The California ePedigree law goes into effect for manufacturers in 2015/2016. In mid-2016 distributors and repackagers will need to comply. The California pedigree law includes the need for manufacturers and repackagers to serialize drugs at the smallest level of distribution to pharmacies. That’s just one of the requirements, they also need to make reference to those serial numbers in the ePedigrees that they create (manufacturers) or update (repackagers, distributors and pharmacies). (For more on the full pedigree regulation see my essays “The California Pedigree Law” and “California Pedigree Law: Historic Change To Commerce”). The implications of this to repackagers are unique. Let’s explore why.
REPACKAGING TODAY—PRE-SERIALIZATION REGULATIONS
Today companies who repackage pharmaceuticals for the U.S. market do a wide variety of repackaging operations to fill an even wider number of needs for the industry. (This essay is not about repackaging in other countries which is often done for other reasons including localization of label language, numbering and other regulatory requirements.) These may include:
Spread the contents of larger quantity manufacturer packages to smaller quantity repackaged packs. An example is the repackaging of 1000-count bottles into 30-count bottles (33.33 output bottles per input bottle in this instance).
Combine multiple smaller quantity manufacturer packages into larger quantity repackaged packs. An example is the repackaging of 30-count bottles into 1000-count bottles (33.33 input bottles per output bottle in this instance).
Combine the contents of multiple manufacturer packages into multiple repackaged packs. This scenario occurs whenever a repackager makes use of a hopper, filler bowl or automatic bulk dispenser of some kind. Multiple manufacturer packages of a given drug are emptied into the hopper/bowl/dispenser before the first output package is filled and the hopper/bowl/dispenser is repeatedly replenished to maintain a supply buffer as the dispensing process proceeds.
Spread the contents of a multi-dose manufacturer package into single-dose packages.
- Convenience kits
Construct kits that include smaller quantities of drugs (and often one or more “devices”) than the manufacturer packaged for individual sale.
I’m not going to go into detail about why every one of these repackaging operations are done but in general they are done for improved economics and the convenience of various kinds of pharmacies or clinical dispensaries.
Today, the FDA regulates repackagers very much like they regulate the packaging operations of original drug manufacturers. There are special regulatory provisions for dealing with lot/batch (input and output) and expiration dates. All of that is beyond the scope of this essay.
In 2006 the FDA issued a proposed rule which, among other things, if adopted into an FDA Final Rule would require repackagers to apply for their own FDA Labeler Code and use it to create and “list” their own National Drug Codes (NDCs) to identify the output packages of their repackaging operations. Up to that time it had been common practice for repackagers to mark their output packages with the same NDC as one of the original manufacturer’s original packages.
That resulted in confusion over who “owned” the NDC and the resulting GTINs that were based on the NDC and who had the right to apply it to their packaging (see my essay “Depicting An NDC Within A GTIN“). It sometimes resulted in confusion over the “Package Size” field of the NDC whenever the repackaging operation resulted in an output package that was a size that the original manufacturer did not make. It also seemed to defeat the apparent purpose of the “Labeler Code” portion of the NDC which seems to imply that it identifies the entity who “labeled” the product, not necessarily the manufacturer of the drug itself (see my essay “Anatomy Of The National Drug Code“).
The proposed rule was used to collect input from the industry and interested parties. As far as I can tell the proposed rule has not yet become an FDA Final Rule and so it cannot yet be enforced, but it has apparently caused some (perhaps many) repackagers to start complying with the potential regulation even before it is made final. These companies have decided to list and mark their repackaged drugs with their own NDCs rather than those of the original manufacturer of the drug. On the other hand, once the patient receives the actual drug the repackager’s package has typically already been discarded and the NDC of the actual dose will now indicate that of the repackager instead of the manufacturer of the drug itself. It seems like that might cause its own confusion at certain times.
REPACKAGING DRUGS UNDER A SERIALIZATION REGULATION
The California pedigree law contains the following references to drug repackagers:
Section 4034 of the California Business and Professions Code “(c) A single pedigree shall include every change of ownership of a given dangerous drug from its initial manufacture through to its final transaction to a pharmacy or other person for furnishing, administering, or dispensing the drug, regardless of repackaging or assignment of another National Drug Code (NDC) Directory number.”
