INACTIVE INGREDIENTS DATABASE AND EMERGING DOSAGE FORMS. ExcipientFest 2016

Transcription

1 INACTIVE INGREDIENTS DATABASE AND EMERGING DOSAGE FORMS ExcipientFest

2 Presented by Meera Raghuram Manager, Global Regulatory Affairs and Strategies Lubrizol LifeSciences Chair Regulatory Affairs Committee, IPEC-Americas 2

3 Agenda Agency Overview of recent IID refinements Survey results input from public Long term strategy for IID Records in IID for novel dosage forms: Current status with examples Long term strategy for drug delivery systems Interactive discussion Intent of this presentation is to stimulate discussion and explore potential solutions 3

4 Why Implantable Systems for Drug Delivery? Life cycle management of drugs is driving invention of new formulations for already approved drugs Extension of patents Protection of intellectual property Regulatory schemes that allow modest changes to approved drugs Site specific drug administration Sustained release of a therapeutic agent Patient compliance 4

5 New Dosage Forms Medical research is moving from traditional dosage forms to targeted systems Histrelin implants for treatment of prostate cancer / uterine fibroids, and early puberty in children Levonorgestrel and etonogestrel implants for contraception Wirelessly controlled, implantable, microchip-based devices that store/release drugs over many years. microchips were implanted to deliver drug to strengthen bones. Chips delivered doses comparable to injections more consistently with no adverse effects Moving forward, the IID is a critical resource for both the industry and regulators Journal of Science Translational Medicine 5

6 Flexible Delivery System Design

7 Where Excipients Are Used in Drug Delivery Systems Intravaginal Rings Contraception HIV prevention Glycerin Vaginal Pessaries Subcutaneous Implants Opioids Antipsychotic Bladder Implants Bladder Cancer Photo courtesy of ViroPan, Inc. Ocular Implants Osmotic Pumps Insulin Sensor Devices Photo courtesy of Axxia Pharmaceuticals, LLC.

8 Polymeric Materials used in Medical Devices Polyvinyl chloride Polycaprolactone Polyethylene terephthalate Polyglycolic acid Polylactic acid Poly (tetrafluoroethylene) Polymethylmethacrylate Silicone Ultrahigh molecular weight polyethylene Thermoplastic polyurethanes (TPU) 8

9 Regulatory Pathway for Combination Products OCP classifies based on: Primary mode of action of the product Article responsible for the primary mode of action then assigns review to the most appropriate center Device (CDRH) * PMA * 510(k) * IDE Drug (CDER) * NDA (505(b)(1) * NDA 505(b) (2) * ANDA * IND Biologic (CBER) * BLA * IND 9

10 Considerations for Device Material (Excipients) Biocompatibility Impact of leachables/extractables Stability Drug adhesion/absorption to the device materials Ability to control release of API Processability at relatively low temperatures Similar to traditional dosage forms, IID is critical for materials (polymers) in DD systems with established history of use in vivo IID listing facilitates/speeds development of novel dosage forms 10

11 Drug Delivery Records Currently in IID Route Dosage Form Implantation Implant Implantation Pellet, implant Route Dosage Form Implantation Implantation Rod Wafer Ophthalmic Suppository, insert, controlled release Intramuscular Injection, microspheres Subcutaneous Implant Intrauterine Intrauterine Intrauterine device Suppository, insert, controlled release Subcutaneous Topical Topical Rod Disc Dressing Intrauterine Drug delivery system Transdermal Film, controlled release Intrauterine implant Transdermal Patch, controlled release Iontophoresis Drug delivery system Transdermal Patch, electrically controlled Iontophoresis Patch, controlled release Vaginal Drug delivery system Vaginal Insert Vaginal Insert, extended release 11

12 Transdermal Patch 1. Backing Layer Film: Occlusive films of varied composition and/or thickness 2. Adhesive or Reservoir: A layer that incorporates the API 3. Release Liner: Removable coated film or polymer based protective layer

13 Transdermal Records In IID Rate controlling membrane? Excipient in the drug formulation?

14 Transdermal Records Evaluation of Precedence What is captured in the IID? Backing layer and release liner do not contact the skin The chemistry information is lacking Should there be differentiation between excipient in the drug product and adhesive layer or a polymer membrane that controls drug release? Lack of understanding whether the listed amounts are relative to units per patch or the API

