 45 minutes at initial stability time point, which was much lower compared to the dissolution for other drug product batches. Additional data and justification for this batch were requested on 02/14/2019 (see Appendix 1, Biopharmaceutics 2nd IR).

In the response submitted on 02/28/2019, the Applicant also confirmed the observation of <11>r4 mean dissolution of this specific batch at initial, and increased dissolution -======bn41 at 45 minutes in buffer stage) in the later time during various stability

testing, however, the Applicant could not provide the explanation of this observation. The out-of-specification result at the initial stability time point is likely due to variations in sampling and analytical procedure at this specific time point.

Therefore, the following data-driven acceptance criteria of "acid stage: NMT~% in 2 hours: buffer stage: NLT(bH~l% (Q) in 45 minutes" for the proposed Thiola EC Tablets 100 and 300 mg are recommended to the Applicant on 03/08/2019 (see Appendix 1, Biopharmaceutics 3rd IR).

Page 10of19

QUALITY ASSESSMENT

In the response submitted on 03/14/2019, the Applicant accepted the above recommendation, and revised the dissolution acceptance criteria in related sections accordingly.

Therefore, the dissolution method (USP apparatus I basket, 100 rpm, acid stage: 900 mL ofO.l N HClfor 2 hours, buffer stage: 9 0 pL of 50 mM potassium phosphateLRi,H 6.8) and acceptance criteria [acid stage: NM (b)( >1. ofor 2 hours, buffer stage: NLT c~U (Q) in 45 minutes] for the drug product have been reviewed and found acceptable.

4. In Vitro Alcohol Dose Dumpin2 Study The in vitro alcohol dose dumping studies of the proposed drug product were conducted in O.lN HCl with 0% (control), 5%, 10%, 20%, and 40% alcohol. As presented in Figures 3 and 4 below, increased dissolution in the presence of alcohol was observed for both 100 mg and 300 mg tablets. The in vitro alcohol dumping of the proposed enteric coating tablets has been communicated with the Office of Clinical Pharmacology, who will address the issue in the drug product labeling.

Figure 3: The Dissolution Profiles of the Proposed Thiola EC 100-mg Tablet (Batch # OlXl 7) in O. lN HCl Containing Different Concentrations of Alcohol

120

100

" ~ so --

~ i:l 60

40

20

0 20

p- I

40 60 80 100 120 n me (minutes)

.....-O%EtOH

--5%Et0H

--10%EtOH

- 20%EtOH

-+-40%EtOH

Figure 4: The Dissolution Profiles of the Proposed Thiola EC 300-mg Tablet (Batch# 02Xl 7) in O. lN HCl Containing Different Concentrations of Alcohol

100

90

80

70

al 2 60 0 IJ)

50 .!11 0 ~ 0 40

30

20

10

0

--o%Et0H

..._5%Et0H

- 10%EtOH

+------------------7"'---- 20%Et0H .._..40%EIOH

0 20 40 60 80 100 120 140 Time (minutes)

Page 11of19

QUALITY ASSESSMENT

5. Biowaiver Request In order to support the biowaiver request for the lower strength (100 mg) of the proposed drug product, the Applicant provided the following supportive data and information:

(1) Two pharmacokinetics studies in healthy subjects, which are relative bioavailability/bioequivalence (BA/BE) study MPC-Tiopronin-002 and food effect study MPC-Tiopronin-001. These pivotal PK studies are reviewed by the Office of Clinical Pharmacology (OCP). In summary, (i) the proposed Tiopronin EC 300 mg (test) and 3 Thiola 100-mg tablets (LD) were equivalent for tiopronin exposure (AUC); (ii) the tiopronin EC 300-mg tablet attained <80% of mean peak exposure (Cmax) of the 3 Thiola 100-mg formulation; (iii) since exposure is more clinically relevant for efficacy than Cmax, no dose adjustment is proposed for Tiopronin EC tablets. Overall, the BA/BE study results of the proposed higher strength (300 mg) product are acceptable from OCP perspective.

Q) As enteric coating formula resented in the Table 10 below

Table 10: The composition of the proposed drug product

Ingredient

EC = Enteric-coated.

Thlo la EC Tablets 100 mg

Th lola EC Tablets 300 mg

Function mg!Tablet % wfw mgfTablet % wfw ~1-----------------.(b)(~)-

(b) (4J

(b)(~Y

(3) Per the Applicant, the proposed Thiola EC 100- and 300-mg Tablets are both produced using the same manufacturing process and the same excipients and produced from the same manufacturing site.

