Upcoming Product-Specific Guidances for Complex Generic Drug Product Development

Introduction
This web page provides information related to upcoming new and revised product-specific guidances (PSGs) to support the development and approval of safe and effective complex generic drug products.

What is a complex generic drug product?
As described in the GDUFA II Commitment Letter, a complex generic drug product generally means the following—

A product with:
- a complex active ingredient(s) (e.g., peptides, polymeric compounds, complex mixtures of APIs, naturally sourced ingredients)
- a complex formulation (e.g., liposomes, colloids)
- a complex route of delivery (e.g., locally acting drugs such as dermatological products and complex ophthalmological products and otic dosage forms that are formulated as suspensions, emulsions or gels)
- a complex dosage form (e.g., transdermals, metered dose inhalers, extended release injectables)

Complex drug-device combination products (e.g., auto injectors, metered dose inhalers); and
Other products where complexity or uncertainty concerning the approval pathway or possible alternative approaches would benefit from early scientific engagement.

How often does FDA publish new and revised PSGs?
To support generic drug development and generic drug approval, FDA issues new and revised PSGs on a quarterly and as needed basis. These PSGs, including PSGs for complex generic drug products, when finalized, describe FDA’s current thinking and expectations on how to develop generic drug products to specific reference listed drugs and are intended to assist the generic pharmaceutical industry with identifying the most appropriate methodology and evidence needed to support a specific generic drug’s approval. The published PSGs are announced in the Federal Register and made available to the public on FDA’s website.

What information is being provided on this web page?
For new PSGs for complex generic drug products under development, this web page provides information on the active ingredient(s), the route of administration and dosage form, and the reference listed drug (RLD) application number. In addition to this information, the list of PSGs for complex generic products under revision also includes the planned revision categories. This web page only describes FDA’s plans for issuing new and revised PSGs for these complex generic drug products.

What do the different planned revision categories mean?
For revised PSGs, the planned revision categories briefly describe the nature of the anticipated revisions. Planned revision categories are defined as the following:

Major revision: A PSG is being revised to include additional bioequivalence studies or evidence recommended to support FDA approval.
Minor revision: Any revision that is not considered major, including but not limited to when a PSG is to be revised to remove certain studies, to provide alternative (less burdensome) approaches to the currently recommended studies, to add information on newly approved strengths of the RLD, or to make other recommendations that would not generally result in additional recommended bioequivalence studies or evidence by an ANDA applicant.
Editorial revision: A PSG is being revised to include non-substantive changes such as updating external references, correcting grammatical issues, and streamlining the format of existing recommendations.

FDA will also provide specific information on the planned revision when such information is available for public release.

How often does FDA update this web page?
This web page will be updated each time FDA issues a new quarterly PSG batch. Each update removes the published PSGs and adds any new PSG under development or revision. This advance notice will help generic drug companies to plan for their development of complex generic drug products.

New and Revised PSGs for Complex Generic Drug Products
Below is the list of PSGs for complex generic drug products that FDA plans to issue and the list of PSGs that FDA plans to revise in the coming year. While this list reflects FDA’s effort to be transparent regarding current plans for developing PSGs for complex generic drug products, it should be noted that timing may be subject to change.