Question 50 of the “Questions And Answers Relating To The California Electronic Prescription Drug Pedigree Law(s)” published in draft form by the California Board of Pharmacy in January 2008 says:
“Q50 What are California’s definitions of ‘manufacturer’ and ‘wholesaler’?
For the purposes of prescription drugs or devices, California law defines a ‘manufacturer’ as any person who prepares, derives, produces, compounds, or repackages any drug or device except a pharmacy that manufactures on the immediate premises where the drug or device is sold to the ultimate consumer. (B&P § 4033(a), (b), (c); see also H&S § 109970.) A ‘wholesaler’ is any person who acts as a wholesale merchant, broker, jobber, customs broker, reverse distributor, agent, or a nonresident wholesaler, who sells for resale, or negotiates for distribution, or takes possession of, any dangerous drug or device. (B&P § 4043(a).)”
Question 58 is particularly pertinent:
“Q58 What is the role of a repackager with regard to receipt and generation of pedigrees?
In California, an entity that repackages prescription drugs is licensed as a manufacturer. (B&P § 4033(a); H&S § 109970.) When a drug is repackaged, it may typically (but not always) acquire a new National Drug Code (NDC) number, a new lot number and perhaps a new expiration date.
The pedigree law mandates that a single pedigree shall include every change of ownership of a given dangerous drug from its initial manufacture through to its final transaction to a pharmacy or other person for furnishing, administering, or dispensing the drug, regardless of repackaging or assignment of another NDC number. (B&P § 4034(c).)
Accordingly, the repackager must receive (from the manufacturer, wholesaler, or other source of the drug) a pedigree with the prescription drug documenting all transactions resulting in a change of ownership up through receipt by the repackager, and all of the new pedigree information (e.g., new NDC number, etc.) must be documented on the original pedigree, certified under penalty of perjury, and passed on/ continue with the newly repackaged prescription drug.
The board is interested in further data and information on the repackaging industry, particularly on the topic of compliance with the requirement of maintenance of a single pedigree.”
The Q&A document was published in January of 2008, but in the fall of 2008 the California Legislature passed the Ridley-Thomas bill (SB 1307) that, among a few other things, set the current enforcement schedule. While the California Business and Professions Code, as quoted above, defines a drug repackager as a drug manufacturer, the enforcement schedule enacted in the Ridley-Thomas bill explicitly sets the enforcement time for repackagers to be the same as the distributors: six months after the last date for compliance by manufacturers. This makes sense because repackagers can only comply with the regulations if they are able to receive valid pedigrees with the serialized drugs they purchase for repackaging. The six month delay gives repackagers the time necessary to obtain drugs that are serialized and pedigreed from the manufacturers before they are required to comply.
There is some confusion in the industry about how to link the NDC and serial number of the repackaged drugs with the original manufacturer’s NDC and serial number on the source drug packages. This linkage cannot be done within an RFID tag or a barcode. That’s because these data carriers are not “the pedigree”. The linkage can only be done properly within the external electronic pedigree itself. For example, the GS1 Drug Pedigree Messaging Standard (DPMS) includes a repackaging pedigree layer with all of the data fields necessary to link these NDCs and serial numbers.
By the way, for those of you counting the ways that GS1’s Electronic Product Code Information Services (EPCIS) standard alone won’t work for compliance with the California pedigree law, here’s another one. There is currently no standard way to link incoming package EPC’s to outgoing repackaged EPC’s on drugs using that standard. There has been talk behind the scenes but nothing has been published in a standard or even otherwise. (See my earlier essays “Why GS1 EPCIS Alone Won’t Work For California Pedigree, Part 1” and “Part 2”.)
HOPPERS, FILLER BOWLS AND BULK DISPENSERS MAY BE PROBLEMATIC
The use of hoppers, filler bowls or automatic bulk dispensers in the Multiple-to-Multiple repackaging scenario may be problematic under a serialization regulation. The need to link the original manufacturer’s NDC and serial number to the repackager’s NDC and serial number becomes complex when exact boundaries of input packages to output packages cannot realistically be determined. The hopper/bowl/dispenser acts as a buffer so that the operation can be done at high speed. But this is exactly what causes the package boundaries to be indeterminable. Drugs from multiple input packages can mix and intermingle with those of other input packages before a unique mix is deposited into the output packages.
