"Excipient Innovation and Regulatory Acceptance for use in Drug ...

AAPS Hot Topic – November 9, 2009"Excipient Innovation andRegulatory Acceptance for use inDrug Products – Solubilizer Solutol ®HS 15 Case Study"Ranga Velagaleti, Ph. D., Manager, Regulatory Affairs,Pharma Ingredients and Services, North AmericaBASF Corporation01.12.2009 Ranga Velagaleti 1

Excipient Innovation and Public Health‣ Excipient Innovation for functionality and better drug delivery isone of the primary drivers of recent advances in medicine.‣ Majority, if not all, Active Pharmaceutical Ingredients (APIs) knownare poorly soluble in water. Development of excipients withsolubilizer and other functionalities have advanced the use ofthese poorly soluble APIs in modern day therapies.‣ For example, use of (then) novel excipient, Polyoxyl 35 castor oilNF (Cremophor EL), for solubilization and consequentbioavailability of poorly soluble APIs for improved efficacy enableddrug development in 1990s for life-threatening Cancer [Taxol(Placitaxel)] and AIDs (e.g., Norvir, Ritonavir, Kaletra) diseases.01.12.2009 Ranga Velagaleti 2

Innovation is Historical and Continuing- Polymerization of N-Vinylpyrrolidone‣ Innovation of Synthetic Polymer excipients has been the hall markof early drug development.‣ The first polymerization product of N-vinylpyrrolidone was solublepolyvinyl pyrrolidone (Povidone USP), patented in 1939.‣ Besides innovative polymerization chemistry, processingtechniques such as spray drying and roller-drying have been partof early innovations in finished excipient development.‣ For example, low and medium molecular weight grades of solublePovidone products are spray-dried (K 12, 17, 25, 30) while highmolecular grades are roller-dried (K-90) to manufacture the finalfinished excipient product.01.12.2009 Ranga Velagaleti 3

Innovation in Polymerization Control -for Diversity in Functionality‣ The mechanism of terminating polymerization reaction makes itpossible to produce soluble Polyvinylpyrrolidone of almost anymolecular weight.‣ This innovation lead to soluble Povidone grades of variousmolecular weights, e.g., Povidone K12, K17, K25, K30 andK90.‣ The varying molecular weights and viscosity properties ofsoluble Povidones expanded their functionality and enableduse in a diverse portfolio of dosage forms, i.e., injectable,solution, suspension (K 12, K 17), and solid dosage forms (K25to K90).01.12.2009 Ranga Velagaleti 4

Innovation within the Same Chemistry -for Different Functionality‣ Innovation also involved physical and chemical variation ofsame polymerization chemistries. For example, insolublePovidone (cross-linked polyvinylpyrrolidone; Crospovidone NF)was prepared by popcorn polymerization or proliferativepolymerization of soluble polyvinylpyrrolidone (Povidone USP).‣ Insoluble Crospovidone is considered to have the samechemistry (polyvinylpyrrolidone) as soluble Povidone and hasthe CAS number 9003-39-8 as Povidone, but different infunctionality – Povidone is considered an excellent binderwhereas Crospovidone is considered one of the superdisintegrants for solid oral dosage forms.01.12.2009 Ranga Velagaleti 5

Results of Discovery and Innovation –Standard, Mixed, Co-processed and NovelExcipientsOver the years, excipient innovation and discovery lead to a numberof excipients which can be categorized as:‣ Standard Excipients – Monographed; e.g., Poloxamer, PEG‣ Mixed Excipients – Generally two or more monographedexcipients by simple mixing, blending; individual excipientsneed quantitation from the mixture.‣ Co-Processed Excipients – Generally two or more monographedexcipients by more complex high shear mixing etc.; individualexcipients need quantitation from the mixture.‣ Novel Excipients – New chemical entities‣ See IPEC Excipient Composition Guide for details.01.12.2009 Ranga Velagaleti 6

