CENTER FOR DRUG EVALUATION AND RESEARCH...2018/12/21 · 4 Per 21 CFR 600.3(bb) Container (referred to also as “final container”) is the immediate unit, bottle, vial, ampule,

CENTER FOR DRUG EVALUATION AND

RESEARCH

APPLICATION NUMBER:

761105Orig1s000

PRODUCT QUALITY REVIEW(S)

DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

Food and Drug Administration Center for Drug Evaluation and Research WO Bldg. 51,10903 New Hampshire Ave.

Silver Spring, MD 20993

Date: December 21, 2018 To: Administrative File, STN 761105/0 From: Michael Shanks, Biologist, CDER/OPQ/OPF/DIA Endorsement: Zhihao Peter Qiu, Ph.D., Branch Chief, CDER/OPQ/OPF/DIA Subject: Original BLA US License: 1889 Applicant: AbbVie, Inc.

Mfg. Facility: Drug Substance:

Drug Product:

Product: Risankizumab, Sterile Solution for subcutaneous injection Strength: 90 mg/vial Indication: Risankizumab for the treatment of adults with moderate to severe plaque

psoriasis. Goal Date: 4/23/2019

RECOMMENDATION

This submission is recommended for approval from a facility review perspective.

SUMMARY Risankizumab is a humanized antibody of the IgG1 isotype , directed against IL-23p19. The molecule is composed of two heterodimers, each composed of a heavy chain (HC) and a light chain (LC). The four chains of the antibody molecule are linked together by disulfide bonds. Risankizumab drug product (DP) is provided 75 mg/0.83 mL Pre-Filled Syringes are supplied as a 90 mg/mL sterile solution for subcutaneous administration. The drug product is supplied in a 1 mL single-use syringe glass, 29 G stainless steel needle fitted with a needle shield and

stopper) with a nominal filling volume of 0.83 mL. The drug product is a , preservative-free solution.

The subject BLA proposes commercial manufacture of Risankizumab drug substance (DS) and DP at .

The scope of this review is primarily for the information included in Modules 3.2.S.2.1. Manufacturers, 3.2.P.3.1. Manufacturers, and 3.2.A.1. Facilities and Equipment of the BLA. As part of this review cycle, a pre-approval inspection (PAI) was conducted at

DS manufacturing facility from .

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

7 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

CONCLUSION Adequate descriptions of the facilities, equipment, environmental controls, cleaning and contamination control strategy were provided for

, proposed for Risankizumab DS and DP manufacture. All proposed manufacturing and testing facilities are acceptable based on their currently acceptable CGMP compliance status and recent relevant inspectional coverage. This submission is recommended for approval from a facility.

_______________________________ Michael Shanks Biologist OPF Division of Inspectional Assessment Branch 1

(b) (4)

(b) (4)

_______________________________ Zhihao Peter Qiu, Ph.D. Branch Chief OPF Division of Inspectional Assessment Branch 1

Center for Drug Evaluation and Research Office of Pharmaceutical Quality Office of Biotechnology Products

Page 1 of 9

LABELS AND LABELING REVIEW

Date of review: April 4, 2019

Reviewer: Vicky Borders-Hemphill, PharmD Labeling Review Specialist Office of Biotechnology Products (OBP)

Through: Milos Dokmanovic, PhD, Product Quality Reviewer OBP/Division of Biotechnology Review and Research I

Application: BLA 761105

Applicant: AbbVie, Inc.

Submission Date: April 23, 2018

Product: Skyrizi (risankizumab-rzaa)

Dosage form(s): injection

Strength and Container-Closure:

75 mg/0.83 mL in a single-dose prefilled syringe

Purpose of review: The Applicant submitted a biologics license application for Agency review

Recommendations: The prescribing information/medication guide/instructions for use (submitted on April 2, 2019) and container labels and carton labeling (submitted on March 19, 2019) were reviewed and found to be acceptable (see Appendix C) from an OBP labeling perspective.

Page 2 of 35

Materials Considered for this Label and Labeling Review

Materials Reviewed Appendix Section

Proposed Labels and Labeling A

Evaluation Tables B

Acceptable Labels and Labeling C

n/a = not applicable for this review DISCUSSION We evaluated the proposed labels and labeling for compliance with applicable requirements in the Code of Federal Regulations (see Appendix B). CONCLUSION The prescribing information/medication guide/instructions for use (submitted on April 2, 2019) and container labels and carton labeling (submitted on March 19, 2019) were reviewed and found to be acceptable (see Appendix C) from an OBP labeling perspective. APPENDICES Appendix A: Proposed Labeling Prescribing Information/Medication Guide/Instructions for Use (submitted on August 24, 2018 \\cdsesub1\evsprod\bla761105\0006\m1\us\114-labeling\draft\labeling\uspi-0214.doc) Container Labels (submitted on April 23, 2018)

(b) (4)

6 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page

Page 9 of 35

Appendix B: Evaluation Tables Evaluation Tables: Label1,2 and Labeling3 Standards

Container4 Label Evaluation

Proper Name (for container of a product capable of bearing a full label)

Acceptable

21 CFR 610.60, 21 CFR 201.50, 21 CFR 201.10

☐ Yes

☐ No

☒ N/A

Recommended labeling practices (placement of dosage form below the proper name):

☐ Yes

☐ No

☒ N/A

Manufacturer name, address, and license number (for container of a product capable of bearing a full label)

Acceptable

21 CFR 610.60 (a)(2), 21 CFR 201, 21 CFR 201.1(a), 21 CFR 201.1(h)(5), 21 CFR 201.1(h)(6), 21 CFR 201.100(e)

☐ Yes

☐ No

☒ N/A

Recommended labeling practices (using the following qualifying statement “Manufactured by:”)

☐ Yes

☐ No

☒ N/A

Lot number or other lot identification (container capable of bearing a full label shall bear)

Acceptable

21 CFR 610.60, 21 CFR 201.18, 21 CFR 201.100 ☐ Yes

☐ No

☒ N/A

Expiration date (container capable of bearing a full label shall bear) Acceptable

21 CFR 610.60, 21 CFR 201.17 ☐ Yes

☐ No

☒ N/A

Recommended labeling practices (the expiration date appears on all aspects of the package)

☐ Yes

☐ No

☒ N/A

Product Strength Acceptable

1 Per 21 CFR 1.3(b) Label means any display of written, printed, or graphic matter on the immediate container of any article, or any such matter affixed to any consumer commodity or affixed to or appearing upon a package containing any consumer commodity. 2 Per CFR 600.3(dd) Label means any written, printed, or graphic matter on the container or package or any such matter clearly visible through the immediate carton, receptacle, or wrapper. 3 Per 21 CFR 1.3(a) Labeling includes all written, printed, or graphic matter accompanying an article at any time while such article is in interstate commerce or held for sale after shipment or delivery in interstate commerce. 4 Per 21 CFR 600.3(bb) Container (referred to also as “final container”) is the immediate unit, bottle, vial, ampule, tube, or other receptacle containing the product as distributed for sale, barter, or exchange.

Page 10 of 35

21 CFR 201.10(d)(1), 21 CFR 201.100(b)(4)

Yes

☐ No

☐ N/A

Recommended labeling practices (expression of strength for injectable drugs) References: Draft Guidance Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 line 176, USP General Chapters: <7> Labeling

Yes

☐ No

☐ N/A

Multiple dose containers (recommended individual dose) Acceptable

21 CFR 610.60, 21 CFR 201.55 ☐ Yes

☐ No

☒ N/A

Statement: “Rx only” Acceptable

21 CFR 610.60, 21 CFR 201.100 Yes

☐ No

☐ N/A

Recommended labeling practices: prominence of Rx Only

Yes

☐ No

☐ N/A

Medication Guide Acceptable

21 CFR 610.60, 21 CFR 208.24

☐ Yes

☐ No

☒ N/A

Comment/Recommendation: partial label No Package for container Acceptable

21 CFR 610.60 ☐ Yes

☐ No

☒ N/A

Proper Name (for container bearing a partial label) Acceptable

21 CFR 610.60, 21 CFR 201.10 Yes

☐ No

☐ N/A

Manufacturer name, address, and license number (for container bearing a partial label)

Acceptable

21 CFR 610.60, 21 CFR 201.10 Yes

☐ No

☐ N/A

Recommended labeling practices: (U.S license number for container bearing a partial label)

Yes

☐ No

☐ N/A

Lot number or other lot identification (for container bearing a partial label)

Acceptable

Page 11 of 35

21 CFR 610.60, 21 CFR 201.10 Yes

☐ No

☐ N/A

Expiration date (for container bearing a partial label) Acceptable

21 CFR 201.17 Yes

☐ No

☐ N/A

No container label Acceptable

21 CFR 610.60 ☐ Yes

☐ No

☒ N/A

Ferrule and cap overseal (for vials only) Acceptable

Recommended labeling practices Reference: United States Pharmacopeia (USP), General Chapters: <7> Labeling (Ferrules and Cap Overseals)

☐ Yes

☐ No

☒ N/A

Visual inspection Acceptable

21 CFR 610.60(e) Yes

☐ No

☐ N/A

NDC numbers Acceptable

21 CFR 201.2, 21 CFR 207.35 Yes

☐ No

☐ N/A

Route of administration Acceptable

21 CFR 201.5, 21 CFR 201.100

Yes

☐ No

☐ N/A

Recommended labeling practices: route of administration statement to appear after the strength statement on the principal display panel