(4) As presented in Figure 2, the dissolution profiles for 100 mg tablets is comparable to that of the pivotal BE batch of 300 mg tablets.

Page 12of19

QUALITY ASSESSMENT

(5) The Applicant provided the pharmacokinetic data from the nonclinical and clinical studies to support the PK linearity, which were summarized in the following Figures 5 and 6.

Figure 5: Graphs of Estimated AUCo-oo in 8 Healthy Beagle Dogs Over a 100- to 375-mg Tiopronin Dose Range

12 11.8

- 11.6 -e 11.4

~ 11.2

E.. 11 ~ 10.8 ~ 10.6 ~ 10.4

10.2

y: 1.1106x+S.076 R' • 0 .7542

...... ············ .....

4.5 4.75

Dog study

.... ~

5

... ··· .... ···

5.25

• . . ... ······· • . .. ········· ... ······· ....

•

5.5 5.75

Ln Dose (mg)

Note: Plot of Ln AUCo_,,, versus Ln dose

Dog study

160000

140000

~ 120000

~ 100000

'! 80000 e. ~ 60000

<t 40000

20000

0 +-~~~~~~~~~~~~~~~~

6

0 so 100 150 200 250 300 350 400

Dose (mg)

Note: Plot of AUCo_,,, versus dose

Page 13of19

QUALITY ASSESSMENT

Figure 6: Graphs of AUCo-oo Computed Across Pharmacokinetic Studies for Tiopronin in 8 Clinical Studies and MPC-Tiopronin-002 for Ascending Tiopronin Doses

11

10.8

~ 10.6 .... ~ 10.4

y = 0.8139x • 5.4083 R' =0.3451

Clinical PK

• .. c: 10.2 5.

10 u ::>

• • ............ , .................... ··· ...........

< 9.8 c: .... 9.6

9.4

9.2 5.2

····· ············· • •

5.4 5.6

• • 5.8

Ln Dose (mg)

Note: Plot of Ln AUCo.,,, versus Ln dose

Clinical PK

60000

50000

i 40000 'tio c: 30000 5. u ~ 20000

10000

0 100 200

Note: Plot of AUCo.,,, versus dose

300

Dose (mg)

6

400

• ····· •

6.2 6.4

500 600

According to OCP' assessment (OCP presentation in mid-cycle meeting dated 01/31/2019), linear PK is evident over a dose range of 100 to 3 7 5 mg in dogs. Data from clinical studies exhibit close to dose proportional PK across the dose range of 200 to 500 mg. Since it is not expected to have a non-linear PK going towards lower dose, 100 mg dose in humans will mostly fall within linear range. Therefore, OCP considered a linear PK is demonstrated between the two strengths of 100 and 300 mg. This Reviewer agreed with this assessment.

When taking into the totality of the data/information, this Reviewer determined that biowaiver for the proposed Thiola ™ enteric-coated (EC) Tablets, 100 mg, can be granted per CFR 320.22(d)(2).

Page 14of19

QUALITY ASSESSMENT

Page 15of19

QUALITY ASSESSMENT

7. Delayed-Release Claim The following information/data support the delayed-release claim of the proposed drug product:

(1) The composition of the proposed drug product has enteric coatin (b)(4Y

(b) (45

(2) The proposed enteric-coated tablets are designed to have minimal drug release in the acidic environment of the stomach, but dissolve quickly in the intestine and upper bowel.

(3) The two-stag (bjl]1 vitro dissolution data demonstrated that the proposed drug product

has no more tha % drug release in acid stage for 2 hours, and immediate and complete drug release in buffer stage.

(4) The proposed Thiola enteric-coating tablets (300 mg) showed delayed Tmax compared to the Thiola immediate release (IR) tablets (mean Tmax: 2.8 hours vs. 1.2 hours; median Tmax: 3 hours vs. 1 hour), as presented in the following Figure 8.

Page 16of19

QUALITY ASSESSMENT

Figure 8: Mean (SE) Total Tiopronin Concentration Over 0 to 72 Hours by Replicate, Per-Protocol Population (from Study MPC-Tiopronin-002)

8500

7500

I 6500

5500 § " ~ 4500 ~ 0 u c

~ &

3500

F c .. ., :<

2500

1500

0 4 6 10

Time(hr}

A • • Tloprooln EC 300 mg RepUuite I (N - 37) -tr--'"!\- --:· T~ronin EC 300 mg R~pUcat@ 2 (N = 33)

- 3 Th Iola IR 1 oo mg ReplX:ate 1 (N • 36) - ----.----A· 3 Thiola IR 100 mg RepEcate 2 {N • 33)

"ate: Mean (SE) observed tiopronin concentrations are plotted by nominal time point.

