Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

The maze of extractables and leachables - Regulatory risk assessment of β-Glucans ***

Dr. Tobias Jaud (Abschlußjahr: 2024)

Summary
Language: English
Existing uncertain regulatory environment concerning extractables and leachables (E&L) leads to a need to assess E&L in a risk-based approach to walk through this maze and built a clearer path. β-Glucans (BG) have been found to have potential immunogenicity risk in biopharmaceutical products and are recognized as contaminants. Recent experiences with market dossier applications triggered questions from competent authorities (CA) on BG such as information on leachable studies and/or summaries of the risk evaluation on BG, which should be considered as potential leachable from the use of cellulose filters in the manufacturing process.
Since those experiences called for adequate control strategies of BG in biopharmaceuticals, this thesis aimed to regulatory risk assess BG. The lack of aligned regulatory guidance framework made it indispensable to use general quality risk management approaches according to ICH Q9.
The first aim encompassed the development of a control-strategy of BG that will be (most-likely) accepted by the CA at market submission stage. This included a risk assessment according to ICH Q9 as well as the development of a testing strategy of BG. Risks identified for BG contamination in DS were the use of raw materials, excipients, and cellulose derived filter after the last bind-and-elute ion-exchange chromatography (IEX) step. For all identified potential contributors a critical classification was made due to significant knowledge and data gaps and were considered as a potential source to jeopardize patient safety. Interestingly, real data calculations against a permitted daily exposure (PDE) revealed factors which were considered as uncritical for patient safety. Consequently, the overall risk of BG contamination was considered as low, which indicated that the specific processes under investigation were under control. Two different approaches of testing strategies for BG were discussed. Approach 1 included testing only on Drug Substance (DS) level, whereas approach 2 included testing of incoming good and on in-process steps as well as on DS level. Both approaches may be applicable depending on the scope. However, approach 1 was chosen to be more appropriate to meet the regulatory expectations, since risk assessment and testing on DS level will provide sufficient information to demonstrate that a respective process in under control.
As second aim, the risk assessment was discussed, interpreted, and embedded in the regulatory framework, if a testing strategy is necessary at different clinical phases and market stage. It was shown that it is reasonable to not test during clinical phases I and II. Similar findings were made for clinical phase III. It was shown that during process validation, it should be demonstrated that the process is robust and has the capability to deliver a product of the intended quality, which also included to prove that BG contamination on DS level is safe and under control. Therefore, a testing strategy was elaborated, which included both approaches from the first aim. It was further shown that approach 1 can be conducted until to the point, where it can be considered to remove testing on BG on a statistically basis. This was discussed to be used until market application stage.
The third aim focused on regulatory dossiers. It was shown in which S sections of the CTD granularity BG should be discussed. Since risk assessment and real data analyses starting before, during and after process performance qualification, a respective statement was suggested for clinical phases I, II and III. For market application dossiers suggestions were made, where information on BG could be included and how this information can be cross-referenced between the sections. Furthermore, it was discussed if changes in the commercial production for market supply could have an impact on the information of BG in dossiers. Potential regulatory changes for EU and USA were assessed and which form of change must be submitted were discussed.
The fourth aim looked in the closer future. Regulatory risk assessments will be helpful in identifying potential risks. However, risk assessments, and the implementation of control strategies of the E&L in question as well as regulatory strategy during clinical development, filing and post-approval stages were identified as only gap fillers until the establishment of ICH Q3E.