Yes

☐ No

☐ N/A

Preparation instructions Acceptable

21 CFR 201.5 ☐ Yes

☐ No

☒ N/A

Recommended labeling practice Reference: Draft Guidance Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 (lines 426-430)

☐ Yes

☐ No

☒ N/A

Package type term Acceptable

Page 12 of 35

Recommended labeling practices References: Guidance for Industry: Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use. USP chapter <659> Packaging and Storage Requirements

☐ Yes

☐ No

☒ N/A

Misleading statements Acceptable

21 CFR 201.6 ☐ Yes

☐ No

☒ N/A

Prominence of required label statements Acceptable

21 CFR 201.15 Yes

☐ No

☐ N/A

Spanish-language (Drugs) Acceptable

21 CFR 201.16 ☐ Yes

☐ No

☒ N/A

FD&C Yellow No. 5 and/or FD&C Yellow No. 6 Acceptable

21 CFR 201.20 ☐ Yes

☐ No

☒ N/A

Phenylalanine as a component of aspartame Acceptable

21 CFR 201.21 ☐ Yes

☐ No

☒ N/A

Sulfites; required warning statements Acceptable

21 CFR 201.22

☐ Yes

☐ No

☒ N/A

Bar code label requirements Acceptable

21 CFR 201.25, 21 CFR 610.67 Yes

☐ No

☐ N/A

Recommended labeling practices: Guidance for Industry: Bar Code Label Requirements Questions and Answers, August 2011, Draft Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 (lines 511-512), lines 780-786)

Yes

☐ No

☐ N/A

Strategic National Stockpile (exceptions or alternatives to labeling requirements for human drug products)

Acceptable

Page 13 of 35

21 CFR 610.68, 21 CFR 201.26 ☐ Yes

☐ No

☒ N/A

Net quantity Acceptable

21 CFR 201.51 Yes

☐ No

☐ N/A

Recommended labeling practices: References: Draft Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors (line 461- 463) , Guidance: Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products, June 2015 (line 68, 93-99), USP General Chapters <1151> Pharmaceutical Dosage Forms (Excess volume in injections).

Yes

☐ No

☐ N/A

Usual dosage statement Acceptable

21 CFR 201.55, 21 CFR 201.100 ☐ Yes

☐ No

☒ N/A

Comment/Recommendation: container label lacks space

Inactive ingredients Acceptable

21 CFR 201.100 ☐ Yes

☐ No

☒ N/A


Recommended labeling practice References: USP General Chapters <1091> Labeling of Inactive Ingredients

☐ Yes

☐ No

☒ N/A


Storage requirements Acceptable

Recommended labeling practices References: USP General Chapters <7> Labeling, USP General Chapters <659> Packaging and Storage Requirements

☐ Yes

☐ No

☒ N/A


Dispensing container Acceptable

21 CFR 201.100

☐ Yes

☐ No

☒ N/A

Page 14 of 35

Package5 Label Evaluation Blister

Proper name Acceptable

21 CFR 610.61, 21 CFR 201.50, 21 CFR 201.10 Yes

☐ No

☐ N/A

Manufacturer name, address, and license number Acceptable

21 CFR 610.61, 21 CFR 201.1(a), 21 CFR 201.1(h)(5), 21 CFR 201.1(h)(6), 21 CFR 201.100(e)

Yes

☐ No

☐ N/A

Recommended labeling practices Reference: OPQ-OBP-RP-014

Yes

☐ No

☐ N/A

Lot number or other lot identification Acceptable

21 CFR 610.61

Yes

☐ No

☐ N/A

Expiration date Acceptable

21 CFR 610.61, 21 CFR 201.17

Yes

☐ No

☐ N/A

Preservative Acceptable

21 CFR 610.61 Yes

☐ No

☐ N/A

Comment/Recommendation: If no preservative, ensure “No preservative” appears on the blister labeling per 21 CFR 610.61(e). The applicant revised as requested Number of containers Acceptable

21 CFR 610.61 ☐ Yes

☐ No

☒ N/A

Strength/volume Acceptable

21 CFR 610.61, 21 CFR 201.10, 21 CFR 201.100 Yes

☐ No

☐ N/A

Recommended labeling practices Yes

5 Per 21 CFR 600.3(cc) Package means the immediate carton, receptacle, or wrapper, including all labeling matter therein and thereon, and the contents of the one or more enclosed containers. If no package, as defined in the preceding sentence, is used, the container shall be deemed to be the package. Thus, this includes the carton, prescribing information, and patient labeling.

Page 15 of 35

References: Draft Guidance Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 line 176, USP General Chapters: <7> Labeling

☐ No

☐ N/A

Storage temperature/requirements Acceptable

21 CFR 610.61 Yes

☐ No

☐ N/A

Recommended labeling practices Reference: USP General Chapters: <7> Labeling

Yes

☐ No

☐ N/A

Handling: “Do Not Shake”, “Do not Freeze” or equivalent Acceptable

21 CFR 610.61 Yes

☐ No

☐ N/A

Comment/Recommendation: Ensure instructions for handling as appropriate appear on the carton labeling per 21 CFR 610.61 (i). Add the statement “Do Not Shake” following the “Do Not Freeze” statement. The applicant revised as requested Multiple dose containers (recommended individual dose) Acceptable

21 CFR 610.61 ☐ Yes

☐ No

☒ N/A


21 CFR 610.61, 21 CFR 201.5, 21 CFR 201.100

Yes

☐ No

☐ N/A

Recommended labeling practices (route of administration statement recommended locations)

Yes

☐ No

☐ N/A

Known sensitizing substances Acceptable

21 CFR 610.61 ☐ Yes

☐ No

☒ N/A


21 CFR 610.61, 21 CFR 201.100 ☐ Yes

☐ No

☒ N/A

Recommended labeling practices References: USP General Chapters <1091> Labeling of Inactive Ingredients, USP General Chapters <7> Labeling

☐ Yes

☐ No

☒ N/A

Source of the product Acceptable

Page 16 of 35

21 CFR 610.61 ☐ Yes

☐ No

☒ N/A

Minimum potency of product Acceptable

21 CFR 610.61 Yes

☐ No

☐ N/A

Comment/Recommendation: Add the statement “No U.S. standard of potency” per 21CFR 610.61 (r). The applicant revised as requested

Rx only Acceptable

21 CFR 610.61, 21 CFR 201.100 Yes

☐ No

☐ N/A


Yes

☐ No

☐ N/A

Divided manufacturing Acceptable

21 CFR 610.63 (Divided manufacturing responsibility to be shown) ☐ Yes

☐ No

☒ N/A

Distributor Acceptable

21 CFR 610.64 (Name and address of distributor) ☐ Yes

☐ No

☒ N/A

Bar code Acceptable

21 CFR 610.67, 21 CFR 201.25 Yes

☐ No

☐ N/A

Recommended labeling practices: References: Guidance for Industry: Bar Code Label Requirements Questions and Answers, August 2011, Draft Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 (lines 511-512), lines 780-786)

Yes

☐ No

☐ N/A


Acceptable

21 CFR 610.68, 21 CFR 201.26 ☐ Yes

☐ No

☒ N/A


21 CFR 201.2, 21 CFR 207.35 Yes

Page 17 of 35

☐ No

☐ N/A


21 CFR 201.5 ☐ Yes

☐ No

☒ N/A

Recommended labeling practices: References: Draft Guidance Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 (lines 426-430), USP General Chapters <7> Labeling

☐ Yes

☐ No

☒ N/A



Yes

☐ No

☐ N/A

Comment/Recommendation: The appropriate package-type term for this product is “single-dose”. A single-dose container is a container of a sterile medication for parenteral administration (injection or infusion) that is not required to meet the antimicrobial effectiveness testing requirements. A single-dose container is designed for use with a single patient as a single injection/infusion. Use of the term “single-dose” container does not imply the entire contents of the container constitute a single dose. In some instances, a single-dose container may contain more drug than is required for a single dose or multiple vials may be needed to obtain a single dose. Revise to the appropriate package type term as follows: “Single-dose Prefilled Syringe”. Applicant’s response: A full single dose of risankizumab (150 mg) requires the administration of the contents of two 75 mg/0.83 mL pre-filled syringes. AbbVie is concerned that use of the "single-dose" package term associated with one pre-filled syringe will lead to confusion and will increase the opportunity for use error (e.g., result in using only one pre-filled syringe and under-dosing). AbbVie contends that the current risankizumab dosing requirements and aforementioned use error concerns are not adequately addressed in FDA's guidance. The draft labels included in the original BLA with the terminology are supported by human factors validation demonstrating that the IFU and carton labels included in the initial BLA submission effectively control the use error (Report located in BLA 761105, eCTD Sequence 0001, Module 5.3.5.4). As a result, the labeling has not been revised as requested by FDA. OBP labeling response: In the past, the term “ container has been used by FDA to describe a package type that contained multiple doses but was intended to

(b) (4)

(b) (4)

Page 18 of 35

be used in a single patient. Unfortunately, the term “ ” was also inappropriately used as if it were interchangeable with the term “single-dose” which was not the Agency’s original intent. To address this confusion regarding the terminology, the Agency has retired the term “ . A single-dose container is designed for use with a single patient as a single injection/infusion. The package type term “single-dose” applies to your product. We acknowledge that two syringes are needed to obtain a dose. We also note the placement of the statement “For a full dose, 2 injections are required, one after the other” is prominently displayed multiple times on

the carton labeling; there are instructions for the healthcare provider to inform patients in the prescribing information, and instructions for the patient in the Instructions for Use. We recommend additional labeling strategies to address your concern, that patients will use only one pre-filled syringe and under-dose, while maintaining consistent and correct use of package type terms among FDA approved products. For the blister (printmat):

