When working through the nuances of moving clinical supplies globally, my mind often wanders back to a scenario that occurred several years ago. During a meeting to determine a course of action to facilitate the customs release of clinical supplies in a South American country, a member of senior management entered the conference room to express disbelief in the possibility of supplies being held by customs authorities. “How can this occur? It’s simple, you grab the supplies, put them in a box, label it, put together a packing slip and you’re done.” Wow, don’t we wish it were that easy!
Some of you may have been in a situation, having survived a painful experience that left both yourself and your Study Team wondering if conducting a clinical trial in certain countries was actually worth it.
As an industry we have come a long way from the days of shipping supplies without much understanding of global governmental regulations and the assumed risk of sending supplies into international commerce. At the same time, governmental agencies have become increasingly aware of industry needs and have implemented reliable guidance, regulation and process change which have contributed to import/export procedures and the movement of commerce and clinical supplies.
In this piece, I’ll cover three new regulations related to clinical supply in the European Union and provide topline recommendations on managing their impact on your business. I’ll also provide thoughts on serialization, one of the hottest global topics to emerge since RFID was bantered around a decade ago.
Electronic Customs
An electronic custom system is being phased in the EU over the next few years. It replaces the Community Customs Code that had legal effect since 1994 and was written at a time when procedures were largely paper based. The volume and speed of trade, as well as the need for proper safety and security risk assessment have increased significantly over the past decades.
As part of the modernization of the EU regulatory framework, the Union Customs Code (UCC) and its Implementing Regulations became effective May 1, 2016. Note that certain provisions of the UCC will only be implemented when the required IT system is either deployed or upgraded. Essentially, once the European Commission has fully deployed a portion of the electronic framework necessary to support UCC, it will then become a portion of the electronic framework that will be viable, usable and enforceable.
Due to infrastructure implementation, the European Commission created an additional regulation that provides provision of a transitional period between May 1, 2016 and December 31, 2020 for electronic customs enhancements to be implemented.
What we should expect:
- Streamline customs legislation and procedures throughout the EU Member States.
- Increase clarity for customs officials.
- Simplified customs rules and procedures that facilitate more efficient customs transactions.
- Greater legal certainty and uniformity to businesses.
- Complete shift by Customs to a paperless, fully electronic environment.
Data Integrity
Data integrity is fundamental in pharmaceutical quality systems. The EU Medicines and Healthcare products Regulatory Agency (MHRA) provides guidance on Good Manufacturing Practice (GMP) data integrity expectations for the pharmaceutical industry. The guidance is intended to complement existing EU GMP related to active substances and dosage forms, recommended to read in conjunction with national medicines legislation and the GMP standards published in Eudralex Volume 4.
The effort and resource assigned to data governance should be commensurate with the risk to product quality, and should also be balanced with other quality assurance resource demands.
Manufacturers and analytical laboratories are not expected to implement a forensic or discovery approach to data checking on a routine basis, but rather design and operate a system that provides an acceptable state of control based on the data integrity risk, and which is fully documented with supporting rationale.
Data integrity requirements apply equally to manual (paper) and electronic data. Manufacturers and analytical laboratories should be aware that reverting from automated computerized to manual/paper based systems will not in itself remove the need for data integrity controls.
Good Distribution Practices
The EU Commission has revised the Guidelines on Good Distribution Practice (GDP), reflecting today’s more complex supply chains. The new GDP were published on March 7, 2013, requiring industry adherence within six months. The prior guidance was in place for 19 years and many of the requirements had been annexed and expanded throughout the years, making initial GDP requirements cumbersome to interpret.
The required storage conditions for medicinal products should be maintained during transportation within the defined limits as described by the manufacturers or on the outer packaging.
- If a deviation such as temperature excursion or product damage has occurred during transportation, this should be reported to the distributor and recipient of the affected medicinal products. A procedure should also be in place for investigating and handling temperature excursions.
- Risk assessment of delivery routes should be used to determine where temperature controls are required. Equipment used for temperature monitoring during transport within vehicles and/or containers, should be maintained and calibrated at regular intervals at least annually.
- Dedicated vehicles and equipment should be used, where possible, when handling medicinal products. Where non-dedicated vehicles and equipment are used procedures should be in place to ensure that the quality of the medicinal product will not be compromised.
- Where transportation is performed by a third party, the contract must encompass requirements of Chapter 7. Essentially, the wholesale distribution should make transporters of the relevant transport conditions applicable to the consignment. Where the transportation route includes unloading and reloading or transit storage at a transportation hub, particular attention should be paid to temperature monitoring, cleanliness and the security of any intermediate storage facilities.
- Provision should also be made to minimize the duration of temporary storage while awaiting the next stage of the transportation route. Containers should bear labels providing sufficient information on handling and storage requirements and precautions to ensure that the products are properly handled and secured at all times. The containers should enable identification of the contents of the containers and the source.
