The Epicenter of Cold Chain Management

The Parenteral Drug Association plays a critical role

By Kevin O’Donnell

2007 was a year of milestones in the world of pharmaceutical cold chain management practices, setting the stage for additional guidance, and regulatory updates with respect to temperature control during storage and distribution.

A significant driver of this change is the Parenteral Drug Association (PDA). Many global activities related to pharmaceutical cold chain management are either in-step with, or the direct result of, PDA’s cold chain management initiatives. So, why the PDA? How did this evolve? What made 2007 such a pivotal year?

Strength in Numbers

The Parenteral Drug Association is a global, non-profit organization of more than 10,000 individual members. Its charter is to improve the quality of medicinal products by advancing all facets of pharmaceutical and biopharmaceutical science and technology through cooperative peer development within industry, regulatory affairs and academia. Its mantra: advance medicine through sound, practical scientific methodology, create an unbiased forum for exchange of perspectives, and provide connections, communication and shared expertise to support global membership. PDA’s pretty good at it too, having stayed the course for more than 60 years.

Bob Myers, president of the PDA, stated in his 2006 annual report that the volume of PDA’s products and services to membership continue to grow at an impressive clip: 47% in the past two years.

Also, PDA’s global headquarters are strategically located in Bethesda, MD, a stone’s throw from the FDA. There is an additional regional office operating in central Europe, and one under consideration in the Asia-Pacific region. While most of the membership is in North America, there is considerable activity among multiple chapters operating in 71 countries worldwide.

Conferences, Education and Publications

Cold chain management conferences have become a popular topic among several commercial conference organizers in recent years and you can find one being held somewhere in the world in just about any month of the year. I received invitations to present or attend no less than eight such events in 2007. The PDA hosts two — one in the U.S. in spring, and the other in Europe in the fall. While the cost and quality of commercial conferences varies widely and the scope of information generally more broad, the PDA’s approach is more focused. What makes PDA different from most others is that its cold chain conference is based — like all its conferences — around the central theme of the mission: “to develop scientifically sound, practical technical information and resources to advance science and regulation for the pharmaceutical and biopharmaceutical industry through the expertise of our global membership.” Because it’s a non-profit organization, it can keep registration fees reasonably low. This philosophy is reflected in a breakdown of its earnings: In 2006, 35% of PDA revenue was generated by conferences, an additional 24% was the result of participation in education programs, and 11% on publications such as its Technical Report Series.1

Among its most prestigious and highest attended meetings are the annual PDA/FDA Joint Regulatory Conference and the PDA/EMEA Joint Conference. Few associations have the reputation to attract regulators at the highest levels of government and engage them in a mutual exchange of scientific and regulatory dialog. The result often leads to an agreement of industry consensus practices recognized by numerous global regulatory bodies. Overall, PDA-sponsored conferences hosted more than 6,500 participants in 2006. Nineteen conferences on a variety of subjects are currently slated for 2008.

Peer Education

The PDA also operates a well-organized training and education program under the title of the Training and Research Institute (TRI), in which it “strive[s] to establish innovative, world-wide education, training and applied research in pharmaceutical sciences and associated technologies.”2 The growth, popularity and quality of its hands-on laboratory training prompted the board of directors to approve a consolidation of the TRI and PDA headquarters in Bethesda in 2007. The resulting training facility is state of the art, simulating real-life manufacturing and testing areas typical in today’s pharmaceutical and biopharmaceutical plants. The new facility includes a vastly updated and improved aseptic filling area, a microbiology lab, a biotech lab, a Clean-In-Place lab and two lecture classrooms and student areas. Most of the equipment, services, and supplies have been donated or subsidized by more than 50 corporate sponsors/ supporters. The facility was dedicated on September 26th 2007, with the first training session held a month prior.

“In addition to providing general education to industry on best practices in a number of areas of manufacturing, we also train inspectorates from many foreign countries,” said Gail Sherman, vice president of Education for PDA. “In fact, we are currently working with 40 delegates from Kazakhstan who are here at our Bethesda offices for three weeks of training. An area of particular interest to them is the cold chain and we have included that as part of the overall program,” she added.

Interest Groups

“There are approximately 20 active interest groups within the PDA,” said Bob Dana, vice president of PDA Quality and Regulatory Affairs. “One of the largest and most active of which is the Pharmaceutical Cold Chain Interest Group (PCCIG).”

The PCCIG evolved from an industry gripe session that took place in 2001, among colleagues of various drug manufacturers hosted by Genentech, in South San Francisco. The dozen individuals in attendance represented a broad range of expertise comprising pharmaceutical and biopharmaceutical manufacturing, product stability, quality, validation, engineering and distribution. They gathered to commiserate over the lack of uniform guidance and the seemingly random and often subjective auditing practices by regulators. They called themselves the Pharmaceutical Cold Chain Discussion Group (PCCDG) and resolved then and there to take a proactive approach to the groundswell of regulatory scrutiny in this area of manufacturing by developing a ‘best practices’ document for temperature-sensitive products with the hopes of establishing a permanent document to be used throughout the industry and one that would be recognized and accepted by regulatory authorities. It was the beginning of what would become widely known as Good Cold Chain Management Practices, occurring simultaneously with the drafting of USP General Chapter Good Storage and Shipping Practices.