1. Consider revising the statement from “ ” to read “For a 150 mg dose, two 75 mg syringes are

required, inject one syringe after the other” 2. Revise the package type term appearing at the top of the blister underneath the

NDC number from “ ” to read “1 x 0.83 mL single-dose prefilled syringe”

3. Revise the bulleted statement from “ ” to read “Discard the prefilled syringe after use. Do not reuse.”

The applicant revised as requested Misleading statements Acceptable

21 CFR 201.6 ☐ Yes

☐ No

☒ N/A


21 CFR 201.15 Yes

☐ No

☐ N/A


21 CFR 201.16 ☐ Yes

☐ No

☒ N/A


21 CFR 201.20 ☐ Yes

☐ No

☒ N/A


(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Page 19 of 35

21 CFR 201.21 ☐ Yes

☐ No

☒ N/A


21 CFR 201.22 ☐ Yes

☐ No

☒ N/A


21 CFR 201.51 Yes

☐ No

☐ N/A


21 CFR 201.55, 21 CFR 201.100 Yes

☐ No

☐ N/A


21 CFR 201.100 ☐ Yes

☐ No

☒ N/A


21 CFR 610.60, 21 CFR 208.24 ☐ Yes

☐ No

☒ N/A

Comment/Recommendation: see carton

Carton

Proper name Acceptable

21 CFR 610.61, 21 CFR 201.50, 21 CFR 201.10 Yes

☐ No

☐ N/A

Manufacturer name, address, and license number Acceptable

21 CFR 610.61, 21 CFR 201.1(a), 21 CFR 201.1(h)(5), 21 CFR 201.1(h)(6), 21 CFR 201.100(e)

Yes

☐ No

☐ N/A

Recommended labeling practices: OPQ-OBP-RP-014

Yes

☐ No

☐ N/A

Lot number or other lot identification Acceptable

21 CFR 610.61

Yes

☐ No

☐ N/A

Page 20 of 35

Comment/Recommendation: Ensure lot number appears on the label per 21 CFR 610.61 (c). The applicant confirmed Expiration date Acceptable

21 CFR 610.61, 21 CFR 201.17

Yes

☐ No

☐ N/A

Comment/Recommendation: Ensure the expiration date appears on the label per 21 CFR 610.61 (d). The applicant confirmed Preservative Acceptable

21 CFR 610.61 Yes

☐ No

☐ N/A

Number of containers Acceptable

21 CFR 610.61 Yes

☐ No

☐ N/A

Comment/Recommendation: Revise the following statement “ ” to read as follows to include the number of syringes per carton: “2 x 0.83 mL

single-dose prefilled syringes” Applicants’ response: Abbvie has not revised the statement (see package type term comment) OBP labeling response: See package type term response. Revise the statement appearing at the top of all panels from “ ” to read “2 x 0.83 mL prefilled syringes” to include the net quantity statement. The applicant revised as requested Strength/volume Acceptable

21 CFR 610.61, 21 CFR 201.10, 21 CFR 201.100 Yes

☐ No

☐ N/A

Recommended labeling practices References: Draft Guidance Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 line 176, USP General Chapters: <7> Labeling

Yes

☐ No

☐ N/A

Storage temperature/requirements Acceptable

21 CFR 610.61 Yes

☐ No

☐ N/A

Recommended labeling practices Reference: USP General Chapters: <7> Labeling

Yes

☐ No

(b) (4)

(b) (4)

Page 21 of 35

☐ N/A

Handling: “Do Not Shake”, “Do not Freeze” or equivalent Acceptable

21 CFR 610.61 Yes

☐ No

☐ N/A

Comment/Recommendation: Ensure instructions for handling as appropriate appear on the carton labeling per 21 CFR 610.61 (i). Add the statement “Do Not Shake” following the “Do Not Freeze” statement. The applicant revised as requested Multiple dose containers (recommended individual dose) Acceptable

21 CFR 610.61 ☐ Yes

☐ No

☒ N/A


21 CFR 610.61, 21 CFR 201.5, 21 CFR 201.100

Yes

☐ No

☐ N/A

Recommended labeling practices (route of administration statement recommended locations)

Yes

☐ No

☐ N/A

Known sensitizing substances Acceptable

21 CFR 610.61 ☐ Yes

☐ No

☒ N/A


21 CFR 610.61, 21 CFR 201.100 Yes

☐ No

☐ N/A

Recommended labeling practices References: USP General Chapters <1091> Labeling of Inactive Ingredients, USP General Chapters <7> Labeling

Yes

☐ No

☐ N/A Comment/Recommendation: Revise components of the ingredient statement as follows: “Each sterile single-dose prefilled syringe contains..” and “Sorbitol….34 mg” and “Water for Injection, USP” See package type term response. The applicant revised as requested Source of the product Acceptable

21 CFR 610.61 ☐ Yes

☐ No

☒ N/A

Minimum potency of product Acceptable

21 CFR 610.61 Yes

Page 22 of 35

☐ No

☐ N/A

Rx only Acceptable

21 CFR 610.61, 21 CFR 201.100 Yes

☐ No

☐ N/A


Yes

☐ No

☐ N/A

Divided manufacturing Acceptable

21 CFR 610.63 (Divided manufacturing responsibility to be shown) ☐ Yes

☐ No

☒ N/A

Distributor Acceptable

21 CFR 610.64 (Name and address of distributor) ☐ Yes

☐ No

☒ N/A

Bar code Acceptable

21 CFR 610.67, 21 CFR 201.25 Yes

☐ No

☐ N/A

Recommended labeling practice References: Guidance for Industry: Bar Code Label Requirements Questions and Answers, August 2011, Draft Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 (lines 511-512), lines 780-786)

Yes

☐ No

☐ N/A


Acceptable

21 CFR 610.68, 21 CFR 201.26 ☐ Yes

☐ No

☒ N/A


21 CFR 201.2, 21 CFR 207.35 Yes

☐ No

☐ N/A


21 CFR 201.5 Yes

☐ No

☐ N/A

Recommended labeling practices Yes

☐ No

Page 23 of 35

References: Draft Guidance Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 (lines 426-430), USP General Chapters <7> Labeling

☐ N/A



Yes

☐ No

☐ N/A

Comment/Recommendation: Revise to the appropriate package type term as follows: “Single-dose Prefilled Syringe” wherever ” appears on the carton labeling. Applicant’s response: A full single dose of risankizumab (150 mg) requires the administration of the contents of two 75 mg/0.83 mL pre-filled syringes. AbbVie is concerned that use of the "single-dose" package term associated with one pre-filled syringe will lead to confusion and will increase the opportunity for use error (e.g., result in using only one pre-filled syringe and under-dosing). AbbVie contends that the current risankizumab dosing requirements and aforementioned use error concerns are not adequately addressed in FDA's guidance. The draft labels included in the original BLA with the terminology are supported by human factors validation demonstrating that the IFU and carton labels included in the initial BLA submission effectively control the use error (Report located in BLA 761105, eCTD Sequence 0001, Module 5.3.5.4). As a result, the labeling has not been revised as requested by FDA. OBP labeling response: In the past, the term “ ” container has been used by FDA to describe a package type that contained multiple doses but was intended to be used in a single patient. Unfortunately, the term “ ” was also inappropriately used as if it were interchangeable with the term “single-dose” which was not the Agency’s original intent. To address this confusion regarding the terminology, the Agency has retired the term “ ”. A single-dose container is designed for use with a single patient as a single injection/infusion. The package type term “single-dose” applies to your product. We acknowledge that two syringes are needed to obtain a dose. We also note the placement of the statement “For a full dose, 2 injections are required, one after the other” is prominently displayed multiple times on

the carton labeling; there are instructions for the healthcare provider to inform patients in the prescribing information, and instructions for the patient in the Instructions for Use. We recommend additional labeling strategies to address your concern, that patients will use only one pre-filled syringe and under-

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Page 24 of 35

dose, while maintaining consistent and correct use of package type terms among FDA approved products. For the carton labeling:

1. Consider revising the statement on the principal display panel from “ ” to read “For a 150

mg dose, two 75 mg syringes are required, inject one syringe after the other”

2. Revise the statement appearing at the top of all panels from “ ” to read “2 x 0.83 mL prefilled syringes” to include the

net quantity statement 3. Revise the bulleted statement from “

)” to read “2 syringe trays (each containing 1 prefilled syringe)”

4. Revise the statement from “ ” to read “Discard prefilled syringes after use. Do not reuse.”

5. Revise the statement from “ :” to read “Each Sterile Single-Dose Prefilled Syringe Contains:”

The applicant revised as requested Misleading statements Acceptable

21 CFR 201.6 ☐ Yes

☐ No

☒ N/A


21 CFR 201.15 Yes

☐ No

☐ N/A


21 CFR 201.16 ☐ Yes

☐ No

☒ N/A


21 CFR 201.20 ☐ Yes

☐ No

☒ N/A


21 CFR 201.21 ☐ Yes

☐ No

☒ N/A


21 CFR 201.22 ☐ Yes

☐ No

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Page 25 of 35

☒ N/A


21 CFR 201.51 Yes

☐ No

☐ N/A

Comment/Recommendation: see number of containers comment above

Recommended labeling practices: References: Draft Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors (line 461- 463)

