Pharma Serialization, Aggregation and DSCSA

Why Aggregation is the Secret Sauce in Warehousing Serialized Prescription Drugs

Why Has Serialization Become Necessary in the Pharma/Life Sciences Industry?

  • Helps to eradicate counterfeit prescription drugs and protect consumers
  • Serialization increases the efficiency of the pharma supply chain
    • Improves inventory visibility
    • Enables collection of advanced metrics that can be used for analytics
  • Aids in reducing or eliminating reimbursement fraud
  • Prevents patients from collecting multiple prescriptions for the same drug
  • Facilitates patient treatment regimen compliance

So, you have taken the first steps towards serialization, now what?

In implementing drug serialization, there is one nagging problem.  Putting a unique serial number on every bottle or package containing pharmaceuticals that will be distributed commercially makes it problematic to determine which bottles or packages were put into which cases.  Without unpacking and scanning each case, how would one know the serial numbers each case contains?

The answer is aggregation.  In the world of unique identifiers, the process of aggregation involves capturing and maintaining parent-child relationships between different packaging levels of goods.  Serialized at the saleable unit level, the serial number is associated with those units in the next level of the packaging hierarchy, the shipper cases.  The aggregation process continues by associating the serialized GTINs or SSCC numbers linked to the shipper cases with pallets, each of which has a unique SSCC number. Tying together and maintaining all the serial numbers in the packaging hierarchy enables supply chain partners to “infer” the contents of a container by simply scanning a barcode.

What Is Aggregation?

The process by which data relationships are built between unique identifiers of saleable units, the cartons into which they are packed, and the next level of packaging, cases and pallets is known as aggregation.  The data is then used by supply chain partners to “infer” that the correct goods and quantity are enclosed within the respective carton, case or pallet without having to open each and conduct an inspection.

Aggregation is the process in which every participant along the pharmaceutical supply chain receives information from its predecessor and then supplements this with its own data.  Data aggregates are stored in a database and then passed along to the next partner along the pharmaceutical supply chain.  The data can be requested at any time and includes aggregation data of the primary, secondary and tertiary packaging. 

Across the World, Serialization Is Being Adopted

Adoption of requirements for serialization and globally unique drug identifiers is increasing to protect the pharma supply chain:

  • Argentina
  • South Korea
  • Saudi Arabia
  • Turkey
  • Brazil
  • India
  • EU Falsified Medicines Directive (FMD)
    • Creates a harmonized unique drug product identifier across Europe

Serial numbers must be organized, printed then sent through national verification processes.  By 2020, it has been estimated that nearly 90 percent of prescription drugs globally will be serialized. Although neither the U.S. DSCSA nor the EU FMD requires the capture or use of aggregation data, in order to streamline pharma operations, aggregation is necessary.

Aggregation enables all companies along the pharma supply chain to build a serialized relationship between unique identifiers that are assigned to packaging containers, facilitating requirements in the U.S. FDA regulation DSCSA and the EU Falsified Medicines Directive (FMD).

Aggregation creates the serialized package hierarchy data to support inference, essential to facilitating the authenticity of medications relatively easily.  Pharmaceutical companies use aggregation to collect and analyze multiple parameters for medications produced on their premises.

While there are not widespread requirements for aggregation at this point, some companies utilize it to facilitate their commercial trade practices and ensure greater efficiency of supply chain operations.  Aggregation is the logical extension of regulatory and industry efforts to secure and strengthen the pharmaceutical supply chain.

Reasons for Aggregation:

  • Simplifies reporting
  • Streamlines verification of the drug product along the supply chain
  • Aids in track and trace
  • Enables faster adaptation to new export markets
  • Aids in decommissioning shipment pallets in bulk
  • Facilitates management of inventory returns
  • Aids manufacturers in performing targeted recalls of specific drug product units
  • Helps produce process improvements that result in cost savings

How Aggregation Works:  The Packaging Perspective

Aggregation can be achieved in numerous ways, depending upon the kind of packaging components and packaging equipment used as well as the level of automation on the packaging line.  Unit level serialization, the initial step in the aggregation process is accomplished by positioning a serial number on a bottle or carton label.  

Often this occurs before packaging, however more frequently this is done at the time of packaging. 

The next step involves associating a shipper case with serialized units and applying a shipper case label with a unique serial number.  Usually, a serialized GTIN is used in the U.S., in which the shipper case has a specific GTIN. An SSCC which is product agnostic can also be applied in order to meet the unique serial number requirement.  After being packed and finally sealed, shipper cases are positioned on pallets.  Pallet SSCC numbers are then associated with the serial numbers of the shipper cases.

