FDA s Inactive Ingredient Database Update on the Substance Registration System Changes

Transcription

1 FDA s Inactive Ingredient Database Update on the Substance Registration System Changes Priscilla Zawislak Chair Compendial Review Committee IPEC-Americas Global Regulatory Affairs Manager Ashland Inc. pszawislak@ashland.com

2 Acknowledgements IPEC Americas Regulatory Affairs Committee IID Core Team Frank Murphy Dow David Schoneker Colorcon Theodore Sullivan Buchanan Ingersol & Rooney Katherine Ulman Dow Corning Ann Van Meter Dow Wolff Cellulosics Priscilla Zawislak Ashland Inc.

3 Overview of the IID and SRS Situation Background - IID SRS Nomenclature Changes and Impact IPEC America s Evaluation of the Situation Existing Safety Data for Common Excipients Communication concerns: Industry OGD IPEC FDA OGD Meetings Outcomes & Actions Possible Future Actions FDA

4 Background October 2010 FDA implemented the Substance Registration System (SRS) Significant impact on the Inactive Ingredient Database (IID) How it is managed How information is utilized for NDA and ANDA drug product reviews

5 IID SRS Nomenclature Changes and Impact Inconsistencies exist in naming of materials (common, generic, brand and monograph names, etc.) Several industry issues resulted based on IID listing changes, including but not limited to: Some listings of un-like products were merged - e.g. polyethylene oxide and polyethylene glycol Some listings disappeared - e.g. dimethicone for use in TDDS, generic listings for HPMC, ethylcellulose Maximum use levels for many listing changed e.g. hypromelloses Customers filing ANDAs requested UNII codes for mixtures (e.g. simethicone) even though UNII codes are not currently applied to mixtures

6 IID SRS Nomenclature Changes and Impact Unrealistic requests from FDA to ANDA sponsors for data that does not make sense and may not exist FDA requests for additional safety data on common excipients Full toxicology studies requested to justify typical uses of common excipients --- ICH Q9? Urgent requests from ANDA sponsors to excipient manufacturers for data that may never be provided by the excipient manufacturer outside of a DMF

7 IID SRS Nomenclature Changes and Impact Industry not informed of FDA OGD s change in requirements until Refuse to File letters were received Delays in review process & ANDA acceptance Based on changes to IID listings and a higher number of deficiency or Refuse to File letters, the generic industry was confused about Which excipients can be used and at what levels and what to submit in ANDAs How excipient precedence of use are determined & used at time of filing New requirements implemented due to new SRS nomenclature & UNII codes

8 IPEC Americas FDA OGD Meeting IPEC Americas initiated a project to address the situation Requested meeting with FDA OGD Formed IPEC Americas project committee Partnered with GPhA Developed backgrounder document Historical information Issues Desired outcome and goals

9 IPEC Americas FDA OGD December 2011 Meeting SRS Nomenclature issues & potential unintended consequences when used by OGD during acceptance to file determinations Generic listing vs. specific grade listing for commonly used excipients max. precedent levels Listing of mixtures Examples of grade & mixture issues from generic drug & excipient manufacturers Hypromelloses Polyethylene Oxides Simethicones Impact on ANDAs unjustified delays & Refuse to File Letters

10 IPEC Americas FDA OGD December 2011 Meeting Realities of existing safety data for common excipients Individual grades vs. family data Use of appropriate risk management concepts Lack of communication from OGD to the Industry regarding their change in approach to grade specific precedent references and certain types of mixtures Potential legal and confidentiality concerns Implications for DMFs Impact of ANDA delays Next steps transition period new mechanisms needed on-going dialog

11 Desired Outcome & Goals from IPEC Acceptance of historical maximum potency levels Mechanism to supply one-time safety data/bridging studies for families of comparable materials Interim transition process to support current ANDA filings Develop mechanism to apply appropriate nomenclature for all excipients (including mixtures) FDA OGD utilization of DMF safety info during assessment for acceptance for filing FDA dialog with Industry to ensure accurate information and optimum utilization of IID references Communication from FDA OGD on expectations and proper use of IID information

12 Desired Outcome & Goals from FDA OGD Clearer understanding of issues / concerns from industry based on changes to IID: FDA OGD wanted to make sure that industry (IPEC) understood the overall background and strategy for their Substance Registration System (SRS) FDA OGD was interested in learning about industry issues and concerns due to changes in the IID FDA OGD expressed an interest in working with the industry (through IPEC) to review ideas and address actions to help resolve industry concerns / issues FDA OGD wanted to work with industry to clean-up and standardize/modernize information contained in the IID