Yes

☐ No

☐ N/A


21 CFR 201.55, 21 CFR 201.100 Yes

☐ No

☐ N/A


21 CFR 201.100 ☐ Yes

☐ No

☒ N/A


21 CFR 610.60, 21 CFR 208.24 Yes

☐ No

☐ N/A

Prescribing Information and Patient Labeling Evaluation PRESCRIBING INFORMATION

Highlights of Prescribing Information

PRODUCT TITLE Acceptable

21 CFR 201.57(a)(2)

Yes

☐ No

☐ N/A

Recommended labeling practices References: Draft Product Title and Initial U.S. Approval in the Highlights of Prescribing Information for Human Prescription Drug and Biological Products - Content and Format Guidance for Industry (January 2018)

Yes

☐ No

☐ N/A

DOSAGE AND ADMINISTRATION Acceptable

Recommended labeling practices Reference: USP nomenclature for diluents and intravenous solutions

Yes

☐ No

☐ N/A

Page 26 of 35

DOSAGE FORMS AND STRENGTHS Acceptable

21 CFR 201.57(a)(8), 21 CFR 201.10, 21 CFR 201.100

Yes

☐ No

☐ N/A

Recommended labeling practices References: Guidance for Industry: Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use (October 2018) USP chapter <659> Packaging and Storage Requirements Draft Guidance Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors, April 2013 line 176 USP General Chapters: <7> Labeling

Yes

☐ No

☐ N/A

Full Prescribing Information

2 DOSAGE AND ADMINISTRATION Acceptable

21 CFR 201.57(c)(3)(iv) Yes

☐ No

☐ N/A

Recommended labeling practices Reference: USP nomenclature for diluents and intravenous solutions

☐ Yes

☐ No

☒ N/A

3 DOSAGE FORMS AND STRENGTHS Acceptable

21 CFR 201.57(c)(4)

Yes

☐ No

☐ N/A

Comment/Recommendation: We added identifying characteristics of the dosage form per 21 CFR 201.57(c)(4) The applicant revised as requested

Recommended labeling practices References: Guidance for Industry: Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use (October 2018) USP General Chapters <659>, USP General Chapters <7>

Yes

☐ No

☐ N/A

11 DESCRIPTION Acceptable

21 CFR 201.57(c)(12), 21 CFR 610.61 (m), 21 CFR 610.61(o), 21 CFR 610.61 (p), 21 CFR 610.61 (q)

Yes

☐ No

☐ N/A

Comment/Recommendation: We added the route of administration per 21 CFR 201.57(c)(12) The applicant revised as requested

Page 27 of 35

Recommended labeling practices References: USP General Chapters <1091>, USP General Chapters <7>

Yes

☐ No

☐ N/A

Comment/Recommendation: These sentences (“ ”) were deleted as this information is not required for this

section and has been stated in section 2 The applicant revised as requested We relocated this information (“ ”) to How Supplied section 16 The applicant revised as requested We revised to read as follows: “Each prefilled syringe delivers 0.83 mL containing 75 mg..”, revised inactive ingredients to appear in alphabetical order per USP General Chapters <1091> Labeling of Inactive Ingredients, and revised “Water for Injection, USP” The applicant revised as requested

16 HOW SUPPLIED/ STORAGE AND HANDLING Acceptable

21 CFR 201.57(c)(17) Yes

☐ No

☐ N/A

Comment/Recommendation: We added the identifying characteristics of the dosage form per 21 CFR 201.57(c)(17). The applicant revised as requested

Recommended labeling practices: to ensure placement of detailed storage conditions for reconstituted and diluted products

Yes

☐ No

☐ N/A

Comment/Recommendation: We relocated this information from section 11 (“supplied in a 1 mL glass syringe…needle”) The applicant revised as requested

MANUFACTURER INFORMATION Acceptable

21 CFR 201.100(e), 21 CFR 201.1, 19 CFR 134.11

Yes

☐ No

☐ N/A

Recommended labeling practices References:21 CFR 610.61 (add the US license number for consistency with the carton labeling), and 21 CFR 610.64 (Name and address of distributor may appear and use a qualifying phrase for consistency with the carton labeling, when applicable)

Yes

☐ No

☐ N/A

MEDICATION GUIDE, PATIENT INFORMATION LABELING, INSTRUCTIONS FOR USE

TITLE (NAMES AND DOSAGE FORM) Acceptable

(b) (4)

(b) (4)

Page 28 of 35

Regulation for Medication Guide: 21 CFR 208.20(a)(7) Yes

☐ No

☐ N/A

Recommended Labeling Practice References: To ensure consistency with the product title in the Highlights of Prescribing Information (see Draft Product Title and Initial U.S. Approval in the Highlights of Prescribing Information for Human Prescription Drug and Biological Products - Content and Format Guidance for Industry (January 2018). For the recommended dosage form (see USP General Chapters: <1> Injections, Nomenclature and Definitions, Nomenclature form).

Yes

☐ No

☐ N/A

Comment/Recommendation: For medication guide and IFU: we revised the dosage form to appear in lower case The applicant revised as requested

STORAGE AND HANDLING Acceptable

Recommended labeling practices References: To ensure that applicable storage and handling requirements are consistent with the information provided in the PI (Reference: Section 2 (Dosage and Administration) and Section 16 (How Supplied Storage and Handling) of the PI)

Yes

☐ No

☐ N/A

INGREDIENTS Acceptable

Recommended labeling practice References: To ensure labeling of inactive ingredients are in alphabetical order (see USP General Chapters <1091>)

☐ Yes

☐ No

☒ N/A

MANUFACTURER INFORMATION Acceptable

21 CFR 201.1, 19 CFR 134.11, 21 CFR 208.20(b)(8)(iii)

Yes

☐ No

☐ N/A

Recommended labeling practice References: 21 CFR 610.61 (add the US license number for consistency with the carton labeling), 21 CFR 610.64 (Name and address of distributor may appear and use a qualifying phrase for consistency with the carton labeling, when applicable)

Yes

☐ No

☐ N/A

APPENDIX C. Acceptable Labels and Labeling Prescribing Information/Medication Guide/Instructions for Use (submitted on April 2, 2019 \\cdsesub1\evsprod\bla761105\0027\m1\us\114-labeling\draft\labeling\neg-lbl-6336.pdf)

Page 29 of 35

Container Labels (submitted on March 19, 2019)

(b) (4)

6 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page

VickyBorders-Hemphill

Digitally signed by Vicky Borders-HemphillDate: 4/04/2019 12:58:23PMGUID: 50814c7000007a3d59329f660d8ddf02

MilosDokmanovic

Digitally signed by Milos DokmanovicDate: 4/04/2019 09:12:25PMGUID: 508da6d8000263907e4dbc81ded2dd97

For use with OPQ-OBP-SOP-3104: OPQ-OBP-TEM-0010-01 [BLA executive summary annotated template]

Page 1 of 20

Department of Health and Human Services Food and Drug Administration

Center for Drug Evaluation and Research Office of Biotechnology Products

First Approval for Indication Recommendation: Approval

BLA Number: 761105 Review Number: 1

Review Date: 04/01/2019 From: Rachel Novak, Ph.D.

Review Chief, DBRR I/OBP/OPQ

Through: Qing (Joanna) Zhou, Ph.D. Review Chief, DBRR I/OBP/OPQ

Drug Name/Dosage Form

Risankizumab/injection (Skyrizi)

Strength/Potency 90 mg/ml (75 mg/0.83 ml) in a pre-filled syringe (PFS)

Route of Administration

Subcutaneous (s.c.)

Rx/OTC dispensed Rx

Indication Treatment of adults with moderate to severe plaque psoriasis

Applicant/Sponsor AbbVie, Inc.

US agent, if applicable NA

Product Overview

Risankizumab is a human IgG1 monoclonal antibody produced in cells. Risankizumab targets the p19 subunit of interleukin 23 (IL-23 p19), to inhibit interaction of IL-23 with the IL-23 receptor (IL-23R). Signaling through the IL-23R is thought to play a role in the pathogenesis of plaque psoriasis by inducing T-helper cells and other innate immune cells that promote inflammation and tissue damage. Aberrant expression of IL-23 has been noted in affected tissue from patients with plaque psoriasis. The mechanism of action of risankizumab results from the binding of risankizumab to IL-23 p19, which in turn inhibits binding to the IL-23R to suppress immune-modulated inflammatory responses.

. Risankizumab drug product is manufactured as a sterile, preservative-

free, 75 mg/0.83 ml solution in a pre-filled syringe (PFS) with a rigid needle shield (RNS). Risankizumab is proposed as a single agent for the treatment of patients with moderate to severe plaque psoriasis.