Returns Management and Aggregation

The process of returning pharmaceutical and life sciences goods is often problematic for many pharmaceutical supply chain partners.  Using aggregation, pharmaceutical manufacturers and wholesale distributors are able to match up returned goods with the original shipment using serial number information.  This will ensure that the product sellers are returning goods that they have actually purchased and facilitate the application of credits to the products with original transactions.

Learning How Inference Works in Aggregation

Inference depends upon the validity of the information and the level of trust between the supplier and customer.  Without being able to trust that the aggregation information provided by the supplier is 100% accurate, nothing can be accomplished.  That complete level of trust enables companies to eliminate the need to open every shipper case and verify the serial number of every carton or bottle.  The contents would need to be removed from each case and the serial numbers scanned on each package to capture information on goods being received or shipped.  The goods would then have to be packed up again, resealed and readied for shipment.  The entire process would bog down the drug distribution system.  Prescription drugs would move more slowly through the pharmaceutical supply chain, causing distribution costs to escalate.  In addition, there would be more opportunities for errors and theft, diminishing drug security.

Following production, drug manufacturers usually pack pharmaceutical serialized unit packages into shipping cases.  The shipping cases bear serial numbers.  Shipping cases are stocked in the manufacturer or contract manufacturer’s warehouse or distribution center before being shipped to customers.  Once the wholesale distributors receive the shipping cases, warehouse workers open most of the cases so that customer orders can be fulfilled.  Small quantities of unit packages are typically moved to totes for delivery.  Case-level aggregation is no longer needed once the manufacturer’s case is opened by the distributor and individual packages are removed from the case.  At this point, the drug distributor usually reads the unit-level serial numbers on each package as customer orders are being picked and fulfilled.  The ePedigrees are then updated showing that the shipment was made to the customer.

Large customer orders may necessitate that the distributor deliver entire case quantities, eliminating the need to open the manufacturer’s case.  In this instance, the manufacturer’s aggregation information would be relied upon regarding the unit package serial numbers that are shipped to the customer.  The information would need to be updated and the correct unit-level ePedigrees would be passed on to the customer.  The aggregation information provided by the manufacturer would be supplied to the customer for the cases that were shipped as well as the related ePedigrees for the packages contained.  The distributor’s customer would likely use the same aggregation information to update the ePedigrees that they received from the distributor to eliminate the need to open each case and read the unit-level serial numbers on every package.

This common scenario demonstrates the urgent need for complete, accurate serial number data.  Each supply chain partner depends upon the accuracy of this information up and down the pharmaceutical supply chain.  What if there is a mistake, if the aggregation information is incorrect at some point?  Mistakes can be made; numbers can be transposed.  This can be a serious, costly problem.  If a supply chain partner cannot find any record of the serial number and does not have a valid ePedigree for the packages, the drug products cannot be sold, returned or dispensed until the discrepancy is resolved.  If the discrepancy occurs between two cases of goods, both errors must be resolved.  Working backward from the supplier, it would be necessary to trace the goods back to the manufacturer to resolve the error.

When a manufacturer agrees that a mistake was made, it is possible for them to transmit the corrected ePedigree to the distributor.  The drug distributor would then update the ePedigrees that were corrected to reflect the amended shipment information and transmit it to their customer.  The customer would also need to update the rectified ePedigree and would be able to sell, return or dispense the drug products.

During the time that each of these corrections were being made, the drug products would be idle and need to be properly warehoused and handled.  Depending upon the shelf life, drug product cost and length of time required to correct the error, the cost could be significant, especially when considering the cost of the labor to research and rectify the mistake.

How to Ensure That the Aggregation Information is 100% Accurate

Adjusting your approach to aggregation can result in aggregation accuracy.  To achieve this, unit-level serial numbers should only be read after the packages are linked in a serialized grouping such as an inner-pack or full case grouping. 

Aggregation Using RFID

Using RFID tags with RFID readers can be very effective in ensuring aggregation accuracy.  An RFID reader can read through cardboard and identify all of the RFID tags in short order as it does not need to be within the “line-of-sight to work effectively.

Applying a unique RFID tag to each package would mean that the case packing operation could be executed without modifications.  Next the case would be sealed.  An RFID tag which contains the case-level serial number would be attached to the case.  The case would then be passed through an RFID reader.  All of the unit-level serial numbers and the case-level serial number would be read and associated with each other, forming the aggregation information for that case.  Sealing the cases before reading the serial numbers ensures that no mix ups can occur between cases.  In the event that an RFID reader does not identify all of the expected serial numbers, that specific case would be rejected.  Quality inspections and re-work would be necessary to correct the issues. 

