The ongoing health care crisis around drug safety and reliability has the attention of the global regulatory agencies responsible for providing the public with safe health care products. Regulatory agencies such as the US Food and Drug Administration (FDA) are charged with protecting the public from unsafe pharmaceutical, biologic, medical device, and dietary supplement finished products (FP). These agencies write regulations and guidance to provide business entities direction they can use to create the systems needed to ensure compliance in the production of safe FPs. In addition, these guidances may also apply to raw materials including active pharmaceutical ingredients (APIs) and excipients that are used to manufacture FP.
Protecting the public from substandard medicines has made providing all the associated entities with up-to-date guidance more important than ever. Organizations such as the World Health Organization (WHO) and pharmacopeias around the world such as the United States Pharmacopeia (USP) also provide business entities with guidance to further support supply chain and distribution processes. The globalization of the supply chain for raw materials and FP has required the writing of guidance documents such as those found in the USP that reach across not only varied distribution industries but also across countries and continents. Part of the inspection conducted by regulatory agencies involves ensuring adequate systems have been established by FP-producing entities so that the safety and efficacy of the FP is intact when it reaches the patient. These entities should stay current with regulations and guidance documents so as to ensure they are working within the latest guidelines. These documents will cover acceptable practices such as those related to current good manufacturing practices (cGMPs), which will include storage and distribution of FP. Coverage of cGMPs will occur both in regulatory agency guidance on the supply chain and in guidance documents developed by the USP. This includes the internal entities’ business practices and the external supply chain processes. There are numerous guidance documents written on the supply chain and distribution process with similar documents from not only organizations such as global regulatory authorities and pharmacopeias, but also by other scientific organizations, trade associations, and vendors. This paper was written to provide an update on USP’s activities on the subject of good distribution practices and the supply chain for FP, including what is currently official, what is currently in the works, and the next steps being considered for USP action.
Historically the USP has worked to ensure their standards and General Chapters (GCs) complement regulatory documents such as the FDA 21 CFR Part 211 on cGMPs. Prior to the publication of <1083> Good Distribution Practices in PF 40 (2) March 2014, there were 2 official USP GDP General Chapters: 1) Good Storage and Shipping Practices GC <1197>, which provided recommendations for those activities and practices that ensure GDPs for finished drug products, and 2) Good Distribution Practices for Bulk Pharmaceutical Excipients <1079>, which provided recommendations for activities and practices that ensure GDP for pharmaceutical excipients. With the publication of <1083>, USP‘s goal of developing an overarching chapter on GDP—Good Distribution Practices <1083> has been met. The creation of this chapter has allowed the elimination of redundancies and inconsistencies related to GDP guidance in the Compendia. It was also decided that several GDP topics needed further clarification, and others needed to be included into the USP-NF (National Formulary). As this was in the works, the USP introduced a new format for presenting GCs through the development of sub-chapters. This allows associated subjects to be grouped together to facilitate the ease of use by USP end-users. The sub-chapter structure allows for more depth per topic and the consolidation of all general information related to a topic under one chapter number. This new format will be utilized on GCs numbered >1000 (which are considered informational) and <1000 (which are mandatory).
The current proposal for revision of the supply chain GC, <1083>, addresses several main GDP topics. These first level documents cover the overarching principles and provide emphasis on the following subjects: The Quality Management System <1083.1> (see Figure 1 for the breakdown of subjects covered); Supply Chain Temperature Management <1083.2> (see Figure 2); Good Importation and Exportation Practices <1083.3> (see Figure 3); and Supply Chain Integrity <1083.4> (see Figure 4), all with the intention of highlighting best practices and principles. These 5 chapters are currently in a review process based on industry feedback from their publication in Pharmacopeia Forum. The Subcommittee is nearing completion of their review of industry feedback and will be determining the next steps on the first 5 chapters.
Figure 1. <1083.1> Quality Management System.
Figure 2. <1083.2> Environmental Conditions Management.
Figure 3. <1083.3> Importation and Exportation Management.