13 Desired Outcome & Goals Shared IPEC needed to understand: What FDA OGD expected from the IID listings How the information will be used at time of filing and during ANDA reviews Clear, documented guidance was needed by industry with regard to: The process for updating the list How the information may be used for acceptance for filing

14 Safety Data Realities for Common Excipients Based on historical use, previous IID levels should be accepted With safety justification from industry Based on safety assessments which have resulted in group ADIs, it should be acceptable to use families of substances Based on similar safety profiles, a process is needed for applying a maximum use level for families of similar excipients With safety justification from industry Based on need to maintain proprietary nature for certain excipient information, FDA OGD should reference safety information from excipient (Type IV) DMFs during ANDA assessment and review

15 UNII Codes Safety Assessment Need to differentiate between Substance ID (particular material / substance) versus safety coverage (may have been designed to cover a family of materials). SRS UNII code Identification of a specific substance which exists in a previously approved drug product One-to- ONE Safety assessment info and max use level All UNII codes for family of similar products UNII #1 UNII #2 UNII #3 One to- MANY

16 IID Listings for Hypromellose If the new SRS nomenclature is used to determine the acceptable level of Hypromellose 2910 (5 mpa s), this would result in saying that levels over 2.02 mg/dose might require full safety data which doesn t make any sense!

17 Safety of Hypromellose There are many grades (industrial, cosmetic, food and excipient) and viscosities (5, 50, 5000 mpa.s etc) for HPMC as well as all other cellulose ethers. Numerous toxicology studies have been performed on all of these with consistent results, regardless of the grade tested. The toxicology of the different types of HPMC is not dependent on the methoxy and hydroxpropoxy content. Viscosity is not specified by the JECFA as a factor related to the safety of these additives. Evaluations of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), Hydroxypropyl Cellulose Toxicology Monograph 687, FAS 26 JECFA 35/85, 1989; CFSAN concluded that for cellulose and cellulose derivatives there is no safety effect arising from a change in viscosity.

18 Polyethylene oxide(polyox) versus Polyethylene glycol (PEG) Polyethylene oxide vs Polyethylene glycol 1) Different physical states 2) Different molecular weights 3) Different manufacturing process 4) Different impurity profiles 80 Polyethylene Glycol POLYOX Organism Test Type Route Reported Dose (Normalized Dose) 70 Polyethylene Oxide WSR N-10 Melting Temperature Average Molecular Weight 1E+05 8E+06 (100,000 daltons) Rat LD50 Oral >4000 mg/kg* (148,000 mg/m 2 ) Rabbit LC50 Dermal >2000 mg/kg* Polyethylene Oxide WSR 301 (4,000,000 daltons) (74,000 mg/m 2 ) rat LD50 Oral >2000 mg/kg* (74,000 mg/m 2 ) Rabbit LD50 Dermal >400 mg/kg* (14,800 mg/m 2 )

19 IID Listings for Cyclomethicone vs Dimethicone Inactive Ingredient Route; dosage form CAS# UNII Max Potency CYCLOMETHICONES - different size cyclic molecules, e.g. (Me 2 SiO) 4, (Me 2 SiO) 5,; (Me 2 SiO) 6,; (Me 2 SiO) 6+, and mixtures of molecules.with different associated tox profiles, yet they all been assigned the same UNII code (also all meet the current Cyclomethicone monograph) cyclomethicone ORAL Powder for solution NMQ347994Z cyclomethicone TOPICAL Cream augmented NMQ347994Z 7.6 % cyclomethicone TOPICAL Emulsion aerosol foam NMQ347994Z 5.3 % cyclomethicone TOPICAL Emulsion, cream NMQ347994Z 13 % cyclomethicone TOPICAL Lotion NMQ347994Z 4 % DIMETHICONE different viscosity family of polymers; however, above a certain viscosity they all have the SAME tox profile and are all referenced in the same USP monograph. Yet these fluids are assigned different UNII codes In addition, the one listing for TDDS was removed from the IIG list without a trace yet different viscosity dimethicones (e.g. 100, 350 and 1000) have all been used in approved TDDS products, some for more than two decades! dimethicone 360 TRANSDERMAL Film, controlled release Pending 564 dimethicone 1000 ORAL Capsule, enteric coated pellets Pending 2.5 mg dimethicone 350 ORAL Capsule Y53S6ATLU 3.7 mg dimethicone 350 ORAL Capsule, sustained action Y53S6ATLU 0.1 mg dimethicone 350 TOPICAL Emulsion, cream Y53S6ATLU 1 % dimethicone 350 TOPICAL Solution Y53S6ATLU 0.5 % D4 rabbit LD50 skin mg/kg D5 rabbit LD50 skin 15.7 mg/kg dimethicone (0.65-1,000,000 cst) rabbit LD50 skin mg/kg