12

Overall, the in vitro and in vivo data support the delayed release claim of the proposed Thiola enteric-coating tablets compared to the Thiola immediate release tablets, indicating the proposed drug product will transit from the stomach into the intestine before drug dissolution and absorption.

Page 17 of19

QUALITY ASSESSMENT

APPENDIX 1 BIO PHARMACEUTICS INFORMATION REQUESTS

1. Biopharmaceutics pt IR (conveyed on 11/08/2018):

1) To support the biowaiver request for the 100-mg strength, we recommend you generate the complete dissolution profile data (individual, mean, RSD, range, and n= 12 units/batch) by including more sampling times in buffer stage (e.g., at 5, 10, 15, 20, 30, 45, and 60 minutes after the start of buffer stage) for both strengths of your proposed drug product from the unexpired registration and/or pivotal clinical batches [e.g. 100 mg tablets, batch OlXl 7, 12X17, 13X17; 300 mg tablets, 02X17 (pivotal clinical batch), 14X17, 15X17, 34Xl7-C, 35X17-C]. Please submit the dissolution profile data and similarity testing results obtained with appropriate statistical tests (e.g.,j2 values) comparing the 100-mg and 300-mg strengths of your proposed drug products.

2) We recommend you include the testing/data supporting the discriminating ability of the proposed dissolution method with respect to critical formulation variables and process parameters. Please refer to the Additional Biopharrnaceutics Comments on the dissolution test in the meeting minutes dated May 1, 2017 (cross-referenced to NDA 019569). In general, the testing conducted to demonstrate the discriminating ability of the proposed dissolution method should compare the dissolution profiles of the reference (target) drug product and the test products that are intentionally manufactured with meaningful variations for the most relevant critical material attributes, critical formulation variables (e.g., the enteric coating), and critical process parameters (e.g., ± 10-20% change to the specified values or ranges for these variables). Please submit the dissolution profile data and similarity testing results obtained with appropriate statistical tests (e.g.,j2 values) comparing the test and reference drug products.

3) Be ad~~tl~ that the selection of the acceptance criterion time point at buffer stage should be where Q Do dissolution/release occurs. The setting of acceptance criterion is based on average dissolution data of the above pivotal clinical batch and/or registration batches at USP Stage 2 testing (n=l2); therefore, sometimes Stage 2 testing and occasional Stage 3 testing (n=24) are needed.

2. Biopharmaceutics 2nd IR (conveyed on 02/14/2019):

We noticed that one batch of your product (300 mg, Batch # 15X17) had mean dissolution of r (blT4» in buffer stage at 45 minutes at initial stability time point, which is much lower compared to the dissolution for other drug product batches. Please provide for this specific batch (a) the complete multi-point dissolution profile data (individual, mean, range, RSD, n=l2) for different stability pulling time points under all stability conditions, if available, and (b) the justification/explanation for lower tha >rr4 drug release at initial time but increased dissolution at later time in stability testing.

Please note, in general, the multi-point dissolution profile data (n=l2) from the pivotal clinical or BE study batches (and primary registration batches) are used for the setting of the dissolution acceptance criteria of the proposed drug product (i.e., sampling time points and acceptance limits). Your proposed dissolution acceptance criteria will be further evaluated, when the additional data/information requested above is submitted.

Page 18of19

QUALITY ASSESSMENT

3. Biopharmaceutics 3rd IR (conveyed on 03/08/2019):

Based on the provided dissolution data for the pivotal BNBE batch (300 mg Tablets, 02Xl 7), ~f. recommends that you implent(bfci1the dissolution acceptance criteria of "Acid sta~e: NMT

in 2 hours: Buffer stage: NL I (Q) in 45 minutes" for your proposed Thiola EC Tablets I 00 and 300 mg. Update the dissol ion acceptance criterion in the drug product release and stability specifications and other relevant sections of your NDA accordingly. All commercial batches are expected to meet the revised dissolution acceptance criteria by using the dissolution QC method in your stability program through your proposed expiry period. If dissolution failures are observed on stability, the failures should be described. Discuss any corrective actions to avert such dissolution failures and provide a new batch to demonstrate correction of the issue, if needed.

Page 19of19

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