Figure 4. <1083.4> Supply Chain Integrity and Security.The next step undertaken was a decision on what subjects, if any, need further written in-depth guidance for the benefit of the USP end-user. Five topics were determined as important to the USP end-user and are currently in process. The GDP Subcommittee activities include the following GDP topics: 1) <1083.5> Finished Drug Products; 2) <1083.6> Excipients; 3) <1083.7> Active Pharmaceutical Ingredients; 4) <1083.8> Clinical Trial Material (CTM); and 5) <1083.9> Packaging. Feedback, both in writing to the USP and orally from conferences, workshops, and other forums, has led the USP Subcommittee to determine there is a continued need for the USP to provide written guidance. As of January 1, 2015, the USP Subcommittee will continue to evaluate subjects needing guidance and proceed to develop the sub-chapters for the USP reader/user.
The finished drug product <1083.5> and the excipient <1083.6> sub-chapters are completed and under final editing and review. The finished drug product sub-chapter covers important information that is was written in the first USP supply chain chapter (<1079>), while the excipient GC covers important information that was provided in the first USP excipient supply chain chapter, <1197>. The eighth sub-chapter, the one on Clinical Trials Materials, is in progress and includes subjects such as un-blinding and recalls, non-commercial trials, risk management, and qualification of the shipping package. Figure 5 provides a visual of the Level 1 documents that have been published and the next series, Level 2, that are under development at this time.
Figure 5. Overview of Chapter <1083> Future Structure.It is important to understand that in developing storage and distribution systems and strategies there is no one-size-fits-all solution but a holistic approach is essential for all entities in the supply chain. Those working in the supply chain must dig through regulation, guidance, and other documents to determine what will work for them and ensure their continued compliance and acceptable FP results. What is being debated at this time is how each entity can read/understand all that has been written on the subject today and make the right decisions for their end user/consumer. Further to this, what is the role of the USP and writing guidance in their general chapters? As the USP <1083> Subcommittee discusses the next best steps to take, we are asking questions such as, “How do we move forward?” “What is the next best step?” “When is enough really enough?” These and other questions are at the heart of the committee as we continue to work on the GDP-related USP guidance. It should be noted that there are several USP Expert Committees (EC) working on the GDP topic: Packaging, Storage & Distribution EC, Excipients EC, Compounding EC, and Physical Analysis EC. Together we will determine the path forward for specific sub-chapter subjects to undergo development, when to delete materials, and when it may be time to rely solely on the FDA for future guidance.
It is clear that every agency and organization plays an important role in the supply chain process. The storage and distribution of finished dosage forms means dealing with increasingly complex and complicated processes. The USP is working with other organizations in the creation of fewer documents with global perspectives on the supply chain for the various products intended for the patient/end user. This sharing of information, lessons, and best practices to create and write fewer documents—yet maintain documents that are current and are providing appropriate guidance—is a hopeful outcome as the 2015 year begins. At an October 2014 IQPC global supply chain forum, a USP PSD EC representative sat with the WHO and the European Medicines Agency discussing this very topic.
Across the globe, the distribution of FP and the associated supply chain businesses must meet the patient need for an adequate supply of safe FP. The assurance of a safe FP reaching the patient makes working together a vital process as we look to this new year and the continued health care crisis. In the context of the USP work on the FP supply chain, we are continuing to move forward in the development of the <1083> with continued dialog and collaboration from USP endusers from around the globe, other health care organizations, and regulatory agencies with the spirit of transparency and the end goal of the creating the best mechanisms— regardless of who creates them.
A Call to Industry Action
It is time for you to join the debate and impact the future direction of supply chain guidance by working alongside the USP with the revision, creation, and maintenance of current and future supply chain guidance. There are 2 ways to get involved:
- Let us hear your voice by applying for membership in the USP PSD EC
- Provide written feedback to the USP with PF documents
Please feel free to contact me directly at [email protected] for input into the supply chain discussion or in consideration of joining the USP work. You may also contact my USP colleague, Desmond Hunt, PhD (who assisted with the preparation of this article), at [email protected].
Mary G. Foster, PharmD, serves on the United States Pharmacopeia (USP) Executive Committee of the Counsel of Experts, 2010-2015, and presides as the Chair of the Packaging, Storage and Distribution Expert Committee. She is a member of the International Air Transportation Association (IATA) Advisory Board representing the pharmaceutical industry, and is on the Advisory Board for the International Quality & Productivity Center (IQPC). Mary is a seasoned pharmaceutical executive with over 30 years of broad-based domestic and international experience in pharma/ bio technologies. She received her Doctor of Pharmacy degree from the University of Kentucky School of Pharmacy in 1983.