Novel Excipients – Definition andRegulatory Requirements‣ Novel Excipient is a new chemical entity; a new innovationthat has not been used in any drug approved by regulatoryauthorities,‣ or‣ A combination of excipients containing new chemicalentity/entities (not in approved drugs) and excipients that arealready in approved drugs in a mixed or co-processedscenario.01.12.2009 Ranga Velagaleti 7

Novel Excipients – Definition andRegulatory Requirements‣ Novel excipients require extensive safety evaluation asspecified in the following FDA guidance.‣ FDA Guidance for Industry: Nonclinical Studies for theSafety Evaluation of Pharmaceutical Excipients, May 2005– “It is important to perform risk-benefit assessments onproposed new excipients in drug products and to establishpermissible and safe limits for these substances”‣ Solutol ® HS 15 Polyoxyl 15 Hydroxystearate is discussed as anexample of a novel excipient in this presentation. Excipient evaluationduring drug approval process by FDA is described first, followed byIPEC-initiated Solutol HS 15 review.01.12.2009 Ranga Velagaleti 8

General Regulatory Review Process forExcipients – FDA Approved Drugs‣ Excipients are not approved or rejected by FDA. They arereviewed only in the context of a drug product application.‣ Manufacturer (Drug Master File Holder; DMF) of an excipient submitsa Type IV (excipient) DMF to FDA. FDA issues a DMF number, andenters in DMF database on FDA website. DMF documents arehoused at FDA and the contents are kept confidential.‣ With the intent of using an excipient in their drug product formulationand filing (NDA/ANDA/NADA or their supplements), drug productmanufacturer requests DMF Holder for a DMF access letter. DMFHolder provides access letter to FDA, with a copy to requester.‣ With the access letter from DMF Holder, FDA reviews excipient DMFduring review of drug product application.01.12.2009 Ranga Velagaleti 9

General Regulatory Review Process forExcipients‣ Questions related to excipient DMF, are sent as a DMFdeficiency letter to DMF holder directly by FDA.‣ Drug product safety is determined by regulators from preclinicalsafety (animal toxicology), and Phase 1, 2, and 3 humanclinical data with Placebo (containing excipients without an API)run simultaneously with finished drug product.‣ Drug product safety assessment provides information related tosafety of excipients (placebo) as well as safety and stability ofAPI in the presence of excipients (drug product).01.12.2009 Ranga Velagaleti 10

General Regulatory Review Process forExcipients - IIG Listing‣ Once a drug product is approved, FDA lists the excipients used in theapproved drug product in FDA’s Inactive Ingredient (IIG) Database.‣ Generally monograph name of excipient, dosage form and amountper dosage unit are listed.‣ Excipient brand names are not listed. Drug product names are notmentioned in the IIG database.‣ For mixed and co-processed excipients, individual components arespecified as stated in the drug application.‣ First time use Novel Excipients are listed by chemical name.‣ USP consults FDA on nomenclature for official monographs.01.12.2009 Ranga Velagaleti 11

Novel Excipients – Constraints for First-Time Use in Drug Products‣ Drug product manufacturers are understandably risk averse inusing Novel excipients that have not been used in FDA (orother regulators around the world)-approved drugs.‣ Primary concern is that a delay from questions on the excipientused could cause delay in drug approvals.‣ If a novel excipient is functionally superior over the existingexcipients and has other desirable formulation, efficacy andsafety advantages, use of such excipient is very attractive.‣ Our experience suggests that FDA encourages use of new andnovel excipients provided safety information is adequate.01.12.2009 Ranga Velagaleti 12

IPEC-Americas Initiative for Novel ExcipientReview by FDA – BASF Solutol HS 15‣ Regulatory concurrence of an excipient before use in approveddrugs is desirable, but there are no avenues to facilitate this.‣ IPEC-Americas has worked with FDA over past several yearsleading to acceptance of one novel excipient safety review ascase study by FDA - ahead of drug product approval toencourage novel excipient and formulation innovation.‣ IPEC Novel Excipient Safety Evaluation Procedure wasdesigned by IPEC-Americas Excipient Safety Committee andcontained a process flow as outlined below.‣ IPEC Safety Committee → BASF and Wyeth → Aclairo →IPEC Safety Committee → FDA (see details next page)01.12.2009 Ranga Velagaleti 13

