USP〈1067〉 BEST PRACTICES FOR THE MANUFACTURE AND QUALITY CONTROL OF RECOMBINANT ADENO-ASSOCIATED VIRUS GENE THERAPY PRODUCTS

1. SCOPE

This chapter describes best practices for the structure, manufacture, and quality control of recombinant adeno-associated virus (rAAV) products that are intended for in vivo gene delivery applications. These rAAV products may be produced either as a drug substance or a drug product, for both nonclinical and clinical applications.

The chapter provides a general overview of the rAAV construct design, along with the control strategy for their manufacture and quality control at small- or large-scale production. rAAV vectors used for other purposes (e.g., as raw materials or drug substance in manufacture of ex vivo gene editing products, etc.) are out of scope. However, several aspects of the design, manufacture, and control of rAAV products described in this chapter may be useful to support the applications where rAAV is intended to be used as a critical component for ex vivo product manufacturing.

2. INTRODUCTION

Gene therapy products are generally classified as either viral vector-based (e.g., lentivirus, adenovirus, adeno-associated virus) or nonviral vector-based [e.g., naked DNA, small interfering RNA (siRNA) and liposome-packed nucleic acids]. Although nonviral vectors have been gaining traction in recent years, viral gene therapy vectors remain the most used as they are highly efficient at delivering transgenes into human cells. Viral vectors are typically comprised of a recombinant virus that has had its viral genes replaced with a therapeutic transgene; this transgene can either provide a functional copy of a missing or damaged gene or knock down the expression of a defective gene within the cell. Delivered transgenes may be expressed episomally, or they can be used to modify the host cell genome depending on the product’s molecular mechanism. Manufacturers have historically applied gene therapy to the treatment of monogenic disorders (i.e., Alpha-1 antitrypsin deficiency) as the genetics are more clearly understood compared to more complex diseases such as heart disease, diabetes, and certain cancers.

AAVs are invaluable gene therapy vectors, demonstrating both long term gene expression and favorable safety profiles. After many years of AAV vector development and clinical trials, the 2012 The European Medicines Agency (EMA) approval of the first rAAV gene therapy product, Glybera (alipogene tiparvovec), for human use was a significant accomplishment. Glybera is comprised of an AAV1 capsid that delivers a functional lipoprotein lipase (LPL) gene to patients suffering from lipoprotein lipase deficiency. Due to the high cost of manufacture and low patient demand, however, the product was withdrawn from European markets in 2017. In the same year, the FDA approved the first rAAV gene therapy product in the US, Luxturna (voretigene neparvovec-rzyl), for the treatment of patients with a progressive form of blindness termed Leber’s congenital amaurosis. This therapy utilizes an rAAV2 capsid to deliver a gene that encodes functional human retinal pigment epithelium 65-kDa protein (RPE65) directly to the retina. In subsequent years, additional rAAV gene therapy products have received regulatory approval (e.g., Zolgensma, Upstaza, Roctavian, Hemgenix, Elevidys).

Due to the increasing interest in developing these drugs, this chapter focuses on the manufacture and quality control of rAAV gene therapy products. General guidance on viral and nonviral gene therapy product manufacturing, testing, and administration is provided in Gene Therapy Products 〈1047〉

Source from USP and Please refer to USP for details:

https://online.uspnf.com/uspnf/document/2_GUID-254EE7B2-DC7B-4D10-A6D0-2345A88A5871_10101_en-US?

Polymer Vial for cell and gene therapies

RTU(ready to use) 2ml COP vial