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What are the Key Differences with Orphan Drug Manufacturing?

I was asked recently what a contract manufacturer such as Neuland Labs saw as the key differences with orphan drug projects. Neuland approaches orphan drug projects slightly differently from our typical project – but I would stress that it’s only a very slight shift.

Orphan Indications – (Almost) Personalized Medicine

Orphan drugs are drugs developed specifically to treat rare conditions. In Europe for example, a disease is defined as ‘rare’ when it affects fewer than 1 in 2,000 people. Because the patient populations are very small, drug companies historically shied away from research into such conditions, given the lack of economic incentives.

That view has shifted over the last two decades as various financial incentives as well as a higher and faster rate of regulatory approval have led to orphan drugs’ rising popularity. Additional incentives – such as extended exclusivity periods – have further strengthened interest in the field. Today, the economic potential of an orphan drug is similar to non-orphan drugs, in spite of the significantly smaller patient populations.

When we talk about orphan drugs at Neuland, Bosentan comes to mind. It’s a drug that has received multiple orphan designations (see Orphanet screenshot, below) over the years. We manufacture Bosentan (Tracleer), which is a dual endothelin receptor antagonist approved for use in the treatment of pulmonary artery hypertension (PAH) – a condition affecting just 100,000 people in the U.S. and Europe.

As a point of comparison, the wider hypertension market affects about one-third of all U.S. adults and accounts for $46 billion in costs each year in the U.S. alone. Hypertension, generally, is one of those indications Neuland is very familiar with, having completed research, development & manufacturing on behalf of our pharma clients. Some of this work has been with orphan drugs.

Orphan Drugs – Just a Matter of Scale.
Orphan drugs don’t come with additional regulatory challenges, per se. In fact, regulatory approvals tend to be faster compared with normal drugs. One of the reasons orphan drug development is on the upswing is because regulatory agencies streamline the approval processes to get therapies into the hands of patients. If I remember correctly, orphan drugs tend to have shorter FDA review times (by about 6 months or so) than non-orphan drugs.

Orphan Drugs – No Difference in Manufacturing Path
Orphan drug manufacturing is treated identically to typical drug manufacturing – adherence to the same, high quality standards, the same analytical work, and the same level of thorough documentation. In many cases, orphan manufacturing will use the same equipment and procedures. For example, one orphan product Neuland manufactured required deuterium exchange. In spite of the much smaller production scales, the process still necessitated special import/export licenses.

Orphan vs. Typical Drugs: A Matter of Scale
There’s really only one (small) thing that differentiates orphan drug production: the scale of production.

Because orphan indications serve smaller patient populations, quantities – even for approved, on-the-market products – will be smaller than a typical drug. With orphan projects, we tend to manufacture in our kilo-scale labs, or one of our mini-plants. This means that internal capacity planning must target and account for the use of specific, ‘orphan-friendly’ facilities in-house.

Another (Slight) Difference: Existing Drugs can mean Streamlined Manufacturing
An orphan drug is sometimes an already-marketed drug for which a new (orphan) indication has been identified (A good example of this would be a drug like raloxifene, which was approved in 2007 to reduce the risk of invasive breast cancer in certain high-risk post-menopausal women, but had been previously approved in 1997 for the prevention of osteoporosis in post-menopausal women.)

Such cases of repurposing a drug or compound for a different indication can offer the benefit of streamlining development work. With mature and fully-developed manufacturing processes, the production flow, infrastructure requirements & potential problem areas are already largely well-known and characterized – which may allow the development & scaling processes to proceed somewhat faster than they would with a new drug.  In some cases, production for orphan drugs might even require “downscaling” manufacturing to adapt to the smaller end volumes.

What have been your experiences with orphan drug manufacturing?


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