Flexible and Pending Monographs

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1 Flexible and Pending Monographs USP Approaches to Accommodate Multiple Approved Products Doreen McDonald Senior National Account Manager U.S. Pharmacopeial Convention

2 Flexible Monographs: Background From USP Guideline for Submitting Requests for Revision to USP-NF V5 January 2011 Flexible Monographs At times, an ingredient and/or a drug product, including dietary supplement ingredients and products and biologicals and biotechnological ingredients and products, exhibit different attributes that have been determined by the FDA not to impact their safety and/or efficacy, i.e., their identity as official ingredients and products impurities, hydrates, and dissolution cases. In these instances, USP will allow different tests, procedures, and/or acceptance criteria reflecting these different attributes within a single monograph, with suitable validation, under its flexible monograph approach. 2

3 Flexible Monographs: Rationale Flexible to account for different routes of synthesis Control of impurities utilizes the approaches contained in ICH Q3A, Q3B, and Q3C Multiple dissolution procedures, especially for extended release products Considers hydrates/solvates, polymorphs Unambiguous document in support of ORA inspection May need procedure-specific USP Reference Standards 3

4 Flexible Monographs: Labeling General Notices : Applicability of Test Procedures multiple procedures may be included in particular monographs specifically for the purpose of assuring the availability of an appropriate procedure for a particular product. In such cases, a labeling statement to indicate the appropriate application of the procedure(s) will be included in the monograph. A labeling statement is not required if Test 1 is used. 4

5 Flexible Monographs: Labeling Always follow the Labeling requirement in the monograph label indicates which (test) is used label indicates which (test) is used if it does not meet Test 1 Not always same for APIs or Drug Products May be Labeling requirement called out as a monograph component May be requirement defined within a Test 5

6 Flexible Monographs: Examples Loratadine Drug Substance Meloxicam Drug Substance Paclitaxel Drug Substance Paroxetine Drug Substance Potassium Chloride Extended-Release Tablets Theophylline Extended-Release Capsules 6

7 Flexible Monographs: Specific Example #1 Loratadine drug substance Labeling If a test for Related compounds other than Test 1 is used, then the labeling states with which Related compounds test the article complies. Related compounds [note On the basis of the synthetic route, perform either Test 1 or Test 2. Test 2 is recommended if 4,8-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin- 11-one is a potential related compound. ] TEST 1 TEST 2 7

8 Flexible Monographs: Specific Example # 1 (cont.) USP Reference standards <11> USP Loratadine RS USP Loratadine Related Compound A RS 8-Chloro-6,11-dihydro-11(4-piperidylidene)-5Hbenzo[5,6]cyclohepta[1,2-b] pyridine. C19H19ClN USP Loratadine Related Compound B RS 8-Chloro-6,11-dihydro-11(N-methyl-4-piperinylidene)-5Hbenzo[5,6]cyclohepta[1,2-b]pyridine. C20H21ClN USP Loratadine Related Compound A and B RS are called for only in TEST 2 8

9 Flexible Monographs: Specific Example #2 Meloxicam drug substance IMPURITIES Organic Impurities, Procedure 1, Perform either Procedure 1 or Procedure 2, depending on the manufacturing process used (Test details ) Organic Impurities, Procedure 2, If an article complies with this test, the labeling indicates that it meets the requirements under Organic Impurities, Procedure 2. (Test details ) 9

10 Flexible Monographs: Specific Example #3 Paroxetine Hydrochloride Labeling Label it to indicate whether it is the anhydrous or the hemihydrate form. Label it to indicate with which impurity tests the article complies. Chromatographic purity [note On the basis of the synthetic route, perform either Test 1 or Test 2. Test 2 is recommended if paroxetine related compound F or paroxetine related compound G is a potential related compound. ] 10

11 Flexible Monographs: Specific Example #4 Potassium Chloride Extended-Release Tablets Labeling The labeling states with which Assay preparation the product complies only if Assay preparation 1 is not used. Assay Assay preparation 1 Assay preparation 2 (For formulations containing crystals coated with hydrophobic polymers) 11

