Authored By: Mo Heidaran, Bob Iser, Keith Chidwick, PAREXEL® Consulting
Manufacturing is defined as all steps in propagation or manufacture and preparation of product and includes but not limited to processing, filling, testing, labeling, packaging and storage by the manufacturer. Processing refers to any manufacturing steps that are performed which may affect its safety, purity and potency of the product (21 CFR 600.3(u)(Z)). Manufacturing at the clinical site may include, for example, 1) collection of the starting biological materials, 2) formulation of the final drug product, 3) thawing and washing of the final drug product, or 4) addition of other agents including small molecules to the final drug product to affect the drug product potency.
In the United States, the manufacturing occurring at the clinical sites is not normally subject to an inspection by FDA. FDA expects that the manufacturer demonstrates in their BLA that they are in full control of any manufacturing performed at the clinical site. The essential elements of demonstrating manufacturing control at the clinical site is not trivial and, in some cases, not well understood by drug developers.
In general, there are several points that should be considered by the manufacturers as part of their product and process quality control systems. These points to be considered include but not limited to the following:
- Any manufacturing performed at the clinical site must be fully validated.
- Validation of the procedures performed should be performed using worst case scenarios.
- Although the manufacturers may not be in full control of the environment in which the source biological materials are collected, or further product manufacturing is performed (e.g. at the hospital) IND and BLA sponsors are expected to develop standard operating procedures that ensure product quality considering the worst-case scenarios envisioned at the site. The worst case scenario may include extreme temperature fluctuations, and maximal number of operators and healthcare providers at the site, etc.
- The manufacturing steps at the clinical site should be performed by individuals who are considered to be well qualified, as such; a robust training program and documentation should be in place.
- Any relevant training should be performed at a regular frequency and documented accordingly
- Manufacturers should establish a robust quality system to identify any deviation from SOP and perform CAPAs, in response to those deviations.
- Implementation of a quality system needs to be designed and implemented to encompass chain of custody (COC) and chain of identity (COI) of the source biological materials, product intermediates and the final drug product during all stages of manufacturing.
- The state of the clinical site in which any manufacturing is performed may impact the quality of the final drug product. For this reason, there has to be predetermined facility requirements suitable for the type of manipulation or manufacturing performed at the site. Because in some cases the facility’s environment may be fixed in commercialization phase and cannot be altered (e.g., at a hospital), or excluded manufacturers are encouraged to use functionally closed system to reduce the likelihood of any product contaminations.
We at PAREXEL have a full range of firsthand knowledge and expertise in the best current good manufacturing practices conducted at the clinical site and can help you with the complex logistics of controlling the COC/COI of the product, product intermediates or source materials.