Quality Review Team

Discipline Reviewer Branch/Division

Drug Substance Milos Dokmanovic OPQ/OBP/DBRRI

(b) (4)

(b) (4)

Page 2 of 20



Drug Product Milos Dokmanovic OPQ/OBP/DBRRI

Immunogenicity Milos Dokmanovic OPQ/OBP/DBRRI

Labeling Vicky Borders-Hemphill OPQ/OBP

Facility Michael Shanks Zhihao (Peter) Qui

OPQ/OPF/DIA

Microbiology Diane Racassi (DS) Maxwell Van Tassell (DP)

OPQ/OPF/DMA

Team Lead Maria Candauchacon OPQ/OPF/DMA

CMC statistics Carin Kim CDER/OB/DBIII

CMC RPM Melinda Bauerlien CDER/OPQ/OPRO

Application Team Lead Rachel Novak OPQ/OBP/DBRRI

OBP Tertiary Reviewer Qing (Joanna) Zhou OPQ/OBP/DBRR1

Multidisciplinary Review Team:

Discipline Reviewer Office/Division

RPM Christina Petruccelli Attinello CDER/ODEIII/DDDP

Cross-disciplinary Team Lead David Kettl CDER/OEDIII/DDDP

Medical Officer Amy S. Woitach CDER/ODEIII/DDDP

Pharm/Tox Jiaqin Yao CDER

Clinical Pharmacology Liping Pan CDER/OCP/DCPIII

Statistics Carin J. Kim CDER/OB/DBIII

1. Names:

I. Proprietary Name: Skyrizi II. Trade Name: Skyrizi

III. Non-Proprietary Name/USAN: risankizumab-rzaa IV. CAS Name: 1612838-76-2 V. Common Name: ABBV-066, BI655066

VI. INN Name: risankizumab VII. OBP systematic name (refer to OPQ-SOP-OBP-3006): MAB HUMANIZED (IGG1 L237A

L238A) ANTI Q9NPF7 (IL23A_HUMAN) [BI655066] VIII. Other names: 655066-01

Submissions Reviewed:

Submission(s) Reviewed Document Date

761105/SDN 0 (Original submission) April 23, 2018

761105/SDN7 (OBP) September 17, 2018

761105/SDN9 (OBP and DMA) October 23, 2018

761105/SDN10 (OBP) November 1, 2018

Page 3 of 20



761105/SDN12 (OBP) November 13, 2018

761105/SDN13 (OBP and DMA) November 20, 2018

761105/SDN14 (OBP) December 6, 2018

761105/SDN15 (OBP and DMA) December 17, 2018

761105/SDN16 (OBP) January 7, 2019

761105/SDN19 (OBP) January 18, 2019

761105/SDN20 (OBP) January 25, 2019

761105/SDN21 (OBP) February 19, 2019

761105/SDN22 (OBP) March 4, 2019

761105/SDN23 (OBP) March 11, 2019

761105/SDN25 (OBP) March 26, 2019

761105/SDN26 (OBP) March 28, 2019

Quality Review Data Sheet

1. Legal Basis for Submission: 351(a) 2. Related/Supporting Documents:

A. DMFs: DMF # DMF

Type

DMF Holder Item

referenced

Code1 Status2 Date

Review Completed

Comments

III 2 Adequate 04/26/2018

III 2 Adequate 10/26/2017

III 3 N/A N/A

III 3 N/A N/A

V 3 N/A N/A

(b) (4) (b) (4)

Page 4 of 20



1. Action codes for DMF Table: 1- DMF Reviewed; Other codes indicate why the DMFwas not reviewed, as follows: 2- Reviewed previously and no revision since last review; 3- Sufficient information in application; 4- Authority to reference not granted; 5- DMF not available; 6- Other (explain under “comments”)

2. Adequate, Adequate with Information Request, Deficient, or N/A (There is notenough data in the application; therefore, the DMF did not need to be reviewed.

B. Other documents: IND, Referenced Listed Drug (RLD), or sister application.

Document Application Number Description

IND 113306 Risankizumab for the treatment of plaque psoriasis

3. Consults:

Discipline/Topic Date Requested

Status Recommendation Reviewer

CDRH/ODE/DAGRID/GHDB

Review of the device component of the combination product, including:

Device performance Release specifications

for the deviceconstituent

Biocompatibility ofthe syringecomponents as thebarrel is the primarycontainer closure

July 11, 2018

Completed CDRH is recommending approval of the device constituent of the combination product for the proposed indication.

Matthew Ondeck

(b) (4)

Page 5 of 20



Executive Summary

I. Recommendations:

A. Recommendation and Conclusion on Approvability: Recommendation: The Office of Pharmaceutical Quality, CDER, recommends approval of STN 761105 for Skyrizi (risankizumab-rzaa) manufactured by AbbVie, Inc. The data submitted in this application are adequate to support the conclusion that the manufacture of Skyrizi (risankizumab-rzaa) is well controlled and leads to a product that is pure and potent. It is recommended that this product be approved for human use under conditions specified in the package insert.

Manufacturing location:

o Drug Substance:

o Drug Product: . Final assembly, packaging

and labeling occurs at AbbVie S.r.l.; Campoverde di Aprilia (LT) Italy

Fill size and dosage form: 75 mg/0.83 ml PFS Dating period:

o Drug Product: 24 months: 5±3°C o Drug Substance: months: °C

For stability protocols: The stability protocol(s) in this license application is

acceptable for the purpose of extending the expiration dating of your drug substance and drug product under 21 CFR 601.12.

Exempt from lot release o Yes o Rationale: specified product in accordance with 21 CFR 601.2a.

D. Benefit/Risk Considerations: Psoriasis is a chronic debilitating autoimmune disease characterized by marked inflammation and thickening of the epidermis resulting in thick, scaly plaques on the skin. Plaque psoriasis is the most common form of psoriasis, affecting the largest percentage of patients. In patients with plaque psoriasis, approximately 20% have moderate to severe disease that can include symptoms such as pain associated with nail bed hyperkeratosis, functional deficits caused by nail plate crumbling and onycholysis, and cosmetic disfigurement that leads to poor self-image and social implications. Biologic products have offered clinical benefit to patients with plaque psoriasis and currently, there are several approved biologic

(b) (4)

(b) (4)

(b) (4) (b) (4)

Page 6 of 20



products on the market. However, even with these products, it is still difficult for patients to achieve significant long-term reduction of symptoms. The targeting of IL-23 is thought to be a promising and more effective treatment for the treatment of patients’ plaque psoriasis. The overall control strategy for risankizumab manufacture incorporates control over raw materials, facilities and equipment, the manufacturing process, and adventitious agents. The manufacturing control strategy coupled with in-process controls, process monitoring tests, release, and stability testing ensures process consistency, and drug substance (DS), and drug product (DP) that have appropriate quality and are free of adventitious agents.

B. Recommendation on Phase 4 (Post-Marketing) Commitments, Requirements, Agreements, and/or Risk Management Steps, if approvable: 1. To perform a leachable study to evaluate the drug product container closure system

through the end of shelf-life when stored under the recommended conditions. Testing will be performed at regular intervals and include appropriate methods to detect, identify, and quantify organic non-volatile (e.g., HPLC-UV-MS), volatile (e.g., headspace GC-MS), and semi-volatile (e.g., GC-MS) species and metals (e.g., ICP-MS). Study results will be updated annually in the BLA Annual Report. The complete data and risk evaluation for potential impact of leachables on product safety and quality will be submitted to the BLA.

II. Summary of Quality Assessments: A. CQA Identification, Risk and Lifecycle Knowledge Management Table 1: Active Pharmaceutical Ingredient CQA Identification, Risk and Lifecycle Knowledge Management. The attributes discussed in Table 1 are applicable to the risankizumab DS and DP. CQA (type) Risk Origin Control Strategy Other

IL-23 binding (potency)

Potency Intrinsic to the molecule. Potency can be impacted by

(b) (4)

(b) (4)

(b) (4)

Page 7 of 20



Identity Safety and Efficacy

Intrinsic to the molecule.

High molecular weight species (HMWS)

Potency and immunogenicity

Manufacturing process and exposure to light stress. The level of HMW is at about % and does increase over shelf-life.

Low molecular weight species (LMWS)

Potency Manufacturing process

The level of LMWS is around

% and does not increase over shelf-life.

Potency Exposure to light and chemical stress.

Pharmacokinetics Exposure to light stress.

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Page 8 of 20



Asp deamidation in the CDR and FcRn binding regions

Potency and Pharmacokinetics

Manufacturing process

Appearance of Solution (visible particulates, color and clarity)

Safety and Efficacy

Formulation, contamination or degradation

Protein Content

Efficacy Manufacturing process

pH Safety and Efficacy

Formulation process

Osmolality Safety and Efficacy

Formulation

Safety Formulation

B. Drug Substance [risankizumab-rzaa] Quality Summary CQA Identification, Risk, and Lifecycle Knowledge Management

(b) (4)

(b) (4) (b) (4)

(b) (4)

(b) (4)

Page 9 of 20



The DS is at 90 mg/ml . Table 2 below is a summary of

critical quality attributes and their control strategies that are relevant to the DS. Table 2: Drug Substance CQA Process Risk Identification and Lifecycle Knowledge Management.

CQA (type) Risk Origin Control Strategy Other

Residual HCP Immunogenicity Production cell line HCP levels in DS are consistent at U/mg (or ng/mg).

Residual DNA Safety Production cell line

(Process-related impurity)

Safety and Immunogenicity

Process related impurity

(Process-related impurity)

Safety

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)(b) (4)

(b) (4)

(b) (4)

Page 10 of 20



Cell Culture Derived Impurities

Safety Process related impurities

Viruses (Contaminant)

Safety Contamination during manufacture, most likely during

Mycoplasma (Contaminant)

Safety Mycoplasma would most likely be introduced during

Endotoxin Safety and Purity Raw materials contamination during manufacturing

Bioburden Safety, Purity and Efficacy due to degradation or modification of the product by microbial contamination

Raw materials and manufacturing process

Description: Risankizumab is a humanized monoclonal immunoglobulin G1 (IgG1

isotype) consisting of two identical heavy chains (HC) and two identical light chains (LC) covalently linked through inter- and intra-chain disulfide bonds. Each HC and LC are composed of 449 and 214 amino acids, respectively. Each HC contains a leucine to alanine substitution at amino acid residues 237 and 238 within the Fc domain to minimize the potential for effector function and deletion

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Page 11 of 20



of lysine at the C terminus to reduce potential for charge heterogeneity. A single N-linked glycosylation site is in the CH2 domain of each HC at asparagine residue 297. The extinction coefficient was calculated and confirmed experimentally to be 1.52 mL x mg-1 x cm-1 at 280 nm.

