The USP has created a new chapter to address the storage and distribution of IDP. This is significant because it is the first time in the long history of USP standards that this topic has been addressed. But in order to fully understand the depth and scope of this new chapter, the history of its inception must be covered first.
The Packaging and Distribution Expert Committee is charged with the maintenance, review and updating of the appropriate chapters covering the storage and distribution of drug products and starting materials. Two chapters that were already official were undergoing review, <1079> Good Storage and Distribution Practices for Drug Products1 and <1197> Good Distribution Practices for Pharmaceutical Excipients.2 While this review was occurring, it was noted that although both chapters were meant to cover Good Distribution Practice (GDP), there were areas of overlap as well as areas covered that were specific to the particular chapter and not covered in the other. This bit of insight led the USP to take a step back and analyze these two chapters at the USP Supply Chain Workshop in 2012. Through this process the USP came to the conclusion that the approach to GDP has been piecemeal. For instance, while GDP is an overarching subject, individual components (e.g. excipients and drug products) were being addressed in separate chapters. Therefore, individual topics, such as storage and shipping, supply chain integrity, and importation/exportation issues were repeated in separate chapters with respect to the individual topics.
The need for the development of a holistic approach to GDP was the main lesson from the workshop. This approach would:
- Integrate individual components and topics under a single overarching GDP chapter.
- Lead to the avoidance of separate USP chapters on GDP with non-sequential chapter numbers. This would provide clarity and make it easier to find guidance on GDP without searching through multiple chapters on multiple subjects.
- Focus on guidance best practices and principles as opposed to specific individual technological approaches. Technologies and their applications change so rapidly that a non-prescriptive approach based on best practice is more durable.
This led to the decision to develop <1083>.3 In order to provide this overarching chapter, a review of where <1079> and <1197> overlap was performed. In addition, the regulatory landscape from a global perspective was reviewed to determine where regulators from different countries had spoken to GDP. Through this examination, the basis for <1083> was determined (Figure 1).
Figure 1.
In addition to what would be covered in <1083>, the system for approaching how GDP would be broken down in the chapter was examined. Four GDP topics covering quality management system, environmental conditions management, importation and exportation management and supply chain integrity and security would serve as the foundation for the GDP chapters (Figure 2). Generally, they apply to all materials and products, regardless of their regulatory category. These topics include the basic principles that provide guidance on how to establish and maintain:
Figure 2.- A quality management system that ensures the quality, integrity, safety and efficacy of materials and products during sourcing and distribution (e.g. personnel, storage buildings, transportation vehicles, etc.).
- Temperature and humidity control during product holding and transportation.
- Supply chain integrity from importation and exportation procedures to minimizing counterfeiting, cargo thefts, diversion.
- Traceability of individual products and shipments throughout the supply chain.
This approach would lead to an overall focus on GDP that would address the areas that had been covered in <1079> and <1197> while expanding into areas not previously addressed as well as going beyond drug products and excipients.
However, Sometimes Things Change…
The Drug Quality and Security Act (DQSA) was enacted on November 27, 2013. At this point in time, the Expert Committee reviewed current chapters, in light of the new law, to determine how USP could further provide support. A gap analysis was performed to determine where the new law could be supported without being redundant. It is important to note that when <1083> was started, there were no laws in place in the United States to address GDP. When the DQSA (sometimes referred to as “Track and Trace”) was introduced, this meant that supply chain integrity and GDP were now being addressed by the FDA. With this occurrence, the USP put the development of the overarching chapter <1083> on hold and shifted focus back to the chapter dealing with finished drug products <1079>. The USP focuses its attention, energy and guidance where there is a need, the goal is not to repeat guidance that has been covered explicitly by the FDA, but to supplement those items where clarification and guidance can be added. The result of this refocusing led to a shifting of the immediate topics of importance to Investigational Drug Products and Environmental Control of Finished Drug Products.
With the first guidance being developed concerning GDP for IDP’s from the USP, it is important to note where guidance has come from in the past. The main source for sponsors and manufacturers has been the FDA, for example, the Code of Federal Regulations Title 21 Sec. 312.57 (Figure 3).4
Figure 3.However, the overall goals for the management of IDP’s were stated, but not the details to get there. In addition, some state boards address IDP’s. While it is important to know the details of the state where the activity is going on, many times, the guidance is state specific and lacks details. As stated earlier, the USP intends to provide guidance where it is needed and complements existing regulations, there is a need in this area.
In order to discuss IDP’s, it is necessary to have a basic understanding of the environment in which they are used, a clinical trial. The definition of a clinical trial according to clinicaltrials.gov is “A clinical study in which participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. The assignments are determined by the study protocol. Participants may receive diagnostic, therapeutic, or other types of interventions”.5 Differences in particular trials may vary greatly. For instance, each trial follows a protocol that is determined by the sponsor of the trial. This protocol serves as a guide for the specific details of what must be done to carry out the trial. While it is beyond the scope of this discussion, it should be noted that the purpose of the trial can vary greatly as well, depending on which phase of research the trial is involved in and whether or not the goal is to show efficacy, safety or both. In addition, many times it is assumed that clinical trials are used to test medications that are not yet approved for marketing by the FDA. However, some trials include approved medications as well. These may serve as control arms, the sponsor may be attempting to get approval for new labelling or the trial may be testing a new treatment option or tweaking a known treatment option to improve it.