Planned New PSGs for Complex Generic Drug Products
Updated 5/23/2019

Active Ingredient(s)	Route of Administration	Dosage Form	RLD Application Number
ACYCLOVIR; HYDROCORTISONE	TOPICAL	CREAM	022436
AMINO ACIDS; CALCIUM CHLORIDE; DEXTROSE; MAGNESIUM SULFATE; POTASSIUM CHLORIDE; SODIUM ACETATE; SODIUM GLYCEROPHOSPHATE; SOYBEAN OIL	INTRAVENOUS	EMULSION	200656
APREPITANT	INTRAVENOUS	EMULSION	209296
BAZEDOXIFENE ACETATE; ESTROGENS, CONJUGATED	ORAL	TABLET	022247
BESIFLOXACIN HYDROCHLORIDE	OPHTHALMIC	SUSPENSION/DROPS	022308
BETAMETHASONE DIPROPIONATE; CALCIPOTRIENE	TOPICAL	AEROSOL, FOAM	207589
BUDESONIDE	ORAL	CAPSULE, EXTENDED RELEASE	211929
BUPRENORPHINE	SUBCUTANEOUS	SOLUTION, EXTENDED RELEASE	209819
BUPRENORPHINE	SUBCUTANEOUS	INJECTION, EXTENDED RELEASE	210136
CHLORHEXIDINE GLUCONATE	DENTAL	TABLET	020774
CLEVIDIPINE	INTRAVENOUS	EMULSION	022156
COPPER	INTRAUTERINE	INTRAUTERINE DEVICE	018680
CROFELEMER	ORAL	TABLET, DELAYED RELEASE	202292
CYTARABINE	INJECTION	INJECTABLE, LIPOSOMAL	021041
CYTARABINE; DAUNORUBICIN	INTRAVENOUS	POWDER	209401
DEGARELIX ACETATE	SUBCUTANEOUS	POWDER	022201
DESMOPRESSIN ACETATE	NASAL	SPRAY, METERED	201656
EPINEPHRINE	INHALATION	AEROSOL, METERED	205920
ESTRADIOL	VAGINAL	INSERT, EXTENDED RELEASE	020472
EXENATIDE	SUBCUTANEOUS	SUSPENSION, EXTENDED RELEASE	209210
FISH OIL TRIGLYCERIDES	INTRAVENOUS	EMULSION	210589
FLUOROMETHOLONE ACETATE	OPHTHALMIC	SUSPENSION/DROPS	019079
FLUOROURACIL	TOPICAL	CREAM	022259
FLUTICASONE PROPIONATE; SALMETEROL XINAFOATE	INHALATION	POWDER	208799
GLYCOPYRROLATE ; INDACATEROL MALEATE	INHALATION	POWDER	207930
GLYCOPYRRONIUM TOSYLATE	TOPICAL	CLOTH	210361
GRANISETRON	SUBCUTANEOUS	INJECTION, EXTENDED RELEASE	022445
HALOBETASOL PROPIONATE	TOPICAL	AEROSOL, FOAM	210566
HYDROCORTISONE ACETATE; PRAMOXINE HYDROCHLORIDE	TOPICAL	AEROSOL, METERED	086457
HYDROXYPROGESTERONE CAPROATE	INTRAMUSCULAR	SOLUTION	021945
LEVONORGESTREL	INTRAUTERINE	INTRAUTERINE DEVICE	208224
LIDOCAINE	TOPICAL	PATCH	207962
LIDOCAINE; TETRACAINE	TOPICAL	PATCH	021623
LOTEPREDNOL ETABONATE	OPHTHALMIC	GEL	202872
LOTEPREDNOL ETABONATE	OPHTHALMIC	SUSPENSION/DROPS	210565
LUTETIUM DOTATATE LU-177	INTRAVENOUS	SOLUTION	208700
MECHLORETHAMINE HYDROCHLORIDE	TOPICAL	GEL	202317
METRONIDAZOLE	VAGINAL	GEL	205223
MICONAZOLE NITRATE; PETROLATUM, WHITE; ZINC OXIDE	TOPICAL	OINTMENT	021026
OXYMETAZOLINE HYDROCHLORIDE	TOPICAL	CREAM	208552
PATIROMER SORBITEX CALCIUM	ORAL	POWDER	205739
RIFAMYCIN	ORAL	TABLET, DELAYED RELEASE	210910
SEMAGLUTIDE	SUBCUTANEOUS	SOLUTION	209637
SODIUM ZIRCONIUM CYCLOSILICATE	ORAL	FOR SUSPENSION	207078
SUMATRIPTAN SUCCINATE	INHALATION	POWDER	206099
SUMATRIPTAN SUCCINATE	SUBCUTANEOUS	INJECTABLE	020080
TESTOSTERONE	TRANSDERMAL	GEL, METERED	204399
TIMOLOL MALEATE	OPHTHALMIC	SOLUTION, GEL FORMING/DROPS	020330
TOBRAMYCIN	INHALATION	POWDER	201688
TRETINOIN	TOPICAL	LOTION	209353
UMECLIDINIUM BROMIDE; VILANTEROL TRIFENATATE	INHALATION	POWDER	203975

