The Cluster Design for the Postmarketing Stability Surveillance Program
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The Cluster Design for the Postmarketing Stability Surveillance Program F. Verbem, MSc Director, StatisticalS m ' c s , @anon Inc, W s t Omnge, New Jersey E. vam 1 1 Heorel, PLD Director, Statistical Department. NV Organon,
Oss,the Netherlands C. Vermot, 1 s t ResponsiblePharmacist, NV Organon, Oss,the Netherlands
Key Words Pasha&etingstability surveillance; Sdccted date approach; Cluster approach; Fixed-interval approach; Labomtory flciency
Cerrespmdemce Address h.C ~ H.E Vamaat, NV
Organon, Postbus 20,5340 BH Oss. the Netherlands (mail: [email protected]).
INTRODUCTION Stability of pharmaceutical products is an important issue. The stability may have an impact on the efficacy as well as on the safety of the product. Efficacy is threatened by chemical degradation of the active substance, but physical changes may also have a negative impact, for example, on bioavailability. Safety can be affected by side effects of degradation products. For safety and efficacy, physical stability may also play a role. The formal stability studies performed during the development of a new drug product provide information about the individual stability profile of each included batch. The shelf life and storage condition are established by statistical evaluation of the data. Recommendations for the design and evaluation of data from formal stability studies are provided in the Intemationa1 Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use's guideline QlA(R2): "Stability Testing of New Drug Substances and Products." Once registration has been obtained, and the product has been marketed, stability testing should be continued. According to current Good Manufacturing Practices, the monitoring of the stability of the product in a postmarketing stability surveillance program is required.
However, details of such a program are not given in any officially valid guideline. The objective of stability testing during the marketing period of a drug product is to confirm the previously established shelf life under the claimed storage condition. For the design of postmarketing stability surveillance studies, the starting points are: Broader experience with the manufacture of the product on a large scale, therefore, more batch data are available, Reaction mechanisms and degradation rates are known, Batches have been produced over a longer period of time, and The influence of light, temperature, and relative humidity on product stability is known from the formal stability studies, and the batches for the market are packaged accordingly.
From the above it can be concluded that a broad range of temperatures and relative humidities is not required for postmarketing stability surveillance studies. In principle, postmarketing stability surveillance studies at the registered storage condition are sufficient. In the formal stability studies, including the commitment studies, the batches are tested at 0.3,6.9,12,18.24. and 36 months, and possibly at 48 and 60 months, after production. T
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