Article: Safety First
By Michael Fleischer
This article reviews the development of global Good Distribution Practices (GDPs) against the background of an increasingly complex pharmaceutical supply chain, five years after the initial implementation of the extended EU GDP Guideline.
This article was first published in Regulatory Affairs, December 2018.
Introduction
On 5 November 2018, the current EU GDP Guideline turned five years old.{1}
What have we learned in those five years? Have we succeeded in achieving a better protection of the integrity of pharmaceutical products and fortified patient safety? What did it mean for the R&D industry, the drug manufacturers and their service partners in the supply chain?
The Early Days of GDP
In Europe, we have transitioned from the original GDP Guideline of 1994 which was just three and a half pages long, providing general guidance, to a greatly expanded guideline with 10 chapters, which are aligned with the European Good Manufacturing Practice (GMP) Guideline.{2,3} To complement and conclude this development, a new GDP Guideline for active substances came into effect in March 2015.{4}
The process of enlightenment however is reaching much further back in time. The World Health Organization published their first GDP Guideline in 2006 (WHO Technical Report 937, Annex 5).{5} The introduction to this document provides the following insight: “The quality of pharmaceutical products can be affected by a lack of adequate control over the numerous activities which occur during the distribution process.” Almost 40 years into the era of a formal GMP regime, the WHO finally addressed the area of distribution and transportation. In their updated GDP Guideline—four years later—WHO Technical Report 957, Annex 5, 2010 states: “The nature of risks involved is likely to be similar to that for risks encountered in the manufacturing environment.”{6}
A new Mindset Develops
All of this initiated an entirely new mindset. After the sudden insight that pharmaceuticals are not normally needed at the point of manufacturing, but further away, the uncomfortable truth dawned that the quality of a pharmaceutical product could actually be seriously impaired in the distribution and transportation process. It suddenly became apparent that GDP compliance is paramount not only in the commercial supply chain, but also and particularly during drug development.
Achieving market realization (and the corresponding marketing authorization) depends on the ability to show that the integrity of the product could not have been compromised during interim storage (GMP) and transportation (GDP). This change in mindset came just in time to meet more challenging industry demands. Gone are the times in which mainly highly profitable, stable and easily manufactured blockbuster drugs had to be shipped around.
The Dynamics of Specialized Products and Therapies
Nowadays highly specialized and even more and more individualized products are under development or have reached the commercial pharmaceutical supply chain already. This in fact means, pharmaceutical product distribution is becoming increasingly complex and global in scope. Specialty products are the new therapeutic alternatives for many patients, be it in the Central Nervous System (CNS) or various cancer diseases. As an example, these could be innovative cell and gene therapies, which are costly and complex to manufacture and highly temperature sensitive with a short shelf life. These highly innovative but rather complex therapies are the future: designed to treat small populations suffering from rare conditions, they offer new hope for cures and effective outcomes. Another example is the fascinating development of cancer vaccines. With the first approved HPV immunization therapy to prevent woman suffering from cervical cancer. The WHO assumes that with this immunization 70% of cervical cancers can be avoided.{7} These preventive pharmaceutical products may be a future kind of blockbuster. What a vision: beat cancer diseases with an immunization. But again, these products are multifarious in their production, storage, shelf life and distribution requirements.
The volume of worldwide biotech products traded in 2017 was $208 billion, but the latest projection of this volume for 2024 is $383 billion. Worldwide orphan drug sales are forecasted to reach $262 billion in the same year.{8} These developments effect significant changes in the way a growing number of pharmaceutical products need to be carefully handled.
The new Complexity in the Pharmaceutical Supply Chain
Indeed these developments impact the supply chain: rigorous transportation and storage requirements have to be followed and sophisticated packaging, monitoring and tracking may be required. Growing regulatory oversight is needed on local and global levels. To make the complexity even larger, advancing direct-to-patient models requires more precise delivery windows as well as attention to patient privacy and safety. Industry professionals also should not forget the increased detection of counterfeit medication, which is probably a result of higher “production,” but on the good side, a positive outcome of stricter GMP and GDP compliance.
The expanding supply chain complexity, in general, leads to higher security needs and a tighter chain of custody.
Implementing GDP as Part of a Wider Quality Management System
Good distribution practice is that part of the pharmaceutical lifecycle which assures that pharmaceutical products and Active Pharmaceutical Ingredients (APIs) are consistently stored, transported and handled under suitable conditions to maintain the integrity of the product and safety of the patient. The EU managed to bring down the 22 chapters in the 2010 WHO document to 10 in the GDP Guideline (2013/C 343/01). There is now a great similarity in the structure of GMP and GDP Guidelines: GDP addresses specifically requirements of a modern Pharmaceutical Quality Management System (QMS) with a risk based approach in Chapter 1.
Requirements for personnel are outlined in Chapter 2 with the new official function of a “Responsible Person for Transportation,” which has to be available at the license holder, i.e., the manufacturer or wholesaler. Provisions for premises and equipment (which have to be “suitable and adequate,”) documentation and operations follow in chapters 3, 4 and 5. Chapter 6 is essentially all about deviation management and has a revealing section on “suspected falsified medicinal products” which mirrors the new idea in the 2010 WHO document (“Falsified medicines present a serious risk to public health.”) A separate Falsified Medicines Directive (2011/62/EU) arrived in the EU in 2013 with further and final changes for safety features to be implemented by February 2019.{9}
Chapter 7 is a particularly interesting one. Here it states that we may well outsource activities, but never our responsibility: “The Contract Giver is responsible for the activities contracted out” and furthermore: “An audit of the Contract Acceptor should be performed (…)”. There has been a lot of uncertainty about this point. While the guideline is very clear on this requirement, stakeholders have tried to circumnavigate this item as much as possible. The number of client requested audits in the European Economic Area (EEA) and those countries which have adopted most of the EU rules has exploded, but still some manufacturers or wholesalers are trying to get out of this obligation by down-scaling the criticality of their outsourced logistics processes. This could backfire in the long run during their next inspection.
