Halo Pharma recently launched its Pediatric Center of Excellence to support the development and manufacture of dosage forms tailored for pediatric indications. The contract development and manufacturing organization (CDMO) has been working closely with pharmaceutical companies to apply its expertise in formulation sciences and its integrated manufacturing capabilities across a broad range of scales and dosage forms to overcome the challenges in developing pediatric dosage forms (PDFs) of already approved adult dosage forms. Contract Pharma had the chance to sit down with Halo’s chief executive officer, Lee Karras, to talk PDFs and Halo’s unique position in this niche market space.  —TW

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Contract Pharma: What is driving the demand for pediatric dosage forms (PDFs)?
Lee Karras: I don’t know when it first started but I know for a long time physicians have been using adult doses for pediatric indications and the FDA said we don’t understand the safety profile of pediatrics so we need to make sure that the pharma companies are developing dosage forms that are not toxic for kids. Limiting off-label use in pediatric patients is certainly something that is a very common mandate by FDA.

Pharmaceutical companies are often asked by FDA to conduct clinical trials for pediatric indications of adult dosage forms. The Agency has created exclusivity around pediatric dosage forms to create an incentive for companies to make the investment in clinical studies for pediatric patients to meet the pediatric safety profile and get the right dose to the patient.

Sustaining revenue growth through pediatric exclusivity typically adds 180 days of intellectual property protection—almost 6 additional months of branded drug sales—which in some cases could translate to billions of dollars of revenue. If a patent is going to run out they can actually sell the product for six more months in the adult dosage form and the pediatric dosage form. One company we work with has a product worth $5 billion a year in sales. Do the math. An additional six-months of exclusivity is worth $2.5 billion in sales for the adult dosage form. So, preventing the generic from coming out during that time is a big deal.

CP: How active has Halo been in the PDF area?
LK: We’ve partnered with several pharmaceutical companies already to develop commercially viable PDFs that have received both U.S. and international regulatory approvals. In addition, the company currently has multiple clinical and commercial PDF programs underway. In support of our Pediatric Center of Excellence, we’ve developed the infrastructure, process trains and equipment needed for efficient, cost-effective, and rapid production of small- to medium-scale cGMP clinical drug products that are used in pediatric clinical studies. We provide technical expertise needed to modify adult dosage forms for pediatric use. This may include reformulation to enable a lower strength or making changes to the adult dosage form to improve patient compliance by making the medication easier to take and/or taste better.

CP: What are common indications for PDFs?
LK: Everything Halo is involved with is in the prescription field and we’re typically focused on a couple key areas. Anti-infectives are a big one along with central nervous system (CNS) disorders, including ADHD and depression. We make PDFs a little bit in the pain management area and for some specialty indications like cystic fibrosis. We’re making one product right now for cystic fribrosis typically given to patients between 6 and 25 years old. It’s a chronic disease so patients take the drug every day or else they could die. You don’t see a lot of PDFs in cardiac care just because kids don’t generally have cardiac issues. There also are not a lot of oncology pediatric products out there.

CP: What types of services does Halo offer?
LK: Our formulation development and clinical manufacturing capabilities can support a variety of oral solid and liquid dosage forms suitable for pediatric applications, such as granules produced using fluid bed technology and mini-tablets that can be packaged into stick packs, powder in bottles for reconstitution, and our liquid products, which are typically oral solutions and suspensions that can also be time release-based. We offer our customers over 40 years of commercial drug manufacturing experience and a proven track record of approvals with regulatory agencies around the world.

CP: What are the challenges when developing PDFs?
LK: There are a number of challenges. Scale is one. PDFs are generally not made in the same scale as their adult counterparts because you’re dealing with a smaller number of patients. So the scale of equipment is a challenge. You have to take what was made in thousands of kilograms and bring it down to say a hundred kilograms. So making PDFs requires specific right-sized equipment. Halo has the capabilities to manufacture batches of PDFs that typically range in scale from 5 kg to 1,000 kg, with many requiring multiple processing steps.

Additionally, in nearly all cases, developing a PDF from an adult dosage form requires additional product development work. In many cases, it is necessary to provide the PDF in various strengths matched to different pediatric age/weight brackets.

Also, in many cases the reformulation requires changing the manufacturing process to turn the drug product into another dosage form. So, for instance, an adult tablet could turn into a mini-tablet or stick pack, or powder in a bottle, or a solution in a bottle for a PDF.

If you’re changing the dosage form, that then requires having to redo your analytical methods. And in many cases the packaging also changes to make it more tailored towards kids.

There are also cleaning issues with PDFs. At Halo we recently redid our cleaning validation in our Whippany, NJ, plant because the carry over limits are different. If you have residual drug and it goes into the next batch and that next batch is only 5 kg versus 1,000 kg, everything changes. Cleaning validation is a very important part of the process.

CP: Are PDFs a global trend?
LK: Brand companies typically operate in multiple geographic locations and jurisdictions, so you have to have the regulatory approvals to make products for multiple countries and that involves not just regulatory approvals for drug products but also packaging and labeling operations. Because pediatric patient populations are smaller in a given geography with the U.S. being the largest globally, it’s still a relatively small patient population. So to get the biggest bang for their buck, pharma companies will apply for the same indication in multiple countries so they can sell more of the product across the globe. Having a plant that is up to par with international regulatory approvals is important. At Halo we provide specialized contract development and manufacturing services that meet the regulatory requirements of the U.S., Canada, and Europe, and are already manufacturing PDFs for commercial sale in these regions.

CP: Is the development and manufacture of PDFs being outsourced for the most part?
LK: Pharma companies typically don’t do this in-house. If you walk into a large pharma manufacturing facility they have these huge blenders and big packaging equipment. The plant manager never wants to change his production line over. He wants to make the same thing everyday. If I came in one day and said told him he has to make this 10 kg batch, he’s got to take everything apart and retool it. So yes, PDFs are a heavily outsourced area.

I was telling somebody recently, pediatric products are typically smaller in terms of the revenues that a contract manufacturing organization (CMO) sees. So the PDF area isn’t large enough in terms of revenues to get the largest contract service providers out there excited about taking on these projects.

Typically what companies have done is they’ve gone to the smaller CMOs to do the work. Well, many smaller CMOs typically only produce for one market, the U.S. market. One of the advantages we have at Halo and one of the key attributes behind our focus on PDFs and our initiative with the Pediatric Center of Excellence, is the fact that we operate internationally independent of scale restrictions. The smaller patient population isn’t a problem for us and we have regulatory approvals in place internationally. We’re kind of in that ideal sort of spot for pharma companies, particularly large pharma companies, to partner with.

CP: Tell me a little more about the center and what it offers.
LK: The core fundamental formulation and analytical support is in Whippany, NJ. It has all the equipment and assets there, and acts as the development center. But both of our plants, the other being in Montreal, can manufacture PDFs.

In addition to the reformulation and development expertise and to-scale manufacturing capabilities we offer, the other thing we do is spend time advising large pharma on what to look out for with PDFs. It’s a very specific thing. Do I create a mini-tablet product, or granule? If I choose mini-tablets do I put two mini-tablets in a pack or 3? If I do 3 does that mean I’m going to have more or less variability in the dose? Things like that.

We’ve actually gone through many of these experiences. So a lot of times we act as an advisor in many cases to pharma companies because they’ve never done it. Don’t get me wrong, they can create their own centers and do a lot of this themselves, but it’s such a unique niche thing that lends itself more towards outsourcing. And if you’re going to outsource, you’re going to outsource to someone that’s done it before.