20 IID Listings for Silicone Wikipedia definition: Silicones are inert, synthetic compounds with a variety of forms and uses. Typically heat-resistant and rubber-like, they are used in sealants, adhesives, lubricants, medical applications (e.g., breast implants), cookware, and insulation. SILICONE silicone is a GENERIC term generally used to describe any number of polymeric materials containing silicon, carbon, hydrogen, oxygen and sometimes other chemical elements. Seldom is the term silicone used to describe a specific chemical molecule or compound yet the term silicone is listed in the IID (and the UNII column shows that numbers are pending). It is my belief that the term silicone referred to below include such forms as: silica, polydimethyl siloxane fluids, gums and elastomers (probably both functional and non-functional) silicone IM - IV Injection Pending silicone INTRAUTERINE Suppository, insert, controlled release Pending 60 mg silicone ORAL Capsule Pending 15 mg silicone ORAL Capsule, hard gelatin Pending 0.42 mg silicone ORAL Capsule, sustained action Pending 0.14 mg silicone ORAL Powder, for suspension Pending 0.1 % silicone ORAL Suspension Pending silicone ORAL Tablet Pending silicone TOPICAL Shampoo, suspension Pending silicone TRANSDERMAL Film, controlled release Pending mg silicone VAGINAL Drug delivery system Pending 8.7 mg silicone VAGINAL Intrauterine device Pending mg

21 IID Listings for Simethicone Taken from the FDA IID SIMETHICONES currently UNII codes have not been assigned to mixtures; however, based on a search of the UNII code nomenclature, components of these products have been listed and referenced separately as dimethicone and silicon. There are several different simethicone products, each potentially being manufactured differently using different viscosities of dimethicone, different types/forms of silica and different additives..but all meeting the simethicone monograph. simethicone ORAL Powder, for oral suspension Multiple 18.9 % SIMETHICONE EMULSIONS currently UNII codes have not been assigned to mixtures; however, see comments above for simethicones.same analogy applies AND, the various simethicone emulsion products available are probably MORE variable (process, dimethicone visc, type/source silica, additives, etc) than even the simethicone products. simethicone emulsion ORAL Capsule, sustained action Multiple mg Taken from the FDA UNII database Preferred Substance Name UNII Substance Name Molecular Formula DIMETHICONE 92RU3N3Y1O Dimethicone component of simethicone C4H12Si(C2H6OSi)n DIMETHICONE 410 TYU5GP6XGE Component of DOW CORNING Q LVA Simethicone C4H12Si(C2H6OSi)n SILICON DIOXIDE ETJ7Z6XBU4 Silicon dioxide component of simethicone 2O.Si

22 Different Viscosity Family of Polymers with Same Toxicology Profile Inactive Ingredient Route; dosage form CAS# UNII Max Potency HPMC Hypromellose/hydroxypropyl methylcellulose chemical composition differences are distinguished only by type, which is defined in compendia monographs, and are based on methoxy and hydropropoxy content. Viscosity is a physical parameter used to differentiate grades within a type. Hypromellose 2208 Capsule, sustained action, ORAL (15000 mpa.s) hard gelatin Z78RG6M2N mg Hypromellose 2208 (15000 mpa.s) ORAL Tablet, sustained action Z78RG6M2N2 480 mg Hypromellose 2208 (60000 mpa.s) ORAL Tablet, extended release 2F7T07H9ZD 175 mg Hypromellose 2208 ( mpa.s) ORAL Tablet, extended release VM7F0B23ZI 54 mg Hypromellose 2910 (15000 mpa.s) Hypromellose 2910 (15000 mpa.s) Hydroxypropyl methylcellulose 2906 Hydroxypropyl methylcellulose 2906 ORAL-21 Tablet 288VBX44JC 0.75 mg ORAL Tablet, enteric coated particles 288VBX44JC 445 mg ORAL Tablet, film coated Pending [none] ORAL Tablet Pending 50 mg