Mechanism of Action (MoA): Risankizumab selectively binds to IL-23 p19 and inhibits binding of IL-23 to its receptor. This in turn, inhibits IL-23 inflammatory responses that contribute to the pathogenesis of plaque psoriasis. The generation and characterization of risankizumab was undertaken to include selectivity for the p19 over the p40 subunit, to overcome the high-affinity binding between IL-23 to IL-23R and favorable biophysical properties.

Potency Assay: Biological activity of risankizumab is evaluated using a chicken lymphoma cell DT-40 line, which constitutively expresses the human IL-23R complex (IL-23R and IL-12Rβ1 subunits) and STAT5B. The DT-40 bioassay assay is a luciferase reporter-gene assay which measures the activation of the human IL-23R/STATB pathway. Upon IL-23 binding to the IL-23R, STAT5B is phosphorylated and activates transcription of STAT5B responsive elements and subsequently activates the firefly luciferase. The luciferase activity is then quantified. In the presence of risankizumab, IL-23 cannot bind the IL-23R, leading to the inhibition of luciferase activity. To measure risankizumab potency, DT-40 cells are co-incubated with increasing amounts of risankizumab and a 4-parameter (4-PL) unconstrained logistic analysis is used to calculate the dose response curve. Potency is reported as a percentage relative to the reference standard.

Reference Materials:

Critical starting materials or intermediates: The production cell line for risankizumab was derived from (b) (4)

(b) (4)

Page 12 of 20



Manufacturing process summary:

Container closure:

Dating period and storage conditions: The dating period for the DS is months when stored at °C.

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Page 13 of 20



C. Drug Product [risankizumab-rzaa] Quality Summary: Table 3 provides a summary of the identification, risk, and lifecycle knowledge management for drug product CQAs that derive from the drug product manufacturing process and general drug product attributes. Table 3: Drug Product CQA Identification, Risk, and Lifecycle Management

CQA (type) Risk Origin Control Strategy

Other

Sterility (contaminant) Safety (Infection), Purity and Efficacy (degradation or modification of products by contaminating microorganisms)

Contamination may be introduced throughout the manufacturing process

Endotoxin (contaminant)

Safety, purity, and immunogenicity

Raw materials; contamination may be introduced throughout the DP manufacturing process

Provides over a 10-fold safety factor.

Container closure integrity

Safety Container closure breaches during storage. May be impacted by storage conditions.

(b) (4)

Page 14 of 20



Extractable volume DP Accurate dosing Fill volume was identified as CPP that is controlled within pre-established limits to ensure accurate dosing.

Leachables (process-related impurities)

Safety Manufacturing equipment and CCS

A PMC was conveyed to perform leachable studies on the DP in the final CCS over the proposed shelf life.

Safety Manufacturing process and CCS


Manufacturing process and CCS

Subvisible Particulate Matter (Product or Process Related Impurities)


Manufacturing process and CCS.

Visible Particles Safety and Immunogenicity

Through the DP manufacturing

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Page 15 of 20



process via extended hold times and contact with materials

Break-out force, gliding force

Accurate dosing

Potency and Strength: Risankizumab (75 mg) pre-filled syringe is supplied at 90

mg/mL in a 1 ml syringe with a nominal fill volume at 0.83 ml. Potency is defined as the percent activity relative to the current reference standard. The potency assay is the same as described for the DS.

Summary of Product Design: Risankizumab 75 mg/0.83 ml pre-filled syringe is presented as a sterile, preservative-free, non-pyrogenic liquid formulation in glass syringes for subcutaneous injection at a concentration of 90 mg/ml. The drug product formulation consists of mM succinate mM succinic acid mM disodium succinate hexahydrate), mM sorbitol, and g/L polysorbate 20 (PS20) at pH . The extractable volume is 0.83 ml.

List of Excipients: mM succinate mM succinic acid/ mM disodium succinate hexahydrate), mM sorbitol, and g/L polysorbate 20 (PS20) at pH .

Reference Materials: The same reference material is used for DS and DP.

Manufacturing process summary: Risankizumab DP is manufactured at

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4) (b) (4) (b) (4)

(b) (4) (b) (4)

(b) (4) (b) (4) (b) (4)

(b) (4) (b) (4)

(b) (4)

(b) (4)

Page 16 of 20



Container closure: The primary container closure system for risankizumab DP consists of a 1 ml glass syringe utilizing USP/Ph.Eur/JP Type glass, and each syringe includes a staked-in place (integrated) 0.5 inch long, 29 gauge, thin wall stainless steel needle for subcutaneous injection, a

rubber stopper and a rigid needle shield (RNS) composed of . Appropriate compatibility studies

were performed for the container closure system. The secondary container closure system consists of a film blister and a box, which is sufficient for protection from light.

Dating period and storage conditions: The dating period for risankizumab DP is 24 months when stored at 2-8oC.

List of co-package components, if applicable: None D. Novel Approaches/Precedents: None

E. Any Special Product Quality Labeling Recommendations: None

F. Establishment Information:

Overall Recommendation:

DRUG SUBSTANCE Function Site Information DUNS/FEI

Number

Preliminary

Assessment

Inspectional

Observations

Final

Recommendation

Bulk pre-filled

syringe

manufacture, in-process

testing, release and

DS PAI

required

Yes-VAI Approve (b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Page 17 of 20



stability testing.

Cell bank storage

AbbVie Bioresearch

Center Inc.

3003684386 Adequate N/A Approve

DS and bulk pre-filled

syringe release and

stability

testing

Adequate N/A Approve

DRUG PRODUCT Function Site Information DUNS/FEI

Number

Preliminary

Assessment

Inspectional

Observations

Final

Recommendation

Bulk pre-filled

syringe

manufacture, in-process

testing, release and

stability

testing.

DS PAI

required

See Drug

Substance

Approve

DS and bulk pre-filled

syringe

release and stability

testing (bioassay)


Bulk pre-filled

syringe release and

stability testing

(sterility)


Final assembly of drug

product,

packaging, labeling,

release and stability

testing of

NSP-PFS (functionality

and appearance).

AbbVie S.r.L. 3002806277 Adequate N/A Approve

(b) (4)

(b) (4)

(b) (4)

Page 18 of 20



G. Facilities: Adequate descriptions of the facilities, equipment, environmental controls, cleaning and contamination control strategy were provided for

All proposed manufacturing and testing facilities are

acceptable based on their currently acceptable CGMP compliance status and recent relevant inspectional coverage. This submission is recommended for approval from a facility perspective.

H. Lifecycle Knowledge Management:

a. Drug Substance:

i. Protocols approved: 1. Annual stability protocol for DS 2. Qualification protocols for future primary and working reference

standards 3. Re-qualification protocols for primary and working reference

standards 4. Qualification protocol for new working cell bank

ii. Outstanding review issues/residual risk: None iii. Future inspection points to consider: None

b. Drug Product

i. Protocols approved:

1. Annual stability protocol 2. Comparability Protocol:

ii. Outstanding review issues/residual risk: None iii. Future inspection points to consider: None

(b) (4)

(b) (4)

(b) (4)

Page 19 of 20



Quality Assessment Summary Tables

Table 1: Noteworthy Elements of the Application

# Checklist Yes No N/A

Product Type

1. Recombinant Product x

2. Naturally Derived Product x

3. Botanical x

4. Human Cell Substrate/source material X

5. Non-Human Primate Cell Substrate/Source Material

x

6. Non-Primate Mammalian Cell Substrate/source material

X

7. Non-Mammalian Cell Substrate/Source Material x

8. Transgenic Animal source x

9. Transgenic Plant source x

10. New Molecular Entity x

11. PEPFAR drug x

12. PET drug x

13. Sterile Drug Product x

14. Other: [fill in information]

Regulatory Considerations

15. Citizen Petition and/or Controlled Correspondence Linked to the Application [fill in number]

x

16. Comparability Protocol(s) x

17. End of Phase II/Pre-NDA Agreements tem x

18. SPOTS (special products on-line tracking system)

x

19. USAN assigned name x

20. Other [fill in]

Quality Considerations

21. Drug Substance Overage x

22.