IPEC Novel Excipient Safety EvaluationProcedure - The Process with SolutolHS 15‣ IPEC-Americas Excipient Safety Committee initiated a processof selection of the first Novel Excipient for FDA review.‣ Dr. Jay Goldring, IPEC Safety Committee Chair at that time(and formerly Director, Toxicology at Wyeth) informed BASFthat the excipient Solutol ® HS 15 (solubilizer) was selected asthe first excipient under IPEC Novel Excipient SafetyEvaluation Procedure. Dr. Goldring coordinated thesubsequent steps of IPEC Safety Evaluation Procedure.‣ Dr. Sherry Ku, Senior Director, Formulation Development atWyeth encouraged this initiative and participated in the projectthrough inputs on Solutol ® HS 15 human clinical safety toAclairo.01.12.2009 Ranga Velagaleti 14

IPEC Novel Excipient Safety Review -BASF Solutol HS 15‣ The IPEC Novel Excipient Safety Review Procedure requiredBASF to submit a safety evaluation package to Aclairo, anindependent toxicology consulting firm under an IPEC-Aclairoagreement for novel excipient evaluation.‣ BASF prepared a comprehensive technical and safety packageto Aclairo on Solutol ® HS 15 that included but not limited to: Technical Information - chemistry, manufacturing, processcontrols, release and stability specifications and data; Toxicology reports including acute and subchronic toxicitystudies – Oral and IV routes of administration.01.12.2009 Ranga Velagaleti 15

IPEC Novel Excipient Safety Review -BASF Role‣ BASF prepared a comprehensive technical and safety package forSolutol HS 15 for submission to Aclairo that included: Dermal and Eye Irritation Studies; Genotoxicity Studies; Reproductive toxicity Studies; BASF Internal Safety Expert Evaluation Report; Safety Evaluation Assessment by EMEA;Information on related chemistries listed in FDA IIG.01.12.2009 Ranga Velagaleti 16

IPEC Novel Excipient Safety Review -Review by Aclairo and FDA‣ After review of data package provided by BASF, Aclairoprovided a report containing safety assessment from threeexpert toxicologists for Solutol ® HS 15 to BASF.‣ Wyeth provided human clinical safety data of a drug productformulation containing Solutol HS 15 to Aclairo directly.‣ BASF Submitted Aclairo Safety Evaluation report and safetydata package to IPEC Safety Committee Chair.‣ IPEC Safety Committee Chair submitted a comprehensiveSolutol ® HS 15 safety package to FDA including the Aclairoevaluation of human clinical data.01.12.2009 Ranga Velagaleti 17

IPEC Safety Evaluation of Solutol® HS 15and USP/NF Monograph‣ IPEC Safety Committee Chair received a response from FDAon their assessment of Solutol ® HS 15 safety.‣ BASF informed USP about Solutol ® HS 15 safety evaluation byFDA under the IPEC Novel Excipient Safety EvaluationProcedure.‣ USP consulted FDA’s Compendial group on this subject anddecided to develop a official monograph.‣ USP has published an official monograph on Solutol ® HS 15“Polyoxyl 15 Hydroxystearate NF” in Pharmacopeial Forum(PF), January-February 2009 issue.01.12.2009 Ranga Velagaleti 18

Summary‣ Excipient Innovation for functionality and better drug delivery is oneof the primary drivers of recent advances in medicine.‣ Innovative New and Novel Excipients are used by drug productmanufacturers based on their superior functionality over existingexcipients or suitability for unmet formulation needs.‣ Solutol ® HS 15 is the first novel excipient reviewed under theIPEC Novel Excipient Safety Evaluation procedure by FDA -ahead of its use in a FDA-approved drug product.‣ Following this review, Polyoxyl 15 Hydroxystearate NF (Solutol ®HS 15) monograph has been published in January-February 2009issue of USP Pharmacopeial Forum (PF).01.12.2009 Ranga Velagaleti 19