The Hidden Orange Book: Breaking Up Is Hard to Do (But Sometimes It’s for the Best)

March 29, 2017By Kurt R. Karst

Cue up Neil Sedaka’s 1962 hit “Breaking Up Is Hard to Do,” or, for some of us younger-minded folk, take your pick from one of many Taylor Swift songs (“We Are Never Ever Getting Back Together,” “I Knew You Were Trouble,” and so many more).  What could break-up songs have to do with the Orange Book, you ask?  More than you think!

We try hard not to judge a book by its cover (though that can be difficult given the subject matter here). Instead, we try to look at the substance behind the cover.  And when you do, you realize that there’s a lot of information packed into the 1,400 pages of the current annual print edition of the Orange Book (and just as much information, though organized a bit differently, in the electronic and app versions of the publication).  But, despite all of that information, the Orange Book has her secrets.  During this blogger’s long relationship with the Orange Book, she has revealed (or let us discover) some of her hidden secrets.  Perhaps her biggest secret – and one that has frustrated us at times, sometimes causing a rift in the relationship, and delighted us at other times, bringing us closer together – is that some product listings are more than they appear.  It’s a result of historical baggage.

Beginning with the publication of the 23rd (2003) edition of the Orange Book, FDA clarified that certain injectable drug products should be identified in the publication on a strength-by-strength basis. This clarification (which we’ve noted before in the context of PDUFA user fees) states, in relevant part (in the current 37th [2017] edition of the Orange Book):

Consistent with the definition of strength included in Section 1.2,Therapeutic Equivalence-Related Terms, the strength of parenteral drug products generally is identified by both the total drug content and the concentration of drug substance in a container approved by FDA. In the past, the strength of liquid parenteral drug products in the Orange Book has not been fully displayed.  Rather, the strength of liquid parenteral drug products in the Orange Book has been displayed in terms of concentration, expressed as xmg/mL.  Generally, the amount of dry powder or lyophilized powder in a container is identified as the strength, expressed as xmg/vial.

With the finalization of the Hatch-Waxman Amendments that characterized each strength of a drug product as a listed drug, it became evident that the format of the Orange Book should be changed to reflect each strengthof a parenteral solution. To this end, the Orange Book now displays the strength of all new approvals of parenteral solutions.  Previously, we would have displayed only the concentration of an approved parenteral solution, e.g. 50mg/mL.  If this drug product had a 20 mL and 60 mL container approved, we would now display two product strengths for this product, listing both total drug content and concentration of drug substance in the relevant approved container, e.g. 1Gm / 20mL (50mg/mL) and 3Gm / 60mL (50mg/mL).

But while new products – injectables and other products, like those in metered doses – are broken out and displayed in the Orange Book on a strength-by-strength basis, older products generally are not . . . at least not until there’s a need for FDA to clarify the Orange Book. Let’s use an example:

Drug X was approved under NDA 999999 on January 2, 2000 in multiple strengths and was listed in the Orange Book as follows:





    2.5MG/ML    NDA 999999  001    Jan 2, 2000

    5MG/ML      NDA 999999  002    Jan 2, 2000

    10MG/ML    NDA 999999  003    Jan 2, 2000

    20MG/ML    NDA 999999  004    Jan 2, 2000

The “How Supplied” section of the prescribing information for Drug X describes each product identified above in terms of both concentration and container size (fill volume):

  1. 25 mg/10 mL (2.5 mg/mL)
  2. 50 mg/20 mL (2.5 mg/mL)
  3. 250 mg/100 mL (2.5 mg/mL)
  4. 500 mg/200 mL (2.5 mg/mL)
  5. 50 mg/10 mL (5 mg/mL)
  6. 100 mg/20 mL (5 mg/mL)
  7. 500 mg/100 mL (5 mg/mL)
  8. 1000 mg/200 mL (5 mg/mL)
  9. 100 mg/10 mL (10 mg/mL)
  10. 200 mg/20 mL (10 mg/mL)
  11. 1000 mg/100 mL (10 mg/mL)
  12. 2000 mg/200 mL (10 mg/mL)
  13. 200 mg/10 mL (20 mg/mL)
  14. 400 mg/20 mL (20 mg/mL)
  15. 2000 mg/100 mL (20 mg/mL)
  16. 4000 mg/200 mL (20 mg/mL)

Thus, despite the Orange Book showing only 4 separate drug products approved under NDA 999999, there are, in reality, 16 separate drug products approved under NDA 999999 as a result of FDA’s definition of the strength of an injectable drug product as both a function of concentration and container size (fill volume).

Under the scenario above, and depending on the patent estate for Drug X, there might be 16 different opportunities for 180-day exclusivity for an ANDA applicant. . . . or multiple opportunities for a subsequent ANDA applicant to be blocked by a first applicant’s eligibility for 180-day exclusivity. (And that’s why breaking up is hard to do, but sometimes it’s for the best.)  That means generic drug manufacturers need to carefully review not only the Orange Book, but also the “How Supplied” section of the prescribing information for a particular brand-name drug product still identified in the Orange Book with the old concentration-only strength nomenclature.

Time will usually cause the Orange Book to finally reveal the various drug products approved and bundled under a particular NDA. It may start with an entry on FDA’s ANDA Paragraph IV Patent Certifications List that does not appear to comport with an Orange Book drug product listing.  And then FDA may finally update the Orange Book to break-out and identify various sub-drug products when an ANDA for a particular concentration and fill volume is approved (or when a decision on 180-day exclusivity is made).  It’s a bit of a flawed system that probably should be revised so that ANDA applicants have the information necessary to make important drug product submission decisions sooner rather than later.  And FDA might just collect additional PDUFA drug product user fees along the way.