Design Space

Formulation x

23. Process x

24. Analytical Methods x

25. Other x

26. Other QbD Elements x

27. Real Time release testing (RTRT) x

28. Parametric release in lieu of Sterility testing x

29. Alternative Microbiological test methods x

Page 20 of 20



30. Process Analytical Technology in Commercial Production

x

31. Non-compendial

analytical procedures

Drug Product x

32. Excipients x

33. Drug Substance x

34. Excipients

Human or Animal Origin

x

35. Novel x

36. Nanomaterials x

37. Genotoxic Impurities or Structural Alerts x

38. Continuous Manufacturing x

39. Use of Models for Release x

40. Other {fill-in}

RachelNovak

Digitally signed by Rachel NovakDate: 4/03/2019 12:43:49PMGUID: 52e163f70002ba9e745b4e39384c76d7

QingZhou

Digitally signed by Qing ZhouDate: 4/03/2019 12:47:51PMGUID: 508da7430002bbad737ae8d4b9c59845

Zhihao PeterQiu

Digitally signed by Zhihao Peter QiuDate: 4/03/2019 12:52:11PMGUID: 508da7480002bfb5825e149b2b4eb91d

ReyesCandau-Chacon

Digitally signed by Reyes Candau-ChaconDate: 4/03/2019 01:06:05PMGUID: 508da7160002977f7ca389c8f849b707

Page 1 of 232



BLA STN 761105

Risankizumab

AbbVie Inc.

OBP Product Quality Reviewer

Milos Dokmanovic

OPF/DMA, DS/DP Microbiology Reviewers

Diane Raccasi (DS-microbiology)

Max Van Tassell (DP-microbiology)

OPF/DIA, Facilities Reviewer

Michael Shanks

OPRO RBPM

Melinda J. Bauerlien

Application Technical Lead

Rachel Novak

Page 2 of 232



OBP CMC Review Data Sheet

1. BLA#: STN 761105

2. Review Date: March 29, 2019

3. Primary Review Team:

a. Medical Officer: Amy S. Woitach

b. Pharm/Tox: Jiaqin Yao

c. Product Quality Team: Milos Dokmanovic (CMC-DS/DP and immunogenicity), Diane

Raccasi (DS-microbiology), Max Van Tassell (DP-microbiology)

d. Facilities: Michael Shanks

e. Clinical Pharmacology: Liping Pan

f. Statistics: Carin J. Kim

g. OBP Labeling: Vicky Borders-Hemphill

h. RBPM: Melinda J. Bauerlien

4. Major GRMP Deadlines:

a. Filing Meeting: June 11, 2018

b. Mid-cycle meeting: September 28, 2018

c. Wrap-up meeting: March 22, 2019

d. Primary review due: December 21, 2019

e. Secondary review due: March 20, 2019

f. PDUFA action date: April 23, 2019

5. Communications with Sponsor and OND:

Communication/Document: Date:

IR#1 (Process validation and/or Qualification) September 10, 2018

IR#2 (Control strategy for upstream manufacture

and Process Performance Qualification [PPQ])

October 18, 2018

IR#3 (Reference Standard or Materials) November 5, 2018

IR#4 (Control strategy for downstream

and polysorbate 20 [PS20] excipient)

November 25, 2018

IR#5 (Control strategy for MCB/WCB; DP

shipping validation, control of materials-cell

banks, and WCB qualification protocol)

December 31, 2018

IR#6 (Control strategy for high mannose species,

and for downstream

)

January 11, 2019

IR#7 (Control strategy for process intermediate

hold times and revisions to the WCB

comparability protocol)

January 18, 2019

(b) (4)

(b) (4)

Page 3 of 232



IR#8 (Analytical method procedures/validation,

DP manufacturing control strategy and DS

stability study)

February 11, 2019

IR#9 (DP manufacturing process control and

Comparability Protocol (CP) for

)

February 26, 2019

IR#10 (DS/DP specifications, and PMC for

leachable study)

March 6, 2019

IR#11 (Comparability Protocol [CP] for

)

March 22, 2019

IR #12 (Post-Approval Stability Protocol) March 28, 2019

6. Submission Reviewed:

Submission: Date Received: Review Completed (yes or no)

761105/0 (Original submission) April 23, 2018 Yes

761105/SDN7 (Response to IR#1,

Process validation and/or

Qualification)

September 17, 2018 Yes


Process Performance Qualification

[PPQ] and control strategy for

upstream manufacture)

November 1, 2018 Yes


Reference Standard or Materials)

November 13, 2018 Yes


Control strategy for downstream

and polysorbate 20

(PS20) excipient)

December 6, 2018 Yes


shipping validation, WCB

qualification protocol, control of

materials-cell banks)

January 7, 2019 Yes


control strategy for high mannose

species, and for downstream

January 18, 2019 Yes


Control strategy for process

intermediate hold times and

revisions to the WCB

comparability protocol

January 25, 2019 Yes


Analytical method

procedures/validation, DP

February 18, 2019 Yes

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Page 4 of 232



manufacturing control strategy and

DS stability study)


DP manufacturing process control

and Comparability Protocol (CP)

for

)

March 4, 2019 Yes

761105/SDN23 (Response to

IR#10, DS/DP specifications, and

PMC for leachable study)

March 11, 2019 Yes

761105/SDN25 (Response to

IR#11; Comparability Protocol

[CP] for

)

March 26,2019 Yes

761105/SND26 (Response to

IR#12

March 29, 2019 Yes

7. Drug Product Name/Code/Type:

a. Proprietary Name: Skyrizi

b. Trade Name: Skyrizi

c. Non-Proprietary Name/USAN: risankizumab-rzaa

d. CAS Name: 1612838-76-2

e. Common Name: ABBV-066, BI655066

f. INN Name: risankizumab

g. Compendial Name: N/A

h. OBP systematic name (refer to OPQ-SOP-OBP-3006): MAB HUMANIZED (IGG1) ANTI

Q9NPF7 (IL23A_HUMAN) [BI655066]

i. Other names: N/A

Reviewer comment: The sponsor proposed nonproprietary name risankizumab-rzaa (see Section 1.18),

and the name was determined to be conditionally acceptable, pending approval of BLA (see General

Advice Letter uploaded in DARRTS on February 14, 2019). In this review memo, risankizumab will be

used without the added suffix (rzaa).

8. Pharmacological Category: IL-23 ligand antagonist

9. Dosage Form: for injection

10. Strength/Potency:

(i): The concentration/strength of the Drug Product: 75 mg/ 0.83 ml (90 mg/ml) in a pre-filled

syringe (PFS)

(ii): Type of potency assay(s): Risankizumab DS and DP potency is tested by a cell-based

(DT-40) based bioassay. DT-40 based bioassay is a cell-based reporter-gene assay which

measures the inhibitory effect of risankizumab on the activation of STAT pathway.

11. Route of Administration: Subcutaneous (s.c.)

(b) (4)

(b) (4)

Page 5 of 232



12. Referenced Drug Master Files (DMF):

DMF# DMF Holder Item Referenced Letter of Cross-

Reference

Comments (status)

Yes No review required.

Sufficient

information in the

BLA


Sufficient

information in the

BLA


Sufficient

information in the

BLA


Sufficient

information in the

BLA

13. Inspectional Activities:

A PLI of ) for the

drug substance manufacturing facility was conducted from by Diane Raccasi

(DMA, Lead Inspector) and Milos Dokmanovic (OBP). A four-item FDA Form 483 was issued to at

the end of inspection which included the following:

The inspection

outcome was classified as VAI.

A PLI inspection for the drug product manufacturing (same site as used for DS manufacturing) was

waived based on the facility profile evaluation which was found to be acceptable.

14. Consults Requested by OBP: OBP requested a consult from CDRH to review information related to

the device constituents of risankizumab injection combination product: needle stick protection device

(NSP) and pre-filled syringe (PFS). Of note, the NSP is a safety device, while the PFS serves is a

primary container for DP and a delivery device. The review was completed on October 25, 2018, and it

was recommended that the device constituent of the combination product be approved for the proposed

indication.

15. Quality by Design Elements:

The following was submitted in the identification of QbD elements (check any that apply):

(b) (4)

(b) (4)

(b) (4)(b) (4)

(b) (4)

Page 6 of 232



Design Space

X Design of Experiments

X Formal Risk Assessment/Risk Management

Multivariate Statistical Process Control

Process Analytical Technology

Expanded Change Protocol

16. Precedents: None

17. Administrative:

Summary of Quality Assessments

I. Primary Reviewer Summary Recommendation

II. List of Deficiencies to be Communicated

III. List of Post-Marketing Commitments/Requirements

1. To perform a leachable study to evaluate the drug product container closure system through

the end of shelf-life when stored under the recommended conditions. Testing be

performed at regular intervals and will include appropriate methods to detect, identify, and

quantify organic non-volatile (e.g. HPLC-UV-MS), volatile (e.g. headspace GC-MS), and

semi-volatile (e.g. GC-MS) species and metals (e.g. ICP-MS). Study results will be updated

annually in the BLA Annual report. The complete data and risk evaluation for potential

impact of leachables on product safety and quality will be submitted to the BLA.

IV. Review of Common Technical Document- Quality Module 1

A. Environmental Assessment of Claim of Categorical Exclusion

A claim for categorical exclusion from the requirement to prepare an environmental

assessment (EA) is included according to 21CFR Part 25.15(d). It is further stated that no

extraordinary circumstances exist that would warrant preparation of an EA.

V. Primary Container Labeling Review

VI. Review of Common Technical Document- Quality Module 3.2

VII. Review of Immunogenicity Assays- Module 5.3.1.4

Description of Drug Substance and Drug Product

Risankizumab is a humanized monoclonal antibody of the IgG 1κ isotype that binds to the p19 subunit

of IL-23.

Note: Reviewer comments are italicized, and tables and figures are copied directly from the application,

unless otherwise noted.

