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A look at the formulation challenges in pancreatic enzyme products.
Specialty pharmaceuticals are an important component of the pharmaceutical market. They are broadly defined as drugs that target a specific patient class to treat a particular disease. As such, the formulation and delivery method is developed to meet those clinical needs. Zenpep (pancrelipase) Delayed-Release Capsules, a proprietary pancreatic enzyme product (PEP) trademarked and marketed by Eurand Pharmaceuticals Inc. (Yardley, PA) is an example of a recently approved specialty pharmaceutical that successfully addressed the challenge of maintaining stability in an enzyme product. John Fraher, chief commerical officer of Eurand Pharmaceuticals, discusses these issues with Patricia Van Arnum, senior editor of Pharmaceutical Technology.
PharmTech: As an enzyme product, what were some of the formulation challenges and issues (e.g., stability, shelf life, and bioavailability) regarding Zenpep delayed-release capsules? Can you explain how these issues were resolved with the formulation such as through salt selection, excipient selection, dosing regime, and other forms of administration?
Fraher: Zenpep, a PEP indicated for the treatment of exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF) and other conditions, was specifically formulated to meet the US Food and Drug Administration's guidelines and regulations for the PEP drug class. The drug is not a single enzyme product, but a mixture of digestive enzymes, principally lipase, protease, and amylase. The stability challenges of such a complex product are considerable because the product requires the stabilization of several enzymes and important cofactors.
The most important enzyme in terms of efficacy is lipase. Consequently, labeling is expressed in terms of lipase activity although levels of protease and amylase also form part of the labeled content. Until very recently, PEPs in commerce had very poor stability. To compensate for the degradation of the enzymes, and the lipase in particular, products were typically overfilled up to 160% of label claim, and the shelf life was considered to extend until 90% of label claim remained, meaning that patients may have consumed almost a double dose from one batch to the next without being aware of it. FDA issued an initial guidance in 2004 on PEPs, addressing stability issues associated with unapproved enzyme therapies and the need to regulate them under new drug applications (NDAs). The guidance stated: 'Since high doses of pancreatic enzymes have been associated with safety problems (see 69 CFR 23411), the finished product should be formulated to 100% of the label-claimed lipase enzyme activity (1).
This guidance presented a significant challenge to all manufacturers of PEPs. Eurand was able to leverage its formulation technology to meet this challenge. In August 2009, Zenpep was approved by FDA and is the only FDA-approved PEP evaluated in clinical studies in adults and children as young as one year old. Zenpep is released at 100% of label claim and has a shelf life of a minimum of two years. To achieve this result, Eurand needed to control a number of product parameters, such that the enzymes were effectively held in stasis but not denatured by the technology used to do this. Not only was it necessary for this to be achieved at the point of production but also throughout the lifetime of the product, which is in a particulate form in a capsule for oral use, not a lyophilized powder in a glass vial, as is often the case for protein therapeutics. The first patent in a series relating to these approaches recently received a notice of allowance from the US patent office.
These formulation changes had to remain compatible with product efficacy. As stated by the FDA guidance (1): 'The bioactivity and/or bioavailability of the active ingredients should be determined at the site of action (gastrointestinal tract). The lipase, amylase, and protease activities should be determined from aspirates from the stomach and duodenum. The data should be obtained under fasting conditions as well as after a standard meal stimulation.'
There is an additional challenge associated with the lipase in this product, in that it is irreversibly denatured below a pH of about 4, meaning the product must have an effective enteric coating and that the product must be readily released in the duodenum. Thus, the technology that was devised had not to reduce the functionality of the polymer coating in terms of it preventing acid penetration while in the stomach and still readily releasing the enzymes on exiting the stomach. These studies formed part of the NDA submission, and together with placebo, controlled pivotal efficacy studies clearly demonstrated the functionality of the product and the formulation.
PharmTech: How is the product administered and why was this route chosen?
Fraher: Zenpep is the only FDA-approved PEP offered in four dosage strengths: 5000, 10,000, 15,000, and 20,000 units of lipase to allow for precise dosing and for potentially reduced pill burden and to meet the varied needs of infants, toddlers, adolescents, and adults with EPI.
Zenpep is a hard-shell capsule containing an enterically coated multiparticulate. This dosing format was chosen because it allows the capsule to be opened, and the particles to be sprinkled on soft foods with some natural acidity such as applesauce and banana pudding to address the needs of patients who may have difficulty swallowing capsules such as pediatric patients or certain older patients. The capsule can also be swallowed whole of course. Thus, both options are available to address the varied needs of patients suffering from EPI.
PharmTech: Can you provide an update on the approval status of Zenpep in other regulatory jurisdictions?
Fraher: In addition to the launch of Zenpep in the United States, there have been a number of additional developments within the past year. In April 2008, the European Medicines Agency (EMA) confirmed that a marketing application for EUR-1008 (Zenpep) was eligible for community (centralized) marketing authorization submission in the European Union. This eligibility was granted under Article 3(2)b of regulation EC No. 726/2004, which relates to products that offer a significant technological innovation. Subsequently, Eurand filed a marketing authorization application through a centralized procedure, the approval of which would allow market access to 27 EU member states.
Additionally, in October 2009, EMA adopted new guidelines for PEP products, specifically stating that 'any PEP [pancreatic enzyme product] should be formulated to 100% of the label-claimed lipase enzyme activity' (2). As referenced earlier, every dose of Zenpep provides patients and physicians with the main pancreatic enzymes: lipase, protease, and amylase. This formulation, with 100% labeled lipase content and without overage, allows healthcare professionals to fine-tune treatment regimens to achieve dosing precision.
And in November 2009, Eurand announced data from a Phase II/III clinical study demonstrating that Zenpep delayed-release capsules significantly improve fat absorption in patients with EPI due to chronic pancreatitis.
1. FDA, Guidance for Industry; Exocrine Pancreatic Insufficiency Drug Products—Submitting NDAs (Rockville, MD, April 2006).
2. EMA Committee for Medicinal Products for Human Use, Guideline on the Clinical Development of Medicinal Products for the Treatment of Cystic Fibrosis (London, Oct. 22, 2009).