Serialization
While serialization - the global track and trace regulations to protect patient safety and ensure product integrity - will be a standard requirement for the global drug supply by the end of the decade, the serialization requirements themselves will be far from standard. Serial number formats vary widely from GS1 global standards to unique versions in China and Brazil. In most countries, the manufacturer can create the serial numbers themselves but in China, they must request the numbers from a CFDA system. Packaging hierarchies requiring serialization range from solely unit level application to multi-tier relationships. Thus, expect diversity and plan for it by isolating serialization diversity in your global IT architecture and identifying potential constraints it places in your global supply planning.
Since serialization regulations will vary from country to country, Life Sciences companies face unprecedented complexity, cost and risk in how they implement strategies globally.
- United States: The Drug Supply Chain Security Act (DSCSA) mandates that manufacturers begin serializing all drug products at the saleable unit and case level for the U.S. market starting in November 2017, with repackage deadlines beginning in 2018. With DSCSA’s January 2016 lot-level traceability deadline behind us, pharmaceutical companies are turning their attention to full drug serialization. DSCSA requires that manufacturers mark packages with a product identifier, serial number, lot number, and expiration date by 2017. Given everything that needs to happen by then, from altering highly regulated packaging and distribution processes to addressing enterprise-wide IT, this is an aggressive implementation timeframe. At the same time, wholesale distributors and other supply chain companies should be gearing up for end-to-end serialization testing with their manufacturing partners well in advance of the deadline to allow time for any necessary adjustments.
- European Union: Manufacturers serving the EU are preparing to meet serialization requirements at the package level that are expected to start in early 2018. These requirements include supporting both global and national identifiers and following strict uniqueness regulations. With the publication of the Delegated Act on safety features, those who manufacture, sell, or dispense medications in the EU have until February 2019 to comply with new track and trace regulations outlined in the Falsified Medicines Directive (FMD).
FMD compliance creates some unique challenges. The main requirements involve serialization, compliance reporting, and verification. Medications in Europe are generally packaged and sold at the “unit of use” level, so the volume of product that needs to be serialized and the magnitude of transactions will be two to five times what companies will see in the U.S. where the saleable unit is in larger bulk quantities. Overall, the universe of data to be produced, managed, and reported on will be massive, with the added complexity that each EU Member State is provided flexibility to apply their own unique requirements.
- China: All levels of product – unit, bundle, case, and pallet – must be serialized with a government-issued number, and aggregation is a regulatory requirement. Pharma companies must run a query on a Chinese government system in order to initiate and capture the serial numbers, which are then provided to the packaging lines. After the serial numbers have been deployed, manufacturers must report back on product events.
There are multiple complications associated with Chinese reporting requirements. First, all reports must be manually uploaded to the China FSDA system by someone based in China; the upload cannot be managed remotely from another country. In addition, there is a size restriction of five megabytes for the uploaded report. If you are reporting on a large batch of data, your file size can easily exceed that, in which case you will need to follow strict guidelines on how to split up the file, what header information to assign, and the sequence in which to upload the multi-part report.
- Brazil: RDC 54 regulations establish very complex new serialization requirements for all registered drug products that started phasing in starting in December 2015. Manufacturers will need to apply unique Brazilian IUM identifiers into 2D DataMatrix barcodes for each saleable unit, serialize each transport container (case) and ensure aggregation relationships.
Brazil has the most complex serialization track and trace regulations in the world today. Compared to other global regulatory requirements, Brazil is a hybrid model: with their serialization, tracking, and government reporting, they are asking for a little of everything. Under their law, the primary burden for compliance falls on manufacturers, with wholesale distributors and pharmacies sharing some reporting responsibility.
In Brazil, the manufacturer is responsible for tracking drug product movement from the point of manufacture to patient dispensation. As a manufacturer, every time your product flows from wholesaler to wholesaler to pharmacy, each of those parties has to send back data into your system, and then you need to provide it all to ANVISA. The challenge for manufacturers has been to establish reliable connections with both direct and indirect supply chain partners. And similar to the U.S. government, Brazil’s government is not prescribing how compliance information must be shared between companies, but is instead leaving it up to industry to decide.
This high level overview of current global supply chain topics portrays the complexities of conducting a global clinical study. Alongside the complexities, there have been tremendous improvements by both governmental agencies and Life Sciences companies. Capsugel’s acquisition of Xcelience in January 2016 demonstrates the value that specialized design, development and manufacturing companies are placing in continued investment and innovation in best-in-class clinical supply solutions.
Past and ongoing global process improvements speak to the sense of pride our industry exudes, knowing that collectively, as a Global Team, we are able to improve the lives of patients. The discovery and approval of life saving drugs is not an easy process, however, definitely one of the most rewarding.