Planned Revised PSGs for Complex Generic Drug Products
Updated 5/23/2019

Active Ingredient(s)	Route of Administration	Dosage Form	Application Number	Planned Revision Category: Brief Reason
ACYCLOVIR	TOPICAL	OINTMENT	018604	Minor Revision: Provide more details on product characterization
ACYCLOVIR	TOPICAL	CREAM, 5%	021478	Editorial Revision: Reorganize information on In-Vitro Release Test (IVRT) and In Vitro Permeation Test (IVPT)
BUDESONIDE	ORAL	CAPSULE	021324	Major Revision: Add additional sprinkle BE study
CALCITONIN SALMON	NASAL	SPRAY, METERED	020313	Minor Revision: Clarify in vivo study design; Add recommendations for device comparisons
COLESEVELAM HYDROCHLORIDE	ORAL	POWDER FOR SUSPENSION	022362	Editorial Revision: Correct typos
FLUOROURACIL	TOPICAL	CREAM	016831	Minor Revision: Add an in vitro BE option as an alternative BE approach
FLUOROURACIL	TOPICAL	CREAM	020985	Minor Revision: Add an in vitro BE option as an alternative BE approach
FLUOROURACIL	TOPICAL	CREAM	016988	Minor Revision: Clarify in vitro studies
LEVONORGESTREL	INTRAUTERINE	INTRAUTERINE DEVICE	203159	Major Revision: Clarify in vitro BE study design; Add in vivo BE study
MESALAMINE	ORAL	CAPSULE, EXTENDED RELEASE	022301	Minor Revision: Change partial AUC parameters
METRONIDAZOLE	TOPICAL	GEL	019737	Minor Revision: Add an in vitro BE option as an alternative BE approach; Comply with Clinical Data Interchange Standards Consortium (CDISC)
METRONIDAZOLE	TOPICAL	CREAM	020531	Minor Revision: Add an in vitro BE option as an alternative BE approach; Comply with Clinical Data Interchange Standards Consortium (CDISC)
METRONIDAZOLE	TOPICAL	CREAM	020743	Minor Revision: Add an in vitro BE option as an alternative BE approach; Comply with Clinical Data Interchange Standards Consortium (CDISC)
METRONIDAZOLE	TOPICAL	LOTION	020901	Minor Revision: Add an in vitro BE option as an alternative BE approach; Comply with Clinical Data Interchange Standards Consortium (CDISC)
METRONIDAZOLE	TOPICAL	GEL	021789	Minor Revision: Add an in vitro BE option as an alternative BE approach; Comply with Clinical Data Interchange Standards Consortium (CDISC)
OMEGA-3-ACID ETHYL ESTERS	ORAL	CAPSULE	021654	Minor Revision: Clarify in vitro study design
PIMECROLIMUS	TOPICAL	CREAM	021302	Minor Revision: Provide more details on clinical study design
PLECANATIDE	ORAL	TABLET	208745	Editorial Revision: Correct typos
SCOPOLAMINE	TRANSDERMAL	FILM, EXTENDED RELEASE	017874	Minor Revision: Change partial AUC parameters
SUCRALFATE	ORAL	TABLET	018333	Minor Revision: Remove recommendation for a comparative clinical endpoint BE study; Add API sameness recommendations
TRETINOIN	TOPICAL	GEL 0.04%, 0.10%	020475	Minor Revision: Reorganize information to include all strengths within a single PSG
TRETINOIN	TOPICAL	GEL	022070	Minor Revision: Add an in vitro BE option as an alternative BE approach
TRETINOIN	TOPICAL	GEL	017955	Minor Revision: Add an in vitro BE option as an alternative BE approach
TRETINOIN	TOPICAL	GEL	017579	Minor Revision: Add an in vitro BE option as an alternative BE approach
TRETINOIN	TOPICAL	CREAM	019049	Minor Revision: Add an in vitro BE option as an alternative BE approach
TRETINOIN	TOPICAL	CREAM	017522	Minor Revision: Add an in vitro BE option as an alternative BE approach
TRETINOIN	TOPICAL	CREAM	017340	Minor Revision: Add an in vitro BE option as an alternative BE approach
TRETINOIN	TOPICAL	CREAM	021108	Minor Revision: Add an in vitro BE option as an alternative BE approach; Comply with Clinical Data Interchange Standards Consortium (CDISC)
TRETINOIN	TOPICAL	CREAM	019963	Minor Revision: Add an in vitro BE option as an alternative BE approach; Comply with Clinical Data Interchange Standards Consortium (CDISC)