If you work in clinical operations, you’re probably aware of how closely that function must work with manufacturing. There are numerous decisions that have to be made around clinical packaging, interactive response technology (IRT) software, labeling of the clinical supplies, and the actual logistics of getting the supplies to the right place at the right time.
Michelle Sparks gained experience in clinical supply over the eight years she spent working for a midsized pharma company and two additional years spent with a non-profit that conducted trials in South Africa. She currently serves as the head of product development at Zafgen, Inc., where she is responsible for the development, manufacturing, and supply/sourcing of all drug product and clinical kit components for trials. When it comes to running a successful supply chain for clinical trials, she believes it always comes down to one-on-one interactions.
“It really doesn’t matter if you have a virtual business model and outsource everything, if you’re doing everything in-house, or if you have something in between,” says Sparks. “Success with your supply chain will ultimately come down to one clin ops person and one CMC (chemistry, manufacturing, and controls) person working closely together to make important decisions. Depending on the size of your company, this can be a two-person function or a team function. Either option will work. If the proper communication is happening, problems that arise can be solved quickly and efficiently.”
A Challenge For Small Companies
Logistics and supply chain issues can be a challenge for any company, but even more so for virtual companies and those with 10 to 100 employees. When those companies are scaling-up from pre-clinical development into their first Phase 1 trial, clinical supply decisions can be very difficult.
“In those cases, your best-case scenario might be to find a clinical trial site that can perform GMP drug product manufacturing on-site,” says Sparks. “Unfortunately, there are very few of those and none of them are in the U.S. Such sites exist in the UK, the Netherlands and to some extent in Australia. Some U.S. sites can provide extemporaneous compounding services, usually in the form of Powder in a Bottle, or dilution of sterile GMP drug product provided by the sponsor.
With on-site manufacturing, drug substance can be shipped directly to the site where a GMP dose is manufactured just-in-time for the patient. This process works especially well for those products with stability issues or where you have limited time for drug product development, manufacturing and release or in situations where a sponsor wants to go as fast as possible to first in man studies.
A more established biotech company, with perhaps 100 to 500 employees, will generally have several individuals working in clinical operations and a few others working in manufacturing or managing their CMO. This is where those one-on-one interactions between clinical operations and CMC come into play. Both individuals need to coordinate packaging, labeling, and the logistical details of getting clinical supplies to the right place at the right time.
“It doesn’t matter whether these decisions are made one-on-one or by teams of three or four individuals,” says Sparks. “There are generally three functions that get involved in these discussions: Clinical operations, CMC, and quality. All are vital to insuring your product makes it to sites and, ultimately, to patients.
Have The Right Conversations
Many of the clinical operations executives I talk to admit they don’t fully understand the demands of CMC or the challenges of getting supplies ready on time. Of course, the flip side is that CMC professionals do not understand the challenges clinical professionals are forced to deal with, such as opening sites, shutting down sites, changing levels of enrollment, and slow enrollment forcing trials to be delayed or cancelled.
“Those are critical conversations that absolutely must take place between the clinical operations group and the CMC team leader,” says Sparks. “One thing that companies should do is give that CMC team leader access to the clinical plan. Clinical groups will generally build overages into their plan. That is to make sure there are plenty of supplies at each site to cover the minimum number of patients that might get enrolled. CMC should be able to see that plan and understand the overages that are built into it.”
Both clinical and CMC also need to understand that sites do not have to be fully stocked with product at the start of the trial. Sites need to have enough product for the number of patients currently enrolled in the trial, not the number expected to be enrolled by the end of the enrollment period. This is especially true for smaller companies. If a product run will cost $200,000, it can be easier to stagger the cost of multiple production runs over the duration of the clinical trial, rather than pay it all upfront. However, this needs to be balanced against the cost of multiple clinical packaging and labeling runs.
Companies also need to be aware of a product’s shelf life. If a product has a shelf life of 6 months or 12 months, a long screening period or delays in getting patients enrolled could result in expensive product going to waste. Producing all the inventory in advance increases the possibility of a product going bad. That, unfortunately, can leave CMC with very little time to produce the product.
“You need folks monitoring expiration dating and the cost of goods,” cautions Sparks. “Those folks need to be from both CMC and clinical operations. This is a highly collaborative discussion, and you need to look at the overall benefit for the company, not just for the trial or for your department.”
JIT Can Be The Right Solution
In many companies, CMC will pay the cost to manufacture the product while clinical operations will budget for the clinical packaging and labeling component. This can create some confusion. If clinical needs 15,000 vials for one trial, they may budget for one packaging and labeling run. In reality, there could be more than one, due to expiration issues and resupply, and that must be worked into budgets.
Sparks notes another topic near and dear to her heart is the idea of just-in-time (JIT) manufacturing at the clinical site. She believes this is one of the biggest value drivers that a vendor can offer a company that has a flexible clinical team and a flexible clinical trial.
“If often depends on what your overriding goals are,” says Sparks. “JIT at the clinical site allows you to ship your GMP (good manufacturing practice) substance to the site and have them make the dosage forms. When you are dealing with a limited shelf life, having that flexibility is important to any biotech company that wants to be fast, flexible, and creative.”
Still, that approach requires even more coordination between CMC and clinical operations.
“CMC is not familiar with your sites, and clinical operations may not be familiar with CMC constraints,” continues Sparks. “This requires a truly collaborative effort. If you have teams that are not willing to collaborate or are not motivated to do so, it will not turn out well. There needs to be a true generosity of spirit. Rather than being concerned with functional or department goals only, everyone needs to be aligned with the corporate goals in order to realize the potential benefits for the company.”