At least a paper-based assessment should be carried out, today also aptly named a “desktop audit.” Turning to the same chapter in the GMP Guideline will further elaborate the need to constantly monitor, review and evaluate outsourced activities. Therefore, an initial assessment alone would probably not be enough. The much cited Annex 15 to this GMP Guideline provides extensive insight into processes related to validation and qualification and has thus a direct relevance to this topic.
The remaining three chapters deal with more practical requirements regarding self-inspection, transportation (operations in the GMP equivalent) and “specific provisions for brokers.”
The reception of these “new” rules in Europe came in three phases: the first phase consisted of concerted complaining in disbelief.
GDP Evolves
The guideline was generally criticized for being too extensive, too complicated and was accused of raising more questions than providing answers. The second phase was resignation as the perception grew that these rules were here to stay. In this phase, everybody was carefully watching what the others were doing and how inspectorates would treat the situation.
Meanwhile, implementation proceeded in a rather heterogeneous fashion, culminating in the introduction of two different maximum limits for transitory storage by MHRA (UK){10} and HPRA (Ireland){11} in August 2014. This resulted in a sudden increase of Wholesale and Distribution Authorizations (WDAs) being applied for (and often being granted) in the British Isles. Continental Europe did not join this hype.
Today, five years later, authorities and the industry have easily reached the consolidation phase and in most cases the change of mindset has been accomplished. There have been improvements to quality management systems with the introduction of risk-based approaches and continuous improvement initiatives. Vendors are being more intensively assessed and contracted with quality agreements. Premises and equipment are being qualified and calibrated according to a traceable standard and defined procedures.
GDP certifications, although not unproblematic and tricky to assess, are highly sought after. Hence, the industry has made a big leap forward: the entire supply chain has been re-designed and in many cases even re-invented, sometimes driven by product requirements, sometimes driven by insight.
Hand in Hand: Good Distribution Practice and Good Manufacturing Practice
GMP can only lead to safe and efficacious products if the final step in the chain, i.e., transport and distribution, is carried out in a way to support these endeavors. The Pharmaceutical Inspection Co-operations Scheme (PIC/S) is an influential cooperation between regulatory agencies in 49 countries. PIC/S has started referring to “Good Manufacturing and Distribution Practice (GMDP)” in early 2012 underscoring the importance of controlled distribution processes.{12} Furthermore, it subsequently published GDP Guides for Medicinal Products (June 2014) and Active Substances (July 2018).{13,14}
How to be Compliant
Some Practical Considerations
Quality around storage, handling and transportation of pharmaceutical products must not be compromised at any given time. The same applies to the security of any shipment, as our industry operates intensively in intercontinental and continental airfreight as well as in continental road transportation environment as well as sea freight. Decision makers have to make such decisions, not only to offer to sustain the future supply chain demands, but also to provide options to the industry, accepting that an in-depth quality management culture supports a healthier future. The industry certainly foresees future investments in this area, which starts with continued very specialized training programs for global supply chain professionals, and goes on with dedicated, risk assessment based global SOPs and working instructions to be implemented.
Every year a decent number of internal/external GMP and GDP audits should be performed at GMP facilities and transport offices of the selected vendor, supporting GDP compliant transport around the globe.
The past five years have underlined the necessity of this effort. Time and experience have proven that it is the right decision to focus on GDP compliance in the entire supply chain, and so industry professionals shall continue this journey moving forward.
Technology as a Quality and Performance Safeguard
GDP is by far more than just quality, and with the Internet, one should see many beneficial technological developments for solid track and trace. For example, real time multisensory data loggers of pharmaceutical products. The next five years will further raise up the various solutions and the combination with data warehouse driven business intelligence will help to optimize the supply chain, reducing risks and increase patient safety.
Global GDP
The idea of GDP truly has gone global today and the varying standards from country to country (even within the EU) can sometimes be confusing. Nevertheless, all regulations trace back to the WHO and all are similar in nature. Adopting a risk-based approach will help you to identify the relevant requirements for your product.
Putting patient safety first will see you in compliance, now and in the coming five years. It is worth it to follow and develop the GDP pathway accordingly.
Conclusion
So what have we really learned in those five years? Have we succeeded in achieving a better protection of the integrity of pharmaceutical products and fortified patient safety?
GDP has evolved and became a robust guideline in the last five years. There is much more clarity in our industry and GDP principles are now interwoven with GMP requirements and accepted as a standard.
What did it mean for the R&D industry, the drug manufacturers and their service partners in the supply chain? It is imperative that the pharmaceutical industry and regulators work closely to overcome the new complexity challenges in the pharmaceutical supply chain. Developments of highly specialized medicinal products and advanced medical and therapeutic treatments are rapidly influencing storage, handling and shipping processes.
GDP goes far beyond just quality management and requires efforts of all parties involved in the supply chain.
Supply chain experts in R&D, manufacturing and service partners are beginning to realize more and more that holistic views along the supply chain will reduce total risks.
Technology enhancements will help to monitor compliance, secure integrity of the products and safeguards the distribution process.
