One side effect of public scrutiny of rising drug prices has been greater visibility into the uniquely complex pharmaceutical supply chain. Previously little known distributors and middlemen now regularly receive attention, highlighting how the line between drugmaker and patient is rarely straight.

Pills and vials made in the manufacturing labs of Merck & Co. and Pfizer Inc. are routed to hospitals and pharmacies by wholesalers like McKesson and AmerisourceBergen. In just one possible iteration, pharmacies buy medicines, are reimbursed by insurers, which in turn work with or own pharmacy benefit managers in negotiations with drugmakers.

Stretching even further back, lines of supply connect drug manufacturers to factories overseas churning out the raw chemicals and ingredients that make up the branded medicine eventually administered to patients.

All of this behind-the-scenes shipping, receiving and payment underpin an industry with customers that rarely can afford a disruption in supply. Transporting medicines, however, brings with it unique challenges, particularly as temperature-sensitive biologic drugs become more commonly used. Cell and gene therapies, a still largely nascent technology commercially, will require further advances in supply.

Read on to dive into some of the most pressing problems facing the manufacturers and shippers that make up the drug supply chain:

1. Visibility

A lack of visibility into the supply chain may be the root of many challenges faced by the pharmaceutical industry.

Drug shortages. Counterfeits. Opioids. Many of the hard-hitting headlines critiquing the industry today highlight how patients, regulators and retailers alike do not often know where drugs are coming from and how they were made.

Today, the global pharmaceutical industry is knee-deep in a journey to solve the visibility problem by attaching product identifiers to every product, and creating a system for all to access.

But for the industry, the path to visibility represents more than an ability to track-and-trace goods for the consumers’ sake. In some cases, it may also boost margins and result in a safer product.

If a critical vial of ingredients was lost due to poor temperature controls in transit, and a company can prove it, a third-party logistics provider would have no choice but address the concern. Or, if a drug was contaminated from the time of its manufacture, a supplier can be called upon to address the source of the issue.

Seemingly simple mistakes can become error rates in studies, shortages in hospitals, and so forth. Being able to see where supply chain problems lie opens the door to addressing them.

2. Logistics coordination

However, just being able to see an issue does not mean it can be easily addressed.

Often, supply chain issues come down to differences in processes or systems. A single drug or treatment may be administered to hundreds of hospitals through distributors, but with more than 5,000 such healthcare facilities in the U.S. alone, it can be tough to keep track of and meet each buyer’s requirements.

The emerging CAR-T treatments provide just one example of many in how differences in process among hospitals can be problematic for a product.

“Some hospitals may require that the product gets to the hospital before they even start the lymphodepletion,” Knut Niss, chief technology officer at clinical-stage CAR-T drugmaker Mustang Bio Inc, said in an interview. Others, though, may start the depletion without the product on-hand, relying instead on a just-in-time delivery.

Differences in process permeate the industry, making any change in standards or control difficult to implement.

3. Compliance

Roughly 80% of active pharmaceutical ingredients and 40% of finished drug product are imported into the U.S. from overseas. Manufacturers in India and China, in particular, are a key source of the generic drugs prescribed to Americans in ever-increasing volumes.

In the U.S., the Food and Drug Administration is tasked with ensuring facilities based in foreign countries remain in compliance with Good Manufacturing Practices, a standard for aseptic production of pharmaceuticals.

Recently, inspectors from the FDA have issued warning letters to manufacturers abroad at an increasing rate, putting quality and compliance in focus as the pharmaceutical industries in China and India look to move up the value chain into novel drug development.

It's not just manufacturing, though. Shippers and distributors will soon have to comply with regulations under the Drug Supply Chain Security Act, which requires any company wishing to sell pharmaceuticals in the U.S. to facilitate product "traceability" by 2023.

Enforcement of the first stage of the law has been delayed by one year, but meeting the new standards for traceability and serialization will require significant changes and investment through the supply chain.

4. Cold-chain shipping

Increasingly, many of the world’s top-selling medicines are of biologic origin, typically grown in industrial-scale bioreactors. Think anti-inflammatory medicines like Humira (adalimumab) or Remicade (infliximab) or vaccines.

While all medicines are sensitive to the rigors of cross-border shipping, biologics in particular are heat sensitive and susceptible to contamination. Keeping these drugs cold, then, is a crucial part of the supply chains that connect drugmakers to patients.

Cold-chain shipping will take on an even greater role as more and more cell and gene therapies progress through clinical testing and onto markets worldwide. In the U.S., for example, two CAR-T cell therapies are currently approved. Manufactured from a patient's own immune cells, CAR-T treatments need to be kept especially frosty in order for the cells to remain viable.

Additionally, as CAR-T therapies are by definition personalized to each patient, cold-chain technology needs to be integrated with tracking software capable of maintaining detailed chain of identity and chain of custody.