One of the committee’s members, Rafik Bishara, championed the document and presented a draft to the PDA for consideration. The PDA agreed to publish the document as a Technical Report provided it passed the rigorous peer review process, which ensures that that all their Technical Reports meet the highest scientific standards and are of maximum benefit and value to its membership and industry at large. This was just the vehicle the cold chain group was looking for to further its initiative. Technical Reports are intended for regulatory and industry guidance on scientific and operational processes.

Like all of PDA’s Technical Reports, it was drafted by an all-volunteer task force sanctioned by the association’s volunteer advisory board and its board of directors. A great deal of time, effort, and negotiation by the PDA Cold Chain Management Task Force was spent on finalizing the document, and in September, 2005, Technical Report No. 39, Guidance for Temperature-Controlled Medicinal Products: Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment, (TR 39) was published.

TR 39 has been widely accepted throughout industry. The United States Pharmacopeia (USP) General Chapter Good Storage and Shipping Practices (also published in 2005) and TR 39 are considered the “go-to” documents for best practices by manufacturers and shippers of temperature-sensitive pharmaceutical and biopharmaceutical products in the U.S. Their collective impact and influence continues to grow worldwide.

TR 39, the Sequel

Technical Report No. 39 underwent a significant revision in 2007. The latest version is more comprehensive, with expanded sections on transportation process flow, package design and development, a new section on handling, and updated regulatory and pharmocopoeial standards. It is also less U.S.-centric — taking into consideration global requirements on the essential principles and practices for shipment of products that require controlled temperature during transit.

It also provides a design approach to the development of specialized packages and systems for temperature-sensitive products during transportation. The 2007 Revision was prepared by a task force which included members from the PCCIG, along with European perspectives provided by the Cold Chain Committee (C3) and the Pharma Logistics Forum (PLF). Additionally, the C3 has thrown its hat into the PDA ring while continuing to work on European objectives while the PLF has decided to keep its group exclusive to European manufacturers of medicinal products.

Today’s PCCIG membership operates under the auspices and full support of the PDA. A 10-member steering committee, headed by chairman Rafik Bishara, includes biologic and pharmaceutical manufacturers as well as representatives from industry partners and academia. “My personal goal is to have one big, happy global cold chain family — where manufacturers, industry partners, organizations and regulators from all over the world can agree on one set of global cold chain standards,” said Mr. Bishara at the PDA Cold Chain Management Conference in Berlin, Germany in October. Encouraging people to be part of the process, he invited them by saying, “The PCCIG is a very active group and we continue to work with sub-committees engaged in second tier cold chain training, data collection and ambient temperature profile development, testing standards for shock and vibration. [. . .] Technical Report was the ‘what’ document. Now we have to double-click and produce the ‘how’,” he added.

He may be on to something. In only its second year, the PDA’s Cold Chain Management Conference held in Bethesda in June 2007, doubled in size and attendance from the previous year and included delegates from Canada, Ghana, Israel, Japan, South Korea, Switzerland, United Kingdom, and the U.S. The 3rd annual Cold Chain event is scheduled for March 13-14, 2007 in Bethesda, with a two-day cold chain management course preceding the conference.

The two courses related to cold chain management developed in 2007 currently offered by the PDA are:

• Pharmaceutical Cold Chain Best Practices, a one-day presentation on the origin and development of pharmaceutical industry consensus practices for the development of packaging used for distribution of temperature sensitive drugs and biomedical products. The course includes demonstrations of the most common packaging materials used to transport frozen, refrigerated and room temperature materials from the manufacturer through the complex distribution chain to the end user or patient. Attendees participate in mock exercises where temperature control packaging options are evaluated for effectiveness and practicality. Participants are also presented with the basis for understanding the individual roles and responsibilities required in the management and oversight of cold chain compliance.
• Global Regulations and Standards: Influences on Cold Chain Distribution, Packaging, Testing and Transport Systems, a comprehensive two-day course developed during the summer of 2007 and first presented at the PDA European Cold Chain Management Conference in Berlin, Germany in October 2007. A subsequent European session was held in Cork, Ireland in November of last year and the PDA intends to roll it out in North America on March 11 and 12 prior to the 3rd Annual PDA Cold Chain Conference in Bethesda, MD. The course provides participants with an introduction to Good Distribution Practices (GDPs) and includes the review of USP Chapter as well as cold chain regulations and documents from Ireland, Canada and the UK. Participants learn the contents of PDA’s Technical Report No. 39 compared to earlier developed guidance. Other discussion topics include the distribution environment (including critical steps to development of realistic ambient profiles for focused simulation testing), standard organization activities related to cold chain package testing, and development of a validation master plan guideline for pharmaceutical distribution packaging. An introduction to GDP through industry consensus practices for thermal package development and qualification is presented and discussed. This course includes case studies and round table discussions with PDA members who are experts in this field. Participants each receive a copy of the newly released and highly coveted PDA Technical Report No. 39.