23 Different Viscosity Family of Polymers with Same Toxicology Profile Inactive Ingredient Route; dosage form CAS# UNII Max Potency Ethylcellullose some listings have viscosity grade, others do not Ethylcellulose 20 mpa.s ORAL Tablet, extended release BJG0S321QY mg Ethylcellulose 50 mpa.s ORAL Tablet, extended release 6I475159RA mg Ethylcelluloses ORAL-28 Tablet 7Z8S9VYZ4B 1.05 mg Ethylcelluloses ORAL Tablet, sustained action 7Z8S9VYZ4B mg Carboxymethylcellulose Sodium CMC Sodium ORAL Capsule, sustained action K679OBS mg CMC Sodium ORAL Capsule K679OBS mg CMC Sodium ORAL Tablet, coated K679OBS mg CMC Sodium ORAL Tablet K679OBS mg CMC Sodium ORAL Tablet, sustained action K679OBS mg Methylcellulose Methylcellulose ORAL Capsule, extended release N/A 2.67 mg Methylcellulose ORAL Tablet N/A mg

24 Use of Appropriate Risk Management Concepts Focus should be on high risk issues ICH Q9 Risk Management Guidelines focus should be on higher risk issues FDA leadership (e.g. Hamburg, Woodcock) intent to focus their limited resources into higher risk (to consumer) areas Reality for many common excipients (e.g. hypromelloses, polyethylene oxide, dimethicones, etc) Original safety data generated many years ago for families of products would result in the same data being submitted for each grade of material, multiple times to different reviewers. Safely used often for DECADES without adverse safety events Risk of adverse event due to safety relatively low Is this how resources should be utilized? Is it value added and are we reducing risk??

25 Communication Concerns Need to ensure communication from FDA OGD to the Industry Need to establish on-going dialog between FDA OGD and the industry Need to establish a formal administrative process for future management of IID changes

26 December & March Meetings - Outcomes & Actions FDA posted historical IID files for past 3 years so industry has access to previously listed information Available on the FDA website under Drug Approvals and Databases (01/05/12): htm FDA to consider posting proposed changes a quarter prior to them being made to allow public comment in progress with intent to post on external webpage FDA will determine a mechanism to highlight changes that are made to subsequent postings of the IID - in progress with the intent to post on the external webpage

27 December & March Meetings - Outcomes & Actions FDA and IPEC meeting minutes made available to the public (via the FDA web site, IPEC website, press release, etc.) to provide information to potential sponsors and other interested persons Dec. & Mar. meeting minutes, backgrounder & presentations are posted on the FDA webpage : evelopedandapproved/approvalapplications/abbreviatednewdrugapp licationandagenerics/ucm htm IPEC will poll member companies and develop a list of priority excipients with identified issues based on recent IID list changes IPEC also agreed to contact non-member companies for excipients identified by members of the FDA OGD FDA to develop list of second priority excipients via review of database of Refuse to File letters and the Controlled Correspondence Files

28 IPEC Priority List of Excipients Initial priorities: Polyethylene Oxides Hypromelloses Simethicones with IID Issues 2 nd Tier: Carbomers Sodium Starch Glycolate Hydroxypropyl Cellulose Hydroxyethyl Cellulose Ethylcellulose Polyvinylpyrrolidone Polyethylene Glycol 3000 and other PEGs

29 December & March Meetings - Outcomes & Actions For immediate filing purposes, FDA will accept a summary sheet of pharm/tox data with reference to the specific location of the data in an excipient DMF as justification in lieu of a complete pharmacology/toxicology submission at time of filing provided the full data already exists in a DMF filing OR if relevant references to published studies (e.g. JECFA & EFSA) are provided Applicants that cite pharm/tox information contained within a DMF must provide reference to specific sections/page numbers within the DMF to assist in the review of this material Material cited in the DMF should comply with the expectations found in CDER's Guidance "Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients"

30 December & March Meetings - Outcomes & Actions ANDA sponsors who intend to justify the level of an excipient in a proposed product by citing an IID level for a related excipient within the same family may provide their rationale and summary information to support their assertion ANDAs which include an adequate justification for bridging to a related excipient will meet the standard for filling A more rigorous review of this information will be completed during the technical review of the ANDA

31 December & March Meetings - Outcomes & Actions FDA will explore adding synonyms and trade names to the IID to help companies map to the correct (historical) ingredient listing IPEC to communicate, through their membership, additional information to provide at the time of ANDA filing, especially for historical substance information that has changed in an IID listing IPEC will develop a comprehensive list of excipients which share familial ties for pharm/tox data for justification of specific grades for an excipient IPEC will work with member companies to expedite electronic DMF filings. IPEC will work with FDA to develop a template and process for submitting electronic DMFs

32 December & March Meetings - Outcomes & Actions Meeting minutes provided to GPhA for dissemination to its members Joint collaboration between FDA Excipient Working Group & IPEC Regulatory Subcommittee: Development of Q&A document to further assist potential sponsors Review what should go into a safety data request How maximum dose might be listed How should a map to safety data be supplied to the FDA Utility of UNII: Industry perspective Additional meetings will be held to continue the dialogue IPEC subcommittee ad-hoc members will attend future IPEC- OGD meetings to address targeted questions related to their specific excipients