15 Inactive Ingredient DIMETHYLSILOXANE/ METHYLVINYLSILOXANE COPOLYMER DIMETHYLSILOXANE/ METHYLVINYLSILOXANE COPOLYMER POLYGLACTIN SILASTIC BRAND MEDICAL GRADE TUBING SILASTIC BRAND MEDICAL GRADE TUBING SILASTIC MEDICAL ADHESIVE,SILICONE TYPE A ETHYLENE VINYL ACETATE COPOLYMER CELLULOSE, MICROCRYSTALLINE Example of Records for Implants Currently in the FDA IID Route IMPLANTATION Dosage Form PELLET, IMPLANT CAS # UNII Max. Potency Unit Pending 142 MG IMPLANTATION ROD Pending 142 MG IMPLANTATION IMPLANTATION PELLET, IMPLANT PELLET, IMPLANT Pending 25.2 MG IMPLANTATION ROD N/A 13 MG IMPLANTATION PELLET, IMPLANT N/A Pending 13 MG IMPLANTATION ROD Pending 61 MG INTRAVITREAL IMPLANT OP1R32D61U 1.66 MG MAGNESIUM STEARATE INTRAVITREAL IMPLANT M6I MG POLYVINYL ALCOHOL INTRAVITREAL IMPLANT B59J MG What does the potency value mean from a precedence standpoint? In this case, the tubing is the excipient. No max potency recorded 15

16 Example of Records for Implants Currently in the FDA IID Inactive Ingredient Route Dosage Form CAS # UNII Max. Potency Unit METHYL PYRROLIDONE PERIODONTAL DRUG DELIVERY SYSTEM JR9CE63FPM POLYLACTIDE PERIODONTAL DRUG DELIVERY SYSTEM TN2L5F5 CARBOXYMETHYLCELLULOSE SODIUM SUBCUTANEOUS IMPLANT K679OBS MG DIMETHYL SULFOXIDE SUBCUTANEOUS IMPLANT YOW8V9698H 104 MG MAGNESIUM STEARATE SUBCUTANEOUS IMPLANT M6I MG POVIDONES SUBCUTANEOUS IMPLANT FZ989GH94E 6 MG SODIUM CHLORIDE SUBCUTANEOUS IMPLANT W47IQ8X 77 MG STEARIC ACID SUBCUTANEOUS IMPLANT ELV7Z65AP 1.04 MG POLYGLACTIN SUBCUTANEOUS PELLET, IMPLANT Pending 25.2 MG ETHYLENE VINYL ACETATE COPOLYMER SUBCUTANEOUS ROD Pending 61 MG 16 What does the potency value mean from a precedence standpoint?

17 Example of Records for Implants Currently in the FDA IID Inactive Ingredient Route Dosage Form CAS # UNII Max. Potency Unit POLY(DIMETHYLSILOXANE/METHYLVI NYLSILOXANE/METHYLHYDROGENSIL OXANE) DIMETHYLVINYL OR DIMETHYLHYDROXY OR TRIMETHYL ENDBLOCKED VAGINAL DRUG DELIVERY SYSTEM Pending 9980 MG Weight of the ring? ETHYLENE-VINYL ACETATE COPOLYMER (28% VINYL ACETATE) VAGINAL INSERT 8ILA5X28VS 1677 MG ETHYLENE-VINYL ACETATE COPOLYMER (9% VINYLACETATE) VAGINAL INSERT OKC630HS6 197 MG LACTOSE MONOHYDRATE VAGINAL INSERT EWQ57Q8I5X MG MAGNESIUM STEARATE VAGINAL INSERT M6I30 23 MG POVIDONES VAGINAL INSERT FZ989GH94E 49 MG HYDROGEL POLYMER VAGINAL INSERT, EXTENDED RELEASE N/A 236 MG POLYESTER VAGINAL INSERT, EXTENDED RELEASE 17 N/A Excipient in the drug formulation?

18 Regulatory Issues and Opportunities Emerging area of drug delivery devices Implant materials like discs, rods, tubes being evaluated as excipients Polymeric materials generally have long history of use in devices Needs careful consideration of how these excipients are evaluated, what data is captured and how precedence is established There should be a transparent process for evaluation and establishment of potency Establishment of clear guidelines and clarity related to precedence of use in IID will help formulators early in decision making Requires collaboration from both industry and the agency (including multiple disciplines)

19 Questions 19