A Regulatory Perspective on Manufacturing Processes Pertaining to Lyophilized Injectable Products
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Regulatory Note A Regulatory Perspective on Manufacturing Processes Pertaining to Lyophilized Injectable Products Steve Y. Rhieu,1,2 David D. Anderson,1 and Kumar Janoria1
Received 4 May 2020; accepted 30 June 2020 Abstract. Freeze-drying, also known as lyophilization, is a dehydration process designed to prolong the shelf life of injectable drug products. Here, we provide regulatory considerations for manufacturing processes specific to lyophilized injectable products. Specifically, a general discussion on each unit operation, including compounding, filtration, filling, and lyophilization, is provided to help the pharmaceutical industry establish reliable manufacturing processes from a regulatory perspective. In addition, a list of manufacturingrelated deficiencies identified from a total of 263 new drug applications (NDAs) and abbreviated new drug applications (ANDAs) submitted for lyophilized injectable products is provided. We hope that the information presented in this report may help applicants avoid some common manufacturing-related deficiencies in regulatory submissions, thereby making high-quality lyophilized pharmaceuticals expeditiously available to the American public. KEY WORDS: deficiencies; freeze-drying; injectable; lyophilization; unit operation.
INTRODUCTION From the pharmaceutical manufacturers’ perspective, every drug product is considered unique as requiring completely different process parameters to build and maintain quality throughout its proposed shelf life. Lyophilized injectable products, comprising half of all new injectable drug products by 2015 (1), are no exception. According to the International Conference on Harmonization (ICH) Q8(R2), the aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. However, despite the recommended guidance stipulated in ICH Q8(R2), manufacturing-related deficiencies issued by the Office of Pharmaceutical Manufacturing Assessment (OPMA) within the US Food and Drug Administration (FDA) have been habitually observed in lyophilized injectable product applications. We herein discuss common manufacturing-related deficiencies identified in regulatory submissions received by the OPMA for evaluation. The intent of this work is not to provide an allinclusive discussion of potential studies an applicant can conduct in order to have a desired quality built into a lyophilized product, but rather to inform the applicant of
1
Office of Pharmaceutical Manufacturing Assessment, Office of Pharmaceutical Quality, Center of Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993, USA. 2 To whom correspondence should be addressed. (e–mail: [email protected])
common deficiencies identified for each unit operation used in the manufacture of lyophilized injectable products. Design of development studies should be based on the applicant’s internal risk assessment strategies as well as any prior experience working with similar products. Howeve
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