Aggregation Using 2D Barcodes

Although barcodes do require “line-of-sight” to operate, the cost tends to be substantially lower than that of using RFID tags with RFID readers.  Some pharmaceutical manufacturers now install temporary inkjet-printed 2D barcodes onto the bottom of empty drug product bottles.  Within the barcode is a unique “bottle identification number” (aka bottle ID).  This number is unique to all the bottles within the current batch of the drug product that is being bottled.  Using this temporary barcode enables tracking of the bottles within the packaging and case packing operation.  This inkjet printed barcode is only used during the packaging operation.

The bottles are filled with the drug after the temporary bottle ID barcode is affixed then the bottles are capped, and the serialized drug label is applied.   The serialized drug label would include the unique serialized National Drug Code encoded within a 2D GS1 DataMatrix barcode image.

Once the label has been applied, a traditional vision system camera would verify that the barcode, lot and expiration date is legible.  A second camera may also be used to simultaneously read the bottle ID barcode at the bottom of the bottle.  To associate the serialized National Drug Code number with the bottle ID, a line management system is typically used.  As these two serial numbers are unique, the association of these two numbers is also unique.

At this stage, drug product bottles can now be bundled together into inner-packs.  Wrapped in clear heat-shrink plastic film, the bottles are bound together into a single unit.  An inner pack serial number label is affixed to the top of the bundle. 

DSCSA and Aggregation

Currently DSCSA does not mandate the use of aggregation, however the statute contemplates the use of aggregation once unit level serialization is required as of 2023. 

Requests for FDA guidance have been submitted to gain clarification on how the industry handles errors in inference/aggregation.  It has been suggested by pharmaceutical industry representatives that the FDA should allow stakeholders to resolve errors among themselves.  The request suggests that only drug products for which errors remain unresolved be treated as suspect or illegitimate.  Further, the pharmaceutical industry has proposed that TS not be considered to be a statement of the accuracy by manufacturers/wholesalers but rather consider commissioned unit-level data from the manufacturers to be considered the source of the truth.

In April 2019, the Pharmaceutical Distribution Security Alliance (PDSA) proposed the creation of a new non-profit organization which would assume the responsibility for establishing and executing governance over DSCSA phase II interoperability.  DSCSA regulations require that the FDA conduct a minimum of 5 topical public meetings prior to 2021 to garner feedback from stakeholders on topics that will aid the FDA in determining how the “Enhanced Drug Distribution Security” (EDDS) phase will work as it is scheduled to begin in November 2023.  One of the topics of discussion is slated to involve the systems and processes needed for the utilization of serialized product identifiers at the package level.  This opens the door for the FDA to allow for aggregation and inference.

As part of EDDS, the regulation requires that all members of the pharma supply chain must include unit-level serial numbers in the Transaction Information (TI).  After 2023, entities selling drug products within the supply chain will be required to know precisely when unit-level serial numbers are included in their shipments.  Those serial numbers must be included in their Transaction Information.  This will necessitate that the entities have their own serial number-based packaging hierarchy data (aggregated data), even if this is not provided to customers.

Any entities using a third party logistics provider (3PL) will be required to provide the respective aggregation data to the 3PL. 

 Third party logistics providers are required to properly document manufacturers’ shipments.  It seems likely that customers may request aggregation data after 2023 to help with their receiving verification process, even if this is not mandated by the FDA.

Today, many companies along the pharma supply chain consider aggregation to be a business requirement, essential to the smooth operation of their organizations.  Even if the FDA does not mandate aggregation as a regulatory requirement, it is likely that aggregation will be common practice or at least, a business requirement due to pressing operational needs.

Conclusion

Although not currently mandated by the FDA, aggregation helps streamline pharmaceutical supply chain operations by eliminating the need to open every case and pallet to get unit-level serialization information.  Without aggregation, costs of prescription drugs would skyrocket, the pace of the pharmaceutical supply chain would slow down significantly without providing added benefits for consumers including increased patient safety.

Pharmaceutical companies and businesses operating in the life sciences sector including those involved with contract manufacturing and contract packaging can utilize cutting edge technology, including pharma/life sciences warehouse management software capable of serialization and aggregation to gain a competitive advantage, streamline operations and ensure compliance with DSCSA.

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