A very basic overview of the management of IDP’s can be described by saying that they must be accounted for from the moment of manufacture to the moment of destruction. This can be described as accounting for the shipment conditions, receipt by the site, storage conditions, accountability of the IDP on hand (including distribution or dispensing) and reconciliation or destruction when the trial is complete. It is preferred that an Investigational Drug Service (IDS) be used for the management of the IDP at the particular trial site. An IDS is a pharmacy that is qualified to handle IDP’s in the manner that supports the GDP and follows the specifics of the protocol.
IDP Distribution Risk Factors
The key risk factors for IDP distribution after manufacture are the distance traveled, time it takes to get to the destination, temperature required for the product as well as temperature variances it will travel through and the number and types of handoffs that might occur. In essence the IDP is being “tracked and traced” on its journey. The relationship of the sponsor or their designee to the courier chosen is vital for this journey. It is important that the courier understands the unique issues involved with IDP’s. The number of sites being used in a trial can depend on the purpose and phase of the trial. This can play a role in the challenges of GDP for these medications. For instance, more sites mean more shipments and larger quantities overall. However, the amount of medication being shipped to each site might be very small. So as the IDP progresses through the supply chain and through any depots or subcontractors being used, the standards apply the same for each step of the journey. The more steps there are to get from manufacturer to site, the more tedious this process becomes. To add to this, the distribution of IDP’s globally add additional challenges such as security, language, culture, tariff codes/taxes, hiring, training, customs, holidays, country specific import and export requirements, time differences, airline schedules and documentation.
With regard to the individual IDP, other unique factors may apply. The environmental conditions of IDP’s are vital throughout the whole life cycle of the medication:
- During transport – the temperature is monitored and validated once the destination is reached.
- On-site storage – the medication is stored according to the directions from the manufacturer/sponsor. This temperature is monitored constantly whether it be room temperature, refrigerator or freezer.
- During dispensing – some medications must be used within a certain timeframe after they are mixed or compounded and dispensed.
- With the study participant – if the medication must be stored in a certain temperature range, it is vital that this be done while it is with the participant as well, for instance, a bottle of capsules may need to be kept in the refrigerator. It is important to make certain the study participant is aware of the storage conditions required.
The expiration dates for an IDP may not be known at the time it is distributed to the trial sites. This is managed by informing the site of the expiration date when it is known or discovered or providing the site with retest dates so that the manufacturer or sponsor can examine the IDP for stability issues. Regarding packaging of the IDP, there is no difference in packaging qualifications for IDP’s and commercially available drug products. There are times when a medication must be returned to the sponsor. The attention to GDP may vary depending on the reason for the return. If the intention is to use the medication at another site, then the supply chain must be maintained and GDP attended to. Blinding of the medication is used in some studies to address potential bias. There are situations where an individual dose or an entire batch of IDP must be unblinded due to patient safety concerns or quality concerns. If the unblinded medication is being returned to the sponsor then it is also vital that the supply chain be maintained and GDP attended to. However, if the trial is complete and the IDP is being returned for destruction then GDP is not vital.
The published version of <1079.1> that appears in PF 42 (4) was released in July, 2016 for public comment. The public comment period will last for three months. At the end of this period, the comments will be reviewed and the chapter revised accordingly.
The attention being shown to GDP of IDP’s by the USP comes at a vital time. Soon, guidance for the issues that have been discussed in the previous paragraphs will exist that supplement and clarify the current regulations. In the end, the maintenance of GDP for IDP’s leads to further confidence in the results of a particular clinical trial. It is vital to know that the medication has been protected along the supply chain.
References
- USP. USP 39–NF 34. <1079> Good Storage and Distribution Practices for Drug Products, Rockville, MD: United States Pharmacopeial Convention; 2016
- USP. USP 39–NF 34. <1197> Good Distribution Practices for Pharmaceutical Excipients, Rockville, MD: United States Pharmacopeial Convention; 2016
- USP. <1083> Good Distribution Practices. Pharmacopeial Forum. 2012;40(2).
- https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.57.Accessed 8/31/16.
- https://clinicaltrials.gov/ct2/about-studies/glossary.Accessed 8/31/16.
Jeffery M. Carrico is a member of the United States Pharmacopeia (USP) Expert Committee for the General Chapters, Packaging and Distribution. He is a member of the FDA Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. He is a Pharmacist by training, he received his Doctor of Pharmacy degree from the University of Kentucky. He is a Board Certified Pharmacotherapy Specialist (BCPS). His experience has involved many facets of the clinical research world and pharmacy operations. He currently works for the Florida Hospital System in Orlando, Florida as the Director of Pharmacy – Investigational Drug Service.