12 Flexible Monographs: Specific Example #5 Theophylline Extended-Release Capsules Labeling The labeling indicates whether the product is intended for dosing every 12 or 24 hours, and states with which in vitro Dissolution Test the product complies. FOR PRODUCTS LABELED FOR DOSING EVERY 12 HOURS TEST 1 If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 1 TEST 2 TEST 5 TEST 9 TEST 3 TEST 7 TEST 10 TEST 4 TEST 8 12

13 Flexible Monographs: Specific Example #5 (cont.) Theophylline Extended-Release Capsules FOR PRODUCTS LABELED FOR DOSING EVERY 24 HOURS TEST 6 If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 6. 13

14 Pending Monographs: Objectives Enables monograph development and publication before FDA approval has been granted to a generic manufacturer Ultimate purpose is to have an official USP-NF monograph ready as soon as possible after FDA approval of an application (i.e., ANDA, BLA) USP Pending Monographs web site is 14

15 Pending Monographs: Sponsor Requirements Available to sponsors who have filed or intend to file with FDA an Abbreviated New Drug Application (ANDA) or Abbreviated New Animal Drug Application (ANADA) within six months; or Who have filed or intend to file with FDA a Biosimilar or Interchangeable Biologics License Application (a Public Health Service Act 351(k) BLA) within six months; or Who have submitted a Drug Master File (DMF) for an article to FDA; or Whose substance is or will be the subject of a Time and Extent Application or citizen petition to amend an FDA OTC drug monograph. 15

16 Pending Standards: Requirements Documentation Statement of intent to file an ANDA, ANADA or BLA within six months Copy of the DMF filing letter Confidentiality Sponsor may request that all or part of Request for Revision be viewed only by USP and FDA for a specified time before the Draft Pending Monograph is posted 16

17 Pending Standards: Process Three main stages for Pending Monographs: Draft (on USP website; 90-day comment) Authorized (by USP Expert Committee) Official in USP/NF (by Revision Bulletin after sponsor receives FDA approval) 17

18 Pending Monographs: Process Sponsor submits monograph; development begins Draft Pending Monograph is posted for 90-day public review period Relevant Expert Committee(s) ballots Not approved Approved Authorized Pending Monograph is posted Determine next steps FDA approves Sponsor s ANDA, ANADA or BLA Relevant Expert Committee(s) ballots Not approved Approved Pending Monograph becomes official via Revision Bulletin (Official date is not less than 6 mos. after the posting) Official monograph published in USP-NF or Supplement 18

19 What if there is an existing official USP or NF monograph? If there is an existing official USP or NF monograph, then information from the Authorized Pending Monograph will be merged with the existing monograph, as appropriate, to create a monograph that reflects all FDA-approved articles (see the Guideline for Submitting Requests for Revision to USP NF). This revision to the existing monograph will advance to official status in the USP-NF via a Revision Bulletin and will be official six months after posting. 19

20 Commentary Minor changes to the original proposal are acceptable without another round of public review and comment; however, the EC needs to consider the impact of more substantial changes. Generally, acceptance criteria should not be tightened based on comments received without republication. Pending Monographs include Commentary information in the Briefing rather than in a separate document. 20

21 USP Reference Standards Unless USP determines otherwise, if the proposed monograph includes the use of a new USP Reference Standard then USP will not publish the proposed monograph on its Web site until it has received the necessary reference material bulk candidate(s) Any USP Reference Standard developed in support of a Pending Monograph may be available for sale at any time before or after Web site publication of the Draft or Authorized Pending monograph 21

22 Pending Monographs: Status 132 unique Pending monographs published to date 33 currently in Draft 77 currently Authorized 22 have migrated to Official status in USP-NF Approximately, 75% of Pending monographs are received and 36% are published by USP before receipt of a proposal from an NDA or ANDA holder. 22

23 Flexible and Pending Monograph: Summary Flexible and Pending monographs improve public health by Enhancing the traditional path of USP-NF revisions Broadening the applicability of USP-NF standards to be more inclusive Allowing earliest participation of ANDA/ANADA/BLA applicants in the development of new monographs 23

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