33 Future Plans - Example Spreadsheet Example of format that might be used in the future to update and improve the type of information and searchability of information in the IID Inactive Ingredient Synonyms Route Dosage Form CAS# UNII Max Potency Max Precedence of Use level for Route HPMC Hypromellose/hydroxypropyl methylcellulose chemical composition differences are distinguished only by type, which is defined in compendia monographs, and are based on methoxy and hydropropoxy content. Viscosity is a physical parameter used to differentiate grades within a type. Hypromelloses Hypromellose 2208 (100 mpa.s) Hypromellose 2208 (250 mpa.s) Hypromellose 2208 (750 mpa.s) Hypromellose 2208 (1,200,000 mpa.s) Hydroxypropyl Methylcellulose Hydroxypropyl Methylcellulose Hydroxypropyl Methylcellulose Hydroxypropyl Methylcellulose HPMC Hydroxypropyl Methylcellulose K-Series Hydroxypropyl Methylcellulose HPMC Hydroxypropyl Methylcellulose K-Series ORAL Capsule, sustained action Based on Safety Data for Family of Related Products CAS # 3NXW29V3W mg mg ORAL mg ORAL mg ORAL mg ORAL mg

34 Future Plans - Example Spreadsheet Column 2 - synonyms to allow for standardization of the names (based on Pharmacopeia naming strategy, when applicable) in Column 1 and an easy search of the database by including historical known IID nomenclature in Column 2 Column 8 - For products where safety data is available to justify a family of related products, this column would contain the historical maximum use level for the ingredient listing from the family having the highest historical use level In order for the FDA OGD to agree to use safety/tox data to support a family of related products, the relevant safety data and, where relevant, bridging documentation, would need to be provided to OGD for their assessment. The source of the safety data might be a reference to a specific DMF (including relevant sections/pages) or to various externally recognized resource references (e.g. published references from JECFA & EFSA studies

35 Future Plans Example Spreadsheet FDA to help define what type of safety/toxicology data would be relevant to them so that industry could tailor their safety data to only include relevant information FDA would make the final assessment whether the safety information provided would be sufficient for them to apply a maximum potency level to a family of related products No spreadsheet approved yet this is a future process still TBD

36 Future Plans Example Spreadsheet Additional column could be added to include Maximum daily dose approved in a previously approved drug product Known daily dose levels for use in food additives could be provided by many excipient makers Known daily dose levels for use in drug products could come from FDA databases or the user community An up-front assessment of Maximum daily dose levels would align with current QbD initiatives and could help minimize OGD safety data reviews for applications with higher than historically approved maximum potency level (e.g. a new ANDA with higher dose) for an intended route of delivery

37 Actions for Excipient What can you provide to FDA now? Bridging document Suppliers & Users Archived IID limits can be used but this document will explain why the current submission is covered by that data Example: Archive: Hypromelloses mg - oral tablet Current submission: HPMC 2910, mpa.s 200 mg oral tablet Summary of studies on various grades to demonstrate why this grade is covered reference DMF/existing studies FDA will not build your rationale they expect the generic company to provide the explanation Users may need more information than before referencing the IID may no longer be sufficient Excipient suppliers will need to provide users with a safety summary and reference to DMF volume & page #s

38 How to Submit IID Questions to FDA FDA currently has a Controlled Correspondence Webpage where interested parties can send their questions specific to IID information (e.g. maximum daily dose for an excipient) Turn-around time for response is around 60 days Results received from the FDA should be included in an ANDA submission, when applicable IPEC members agreed to communicate the existence and pathway to the web-address for the Controlled Correspondence Webpage to their members and on their webpage

39 FDA Information FDA Control Correspondence webpage MedicalProductsandTobacco/CDER/ucm htm Mailing address: Control Correspondence Coordinator Office of Generic Drugs (HFD 600) Metro Park North VII 7620 Standish Place Rockville, MD Fax number:

40 Impact Outside the US? Currently a US focused issue for generic drugs Other countries have their own systems for drug approvals (e.g. EU, Japan, China) BUT other countries may reference the IID as an unofficial guide and could model their system after the US FDA s IID

41 How Can Your Company Get Involved? IPEC Americas Regulatory Affairs Subcommittee core team is looking for (ad-hoc) additional members & experts to discuss the process & data at future IPEC and FDA meetings Provide input on excipients that should be on the prioritized list

42 Questions? Thank you!