(b) (4)


(b) (4)

MilosDokmanovic

Digitally signed by Milos DokmanovicDate: 4/01/2019 07:52:17PMGUID: 508da6d8000263907e4dbc81ded2dd97

RachelNovak

Digitally signed by Rachel NovakDate: 4/01/2019 08:16:28PMGUID: 52e163f70002ba9e745b4e39384c76d7

1

Determining When Pre-License / Pre-Approval Inspections are Necessary Inspection Waiver Memorandum

Date: 12/20/2018 From: Michael Shanks, OPQ/OPF/DIA I Milos Dokmanovic, Ph.D., OPQ/OBP/DBRR I

Maxwell Van Tassell, Ph.D., OPQ/OPF/DMA IV To: BLA File, STN 761105/0 Through: Zhihao (Peter) Qiu, Ph.D., Branch Chief, OPQ/OPF/DIA Branch 1 Subject: Inspection waiver memo for manufacture of risankizumab drug product at

the

Applicant: Abbvie Inc. Facility: Product: Skyrizi® (risankizumab) for Injection Dosage: Sterile, , preservative-free solution in prefilled syringe (PFS), 75

mg/0.83 mL of Risankizumab, for subcutaneous injection. Indication: Therapeutic for the treatment of adults with moderate to severe plaque

psoriasis. Waiver Recommendation

Based on the firm’s compliance history and current acceptable GMP status, and the fact that the facility, similar processes, and most of the equipment at

proposed for risankizumab drug product manufacture are currently

Reference ID: 4368010

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

2

approved for the manufacture of we recommend that inspection of facility be waived for STN 761105/0.

Summary BLA STN 761105/0 was submitted by Abbvie Inc. and it provided information and data to support the manufacture of Skyrizi® (risankizumab) for Injection PFS. The manufacture of risankizumab drug product is performed a

The current waiver recommendation is in regard to drug product manufacture at

Facility Information


(b) (4) (b) (4)

(b) (4)

(b) (4)

(b) (4)

3

Signed: Michael Shanks, DIA I/OPF Reviewer/DATE __________________________________ Maxwell Van Tassell, Ph.D., DMA IV/OPF Reviewer/DATE ______________________ Milos Dokmanovic, Ph.D., DBRR I/OBP Reviewer/DATE ________________________ Rachel Novak, Ph.D., DBRR I /OBP Review Chief/DATE ________________________ Reyes Candau-Chacon, Ph.D., DMA IV/OPF Quality Assessment Lead and acting Branch Chief for Patricia Hughes, P.D./DATE __________________ Zhihao Qiu, Ph.D., DIA I/OPF Branch Chief/DATE _____________________________

Kathleen Clouse, M.D. CONCUR DO NOT CONCUR DATE Director, Division of Biotechnology Review and Research I Office of Biotechnology Products, Office of Pharmaceutical Quality, CDER


12/21/2018CONCUR/////// Ph.D.

Michael R. Shanks -S

Digitally signed by Michael R Shanks S DN: c=US o=U S Government ou=HHS ou=FDA ou=People 0 9 2342 19200300 100 1 1=2001408317 cn=Michael R Shanks S Date: 2018 12 20 16:28:13 05'00'

Milos Dokmanovic -S (Affiliate)

Digitally signed by Milos Dokmanovic S (Aff liate) DN c=US o=U S Government ou=HHS ou=FDA ou=People 0 9 2342 19200300 100 1 1=1300429673 cn=M los Dokmanov c S Affil ate) Date 2018 12 20 16 30 43 05 00'

Zhihao Qiu -S

Digitally signed by Zhihao Qiu -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, cn=Zhihao Qiu -S, 0.9.2342.19200300.100.1.1=2000438274 Date: 2018.12.21 07:01:46 -05'00'

Maxwell L. Van Tassell -S

Dig tally signed by Maxwell L Van Tassell S DN c=US o=U S Government ou=HHS ou=FDA ou=People 0 9 2342 19200300 100 1 1=2002185517 cn=Maxwe l L Van Tassell S Date 2018 12 21 08 14 09 05'00'

Maria D. Candauchacon -SDigitally signed by Ma ia D Candauchacon S DN c US o U S Government ou HHS ou FDA ou People 0 9 2342 19200300 100 1 1 2000639745 cn Maria D Candauchacon S Date 2018 12 21 08 44 42 05 00'

Rachel L. Novak -S

Digitally signed by Rachel L. Novak -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 0.9.2342.19200300.100.1.1=0013719878, cn=Rachel L. Novak -S Date: 2018.12 21 09:16:41 -05'00'

Kathleen A. Clouse Strebel -S

Digitally signed by Kathleen A. Clouse Strebel -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 0 9.2342.19200300.100.1.1=1300054511, cn=Kathleen A. Clouse Strebel -S Date: 2018.12.21 09:34 53 -05'00'

(b) (4)

--------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically. Following this are manifestations of any and allelectronic signatures for this electronic record.--------------------------------------------------------------------------------------------/s/------------------------------------------------------------

MICHAEL SHANKS12/22/2018 11:18:16 AM

Signature Page 1 of 1


DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

Food and Drug Administration

Center for Drug Evaluation and Research WO Bldg 51

10903 New Hampshire Ave. Silver Spring, MD 20993

To: Administrative File, STN 761105 From: Diane Raccasi, Reviewer, CDER/OPQ/OPF/DMA/Branch IV Through: Reyes Candau-Chacon, Ph.D. Quality Assessment Lead, CDER/OPQ/OPF/DMA/Branch IV Subject: New Biologic License Application (BLA) US License: 1889 Applicant: AbbVie, Inc. Facilities: Product: Risankizumab Dosage: 75mg/0.83mL in prefilled syringe, supplied as 90mg/mL for subcutaneous injection Indication: For the treatment of moderate of adults with moderate to severe plaque psoriasis Due date: December 21, 2018 Recommendation for Approvability: The drug substance part of BLA 761105 is recommended for approval from a microbial control and microbiology product quality perspective.

Review Summary This review contains the microbiology drug substance quality assessment of the manufacturing process of risankizumab . All other aspects of the submission are deferred to OBP.

BLA 761105 was submitted in eCTD on April 23, 2018 in electronic format under sequence 0001.

Drug Product Quality Microbiology Information Reviewed

Description eCTD Date Information request #1 0009 10/23/2018 Information request #2 0013 11/20/2018 Information request #3 0015 12/10/2018

S DRUG SUBSTANCE

S.1 General Information

(b) (4)


(b) (4)

STN 761105/0, Abbvie

Page 20 of 21

Conclusion

(b) (4)

STN 761105/0, Abbvie

Page 21 of 21

I. The Drug Substance section of this BLA, as amended, was reviewed from a microbial control and microbiology product quality perspective and it is recommended for approval.

II. Information and data in this submission not related to microbial control of the drug substance should be reviewed by the appropriate division.

III. A pre-license inspection of is planed from .

(b) (4)

(b) (4)

DianeRaccasi

Digitally signed by Diane RaccasiDate: 12/21/2018 03:15:18PMGUID: 508da718000298f524e710115cc9bfb3

ReyesCandau-Chacon

Digitally signed by Reyes Candau-ChaconDate: 12/21/2018 04:27:26PMGUID: 508da7160002977f7ca389c8f849b707

Page 1 of 27

Center for Drug Evaluation and Research Office of Pharmaceutical Quality Office of Process and Facilities Division of Microbiology Assessment

PRODUCT QUALITY MICROBIOLOGY REVIEW AND EVALUATION To: Administrative File, STN 761105/0 From: Maxwell Van Tassell, Ph.D., DMA Branch IV Through: Reyes Candau-Chacon, Ph.D., Acting Quality Assessment Lead, DMA Branch IV Subject: Review of Original 351(a) BLA Applicant: AbbVie Inc. US License: 1889 Product: Skyrizi (risankizumab) Indication: Moderate to severe plaque psoriasis in adults Dosage: Solution for injection, 90 mg/mL, 75 mg/0.83 mL in pre-filled syringe DP Facility:

Receipt Date: 04/23/2018 Action Date: 04/23/2019 Recommendation for Approvability: STN 761105/0 was reviewed from a sterility assurance perspective and is recommended for approval. Product Quality Microbiology Assessment: Drug Product Product Quality Microbiology Information Reviewed

Sequence number Date Description eCTD 0001 04/23/2018 Original Submission eCTD 0009 10/23/2018 Response to Information Request eCTD 0013 11/20/2018 Response to Information Request eCTD 0015 12/17/2018 Response to Information Request

Letters of Authorization were provided for referencing the following DMFs, which were previously reviewed within the Division of Microbiology Assessment and found to be adequate:

DMF # Content Date Reviewed Finding Document Name

04/26/2018 Adequate d501m54r01.doc

10/26/2017 Adequate d00501m48r01.doc


(b) (4)

(b) (4)(b) (4)

STN 761105/0, AbbVie Inc., Skyrizi (risankizumab)

Page 27 of 27

SATISFACTORY

Conclusion

I. The drug product section of this BLA, as amended, was reviewed from a microbial product quality and sterility assurance perspective and is recommended for approval.

II. Information and data in this submission not related to microbial control of the drug product should be reviewed by the appropriate division.

III. Refer to Panorama for cGMP status of the relevant facilities.

(b) (4)

MaxwellVan Tassell

Digitally signed by Maxwell Van TassellDate: 12/20/2018 07:25:10AMGUID: 588f9a18000bb6ac3ec7300751755758

ReyesCandau-Chacon

Digitally signed by Reyes Candau-ChaconDate: 12/20/2018 09:04:47AMGUID: 508da7160002977f7ca389c8f849b707