Pharmaceutical companies are looking to paediatric indications of approved adult dosage forms (ADFs) to sustain and fuel growth. The desire to develop paediatric dosage forms (PDFs) of drugs with existing adult indications has two main drivers: the US Food and Drug Administration’s (FDA’s) role in limiting off-label use in pediatric patients, which aligns with the FDA’s role in ensuring the safety and efficacy of approved products for all patients; and sustaining revenue growth through paediatric exclusivity that typically adds 180 days of intellectual property protection and thus almost six additional months of branded drug sales, which in some cases could translate to billions of dollars in revenue.
PDF scale and reformulation challenge manufacturers
The demand for PDFs of drugs spanning a broad range of therapeutic areas will likely continue to grow. But the challenges for drug producers developing PDFs are numerous and varied. Formulation decisions made in the development of PDFs can have important implications for drug stability, patient compliance, and accurate dosing. Various modifications to adult dosage forms (ADFs) are often needed to make a drug easier for children to take and easier for parents to administer.
The differences between adult and paediatric dosage forms are typically significant. In many cases, pharma companies select a contract development and manufacturing organisation (CDMO) to develop products versus doing the work themselves for reasons related to cost, convenience, and capacity.
First and foremost, CDMOs must have expertise in formulation sciences and proven formulation success in clinical development and commercial approvals. Many of today’s drug products are complex release and combination products that require innovative formulation approaches and technology. A formulator/developer must have the process and production equipment appropriate for quick turnaround of small- to medium-sized clinical, and ultimately commercial, batches that are typically required for PDFs that target smaller patient populations.
Cambrex, for example, has a track record of success in partnering with several pharmaceutical companies in the development and commercialisation of clinically suitable PDFs. Cambrex, along with several customers, has received both US and international regulatory approvals for PDFs as a result. Cambrex and its customers currently have multiple clinical and commercial PDF programs underway.
Advanced manufacturing technology and expertise in formulation sciences and process development are critical. In nearly all cases, developing a PDF from an ADF requires additional product development work. Cambrex has the capability to manufacture batches of PDFs that range in scale from 1kg to 1000kg, and most of the PDFs in Cambrex’s pipeline require multiple processing steps.
The solubility and stability of the API are some of the important factors to consider when deciding between liquid and solid oral dosage forms. The need to add flavouring, known as “taste-masking,” to make a drug more palatable for children is another key facet of the reformulation process. Cambrex’s broad range of formulation options includes all of these liquid-based dosing solutions in addition to solid dosage forms such as granules produced using fluid bed technology, beads, and the increasingly popular 2mm mini-tablets.
Cambrex’s formulation scientists and development and manufacturing teams work closely with pharma companies to identify the best options for reformulating a particular drug for the targeted paediatric patient population. Patient age and weight ranges, dosage strengths, frequency of dosing, and relevant disease factors (that might make it more difficult for a patient to swallow, for example) are all important aspects of formulation decisions. Sometimes parents just need the ease of being able to reach into the refrigerator and pull out a ready-to-use oral solution, without the need for reconstitution.
The trend toward combining two or more APIs in one formulation, the use of controlled-release medications, and, of course, cost considerations are all key factors that must be weighed during the design and development of a PDF.
While drugs for paediatric patients typically involve lower doses than those given to adults, concerns in minimising drug toxicity in paediatric patients are always paramount. This can be overcome during formulation of PDFs by carefully choosing the dosage form, excipients, and concentrations used during the manufacture of the drug product.
Innovative solutions to complex challenges
A frequent example of a client challenge is the growing trend in which pharma companies are combining two or even three APIs in one formulation. This requires a fixed ratio of the drugs in a single dosage form. These types of scenarios become even more complicated when one of the two drugs must be released before the others. In one specific case, Cambrex developed a PDF containing two APIs in suspension in an 80/20 ratio. The API present at 20% was formulated for immediate release, whereas the API that comprised 80% of the total was formulated as extended release over 24 hours. Yet another example necessitated a formulation that allowed two of the APIs in a three drug combination to release before the third API.
One can imagine that these complex and challenging examples of PDFs could take many years to bring to fruition. The challenges include, but are not limited to:
- Just-in-time production of material for clinical trials in pediatric patients, which typically face recruitment challenges
- More stringent cleaning requirements (including situations where PDFs are manufactured on the same equipment as ADFs in the same plant) due to lower recovery carry-over limits versus larger batch/adult product batch-scale sizes
- Manufacturing clinical materials under full GMP conditions
- Having the bandwidth and lab support to conduct all method revalidations and stability studies on PDFs
None of these challenges are insurmountable however, and the path from ADF to commercialisation of a PDF can be shortened significantly by partnering with an experienced CDMO that has expertise and appropriate process and manufacturing capacity targeted to this niche application.
A key factor in time to market is manufacturing capacity and the ability of a CDMO partner to produce small batches on demand to allow for quick assessment of different formulation approaches. Waiting in a long queue of higher priority large-scale manufacturing runs makes for lengthy and uncertain delivery timelines. A dedicated team-based approach to project management from formulation and development through manufacturing, analytical, packaging, and regulatory review can also streamline PDF production.
Faster to market
Collaborating with a partner that has its own in-house team of formulation scientists, a dedicated development group, and pilot and commercial-scale manufacturing in one location can yield direct benefits in the form of faster, more reliable turnaround and delivery times.
At Cambrex, three shifts operate across 24 hours, allowing Cambrex to achieve an on-time rate for deliverables to clinical sites of greater than 96%. In a CDMO of Cambrex’s size, customers get the advantage of all the necessary technology and capabilities, but not the silos or bureaucracy of larger CDMOs. As a result, projects can progress more quickly, as a single, dedicated project management team can follow your project from start to finish. Furthermore, the experience that comes from having been through numerous FDA inspections – including general and preapproval inspections – and familiarity with local teams of FDA inspectors are invaluable.
Many pharmaceutical companies have already benefited from Cambrex’s extensive expertise in formulation sciences and its fully integrated manufacturing capabilities across a broad range of scales and dosage forms to overcome the challenges in developing PDFs of already approved adult dosage forms.
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