During PDA’s training session in Cork, Ireland, this past November, PDA president Bob Myers said, “Cold chain management has quickly grown in importance within the industry and in scrutiny among regulators. PDA is proud that the publication of Technical Report No. 39 has been so widely received and accepted on both sides of the industry and we are committed to providing technical training as an adjunct for the application of that document.”

A subcommittee of the Pharmaceutical Cold Chain Interest Group is working on a second tier of cold chain training to compliment the two courses already offered by the PDA. Gail Sherman cited that the course would be available later this year.

Publications

In addition to the more than 40 Technical Reports published to date, The bi-monthly PDA Journal of Pharmaceutical Science and Technology, first published in 1946, is considered one of the most relevant and highly cited vehicles for peer-reviewed scientific and technical papers in the pharma and biotech industries.

Everybody Loves a Winner

Other organizations have been keen to recognize the PDA’s influence on the biopharmaceutical industry and its ability to reach a global audience. They have established relationships to further their own pursuits, and keep pace with regulatory change. They attend PDA cold chain training courses to gain insight and understanding on what it takes to be “cold chain compliant” while remaining apprised of industry consensus practices. One of the first to recognize the advantage of such an affiliation was the International Air Transport Association (IATA).

New Air Regulations For Temperature-Sensitive Freight

On July 1, 2007, IATA replaced its vaguely written guidance for the transport of medical freight — which was scattered throughout previous editions of its Perishable Cargo Manual, with the newly written 7th Edition Perishable Cargo Regulation. It is significant in two respects. First, it is no longer a guidance document but a regulatory requirement that its 240 member airlines must meet. Secondly, it is a stand-alone chapter. In an effort to differentiate healthcare products from all other perishable cargo (fresh fruit, flowers, meat, fish, pet cargo, etc.) for which there are clearly different handling requirements and expectations, the IATA Live Animals and Perishables Board followed the suggestion of a cross-industry committee who wrote the document led by several PDA-PCCIG members, and established a separate chapter: Air Transport Logistics for Temperature-Sensitive Healthcare Products, otherwise referred to as “Chapter 17.” The new chapter is intended to improve quality within the healthcare distribution system by reducing the risk of improper handling of medicinal freight. It provides greater background and more detail to the airline industry and ground handlers on the unique challenges of medicinal freight in transportation. It has been widely lauded by the pharmaceutical industry as a proactive solution by the airlines, which worked closely with the PDA interest group to get the document written and published under a tight timeline. Future editions of Chapter 17 will need to incorporate the inevitable changes within the transportation industry and meet the ever-evolving regulatory expectations. IATA has formed a Time & Temperature Control Task Force to address these issues.

IATA considers this topic to be of enough importance to include a one-day track dedicated exclusively to the pharmaceutical industry entitled “The Logistics of Healthcare: the Cure is in the Air!” at its World Cargo Conference in Rome, Italy, March 3-6, 2008.

Elsewhere

In North America, the United States Pharmacopeia, and Health Canada’s Health Products and Food Branch (HPFB) are undergoing wholesale rewrites of their guidance documents, General Chapter and Guide-0069, respectively. Both were initially published in 2005. The feedback from the healthcare industry has necessitated that these documents be more comprehensive, that they more accurately reflect technological limitations, and capture current best practices. Both documents are expected to be published in 2008.

The Canadian Association for Pharmacy Distribution Management (CAPDM) also implemented guidance in 2007, working closely in association with PDA PCCIG, and have presented their guidance to the HPFB for comment.

In addition, several working groups and committees have popped up within individual pharmaceutical and biotech manufacturers in Europe and North America in an effort to sort out and understand the growing complexities of what once was considered the mystical distribution process — and what regulators are viewing as an extension of the manufacturing process. Shippers, distributors, wholesalers, freight forwarders, consolidators, and the airlines are working more closely with drug manufacturers to reign in the process under the careful eye of regulators. Also of note: the introduction of a new generation of active packaging solutions specifically addressing risks associated with cold ambient temperatures and long transit times. They hit the market late in 2007 after a long and difficult airline industry approval process.

As demand and value of temperature-sensitive medicinal products continues to grow globally, so does regulatory compliance — forcing manufacturers to become more risk averse, more knowledgeable about their distribution processes, and more demanding of their packaging and transportation requirements. Guidance, such as those developed by — and in conjunction with the PDA — have proven to be a reliable source for staying in step with the rapidly growing field of pharmaceutical cold chain management.

References

1 Parenteral Drug Association 2006 Annual Report.

2 ibid.

Kevin O’Donnell is director and chief technical advisory of ThermoSafe Brands. He also writes the Advanced Degrees column for this magazine.