Design, quality, safety and efficacy of extensively hydrolyzed formula for management of cow's milk protein allergy: What are the challenges?

Cow's milk protein allergy (CMPA) is one of the most common food allergies in infancy. Clinical food allergy guidelines recommend an extensively hydrolyzed formula (EHF) as the first-line treatment in nonbreastfed infants with CMPA. Designing and commercializing EHF poses both technical and regulatory challenges. Each manufacturing step, from sourcing of raw materials to release of the final product, needs to be managed in accordance with comprehensive quality systems. To avoid cross-contamination via externally sourced ingredients, suppliers should be carefully selected based on quality requirements. Strict zoning of the manufacturing areas according to contamination risk and air flow control are effective strategies to prevent accidental allergen contamination. Furthermore, dedicated manufacturing lines for hypoallergenic products are used to prevent potential cross-contamination from other products produced on the same line. The enzymatic hydrolysis, heat treatment and ultrafiltration used are specific to each manufacturer. Consequently, EHF are a heterogenous group of products with differences in the molecular weight profile of peptides, content of residual immunogenic cow's milk allergens, and residual in-vitro allergenicity. These differences are likely to affect clinical efficacy and safety. As not all commercialized EHF products have undergone formal testing in the laboratory and clinical trials, there is a need to develop guidelines for minimum technical and regulatory requirements for EHF products, including validated assays for ongoing quality control. Clinical trials assessing new EHF products for their hypoallergenicity and ability to support normal growth remain the definitive proof of efficacy and safety in infants and young children with CMPA.