The problem is, which input package serial number(s) do you link to a give output package serial number?
One possible solution to this problem is to link all input package serial numbers that have been placed into the hopper/bowl/dispenser prior to each output package being filled. Those serial numbers would represent every possible input package up to the moment that an output package is filled. Each successive output package would end up being linked to more and more input packages to the point where the last package filled by the hopper/bowl/dispenser would be linked to every single input package that had been deposited into it.
That might be a lot of packages, and correspondingly, a lot of serial numbers. As long as all of those input packages share the identical pedigree it might not be too bad, but if every input package has a different pedigree, the resulting output pedigrees could get very complex. In fact, I’m not even sure at this moment if DPMS can properly document that complexity.
Hoppers, filler bowls and automatic bulk dispensers are critical to a significant portion of the repackaging business of most repackagers. If they can’t use those components under a serialization regulation it would significantly change their business formula. Fortunately it appears that the California Board of Pharmacy recognizes issues like this. Note the last sentence in the answer to Question 58 above. Repackagers should take advantage of that invitation and work with the board to work out this and any other issues before the regulation goes into effect.
THE FDA AND REPACKAGING USING SNI
Ordinarily the non-binding FDA guidance on Standardized Numeric Identifiers (SNI) wouldn’t offer any particular guidance on compliance with a California state law, but the SNI guidance document contains a very logical example of repackaging that I think certain repackagers should pay close attention to. Here is the example:
“…For the purpose of this guidance, FDA considers the prescription drug package to be the smallest unit placed into interstate commerce by the manufacturer or the repackager that is intended by that manufacturer or repackager, as applicable, for individual sale to the pharmacy or other dispenser of the drug product. Evidence that a unit is intended for individual sale, and thus constitutes a separate ‘package’ for purposes of this guidance, would include the package being accompanied by labeling intended to be sufficient to permit its individual distribution. For example, if a manufacturer’s smallest unit of sale package is a container holding six drug-filled syringes, a single SNI would be the package-level identifier for the container holding the six drug-filled syringes; there would be no SNIs for the individual syringes, not intended by the manufacturer for individual sale. If a repackager then breaks that container down and repackages each syringe for individual sale, then the repackager must ensure that appropriate labeling accompanies each individual syringe and a new and unique SNI would be the package-level identifier for each individual syringe and a new and unique SNI would be the package-level identifier for each new package (e.g., each individual drug-filled syringe). SNIs applied to each new package by the repackager are to be linked back to the manufacturer’s SNI for the container of six drug-filled syringes (505D(b)(2)). …”
This example may be very instructive for repackagers who perform this specific type of unit-dose repackaging. This may include companies who are in the business of building emergency response kits for dental and doctor’s offices. These kits are commonly composed of single doses of various medications (like Epinephrine, Atropine and Solumedrol injections for example) that are most often needed for unexpected reactions by patients in those kind of offices.
Like the FDA’s example, the drugs included in these kits are normally sold by the original manufacturers in multi-packs that are meant by them to be the smallest unit of sale so the single-dose form doesn’t always have a specific NDC. The single-dose form is also not packaged by the original manufacturer for distribution or sale. These kit-makers break those multi-packs down further into the single-doses and package them into their kits.
For the purposes of the FDA SNI guidance, these companies appear to be acting as a repackager of unit-dose medication and, to properly follow the guidance, they may want to apply their own NDC to each single-dose unit and serialize them using the sNDC approach defined in that document (see my recent essay “Anatomy Of An FDA SNI”). Applied to California, the sNDC’s on the single-dose packages could then easily be linked to the sNDC of the manufacturer’s multi-pack in the electronic pedigree.
Does the FDA SNI guidance example offer any good advice for repackagers to help them know how to comply with California? Is the example in the FDA SNI guidance the only way for these companies to comply with the California pedigree law? I don’t know. Companies should review the source material, check with the California Board of Pharmacy and draw their own conclusions, but the example seems to make a lot of sense.
If you can think of other implications of the California pedigree law that are unique to repackagers leave a comment and share your thoughts.