Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Regulatory Considerations for Pre-filled Syringes in Clinical Development - an EU and US Perspective

Dr. Jens-Uwe Künstler (Abschlußjahr: 2019)

Summary
Language: English
The thesis provides an overview about regulatory requirements for pre-filled syringes in clinical development in the EU and US.
Pre-filled syringes represent a more complex container closure system than vials or ampoules due to their constitution of more different parts and their additional delivery and measuring function.
The term combination product is not legally defined in the EU in contrast to the US. In the EU, a pre-filled syringe is classified as a medicinal product that includes the syringes as an integral part and is therefore mainly governed by drug legislation. Thus, for clinical development in the EU, a clinical trial authorisation application that includes inter alia an Investigational Medicinal Product Dossier applies. In the US, a pre-filled syringe is a combination product. For combination products, either an Investigational New Drug Application or an Investigational Device Exemption Application applies when requesting authorisation for a clinical trial. Since a pre-filled syringe has a drug or biologic primary mode of action, an Investigational New Drug Application is typically filed.
A basic element to guide product development is a Target Product Profile (TPP) that should also include considerations with regards to the pre-filled syringe. A TPP is not legally binding. A TPP can be voluntary submitted to the FDA to facilitate communication between applicant and authority.
In the EU and US, requirements are set forth to minimise medication errors which suggest considering certain design features together with risk management during development of a pre-filled syringe.
Regarding GMP, the same requirements apply for a pre-filled syringe as for an investigational medicinal product in the EU.
In the US, cGMP requirements are defined separately for drugs and device. In order to demonstrate compliance with cGMP for single-entity combination products like pre-filled syringes, the streamlined approach is typically followed by demonstration of compliance with either the drug or device cGMP regulation and specific provisions taken from the other regulation. For investigational combination products, design control requirements are the only cGMP requirements of the cGMP rules for devices that apply also for the investigational phase.
Usability engineering, in the US referred to as human factors engineering, considers the interplay of users, the use environment and the device user interface to develop a device resulting in effective and safe use. Usability engineering is an iterative process that should include risk management. Human factors validation testing is performed at the end of the device development process to demonstrate that the device can be used without serious errors or problems. Should a human factors validation study be necessary is dependant on the use-related risk analysis and evaluation by the FDA. Human factors validation testing may be performed under conditions of simulated use (which is regarded sufficient for most of the combination products) or as part of a clinical study.
The development process of a pre-filled syringe presentation is ideally completed when entering phase 3 clinical studies and the phase 3 studies uses the (nearly) to-be-marketed pre-filled syringe presentation.
For materials of construction of a pre-filled syringe, several pharmacopoeial monographs are applicable that define specifications and tests methods.
Test methods for the functioning of a pre-filled syringe are laid down in ISO norms.
When applying for a clinical trial authorisation, quality data related to a pre-filled syringe should be provided in the drug product section with a CTD module structure. Specific information for pre-filled syringes should be provided mainly in the sections for pharmaceutical development, manufacture, control of drug product, container closure system and stability.
Pages: 43