Regulatory aspects of modifications to innovator bronchodilator metered dose inhalers and development of generic substitutes.

Regulatory requirements for modifications to an approved innovator metered dose inhaler (pressurized MDI; USP nomenclature: inhalation aerosol) and for development of a new generic product are discussed. Although many of the requirements apply generally to MDI's, they are discussed with specific reference to albuterol. Changes to the container and closure system may impact on the dosimetry of the redesigned product, as well as upon toxicologic and chemistry, manufacturing and controls (CMC) concerns. Changes to the formulation, including the use of alternate propellants, may raise issues requiring both clinical and in vivo performance evaluation. In view of the level of interest of a number of firms in approval requirements for generic Albuterol Inhalation Aerosol products, the article discusses in considerable detail the CMC and bioequivalence requirements for a generic product. Similarities in the CMC requirements for innovator and generic products are evident. Three comparative in vivo bioequivalence tests, particle size distribution, spray pattern and plume geometry, and unit spray content, established by the Division of Bioequivalence are discussed. Similarities and differences in the in vivo requirements for innovator and generic products are evident. Differences are the result of U.S. statute, which requires safety and efficacy testing for a product approved under a new drug application (NDA), but documentation of bioequivalence for a product approved under an abbreviated new drug application (ANDA). The advantages and disadvantages of three pharmacodynamic study designs which have potential usefulness for documentation of in vivo bioequivalence are discussed.

Anti-keyhole limpet hemocyanin antibody in normal unsensitized individuals.

Antibody to keyhole limpet hemocyanin (KLH) has been detected in normal unimmunized subjects by means of a sensitive micropassive hemagglutination technique. Prior sensitization was not detected by either skin testing or lymphocyte transformation. After immunization with KLH there was no correlation between the level of this antibody and subsequently acquired skin test reactivity and lymphocyte transformation.

Ssytemic effects of intravenous polyriboinosinic-polyribocytidylic acid in man.

To investigate the systemic, clinical and laboratory effects of iv polyriboinosinic-polyribocytidylic acid (poly I-poly C), 32 doses of poly I-poly C were administered to 22 patients. Doses between 1 and 10 mg/kg induced the formation of serum interferon (IF) and fever. Whereas a direct relationship was seen between the poly I-poly C dose and fever, serum IF levels were not significantly changed by increasing the dose of poly I-poly C over a log range from 1 to 10 mg/kg. Transient abnormalities were noted in liver function tests in 4 of 13 patients who received greater than 6.0 mg/kg. Other laboratory changes were confined to an increase in the absolute granulocyte count that paralleled fever development and abnormalities in coagulation parameters of 1 patient. In vitro lymphocyte DNA synthesis in response to mitogens was transiently impaired at times corresponding to serum IF appearance. These studies have established dose levels of poly I-poly C that can be safely administered to man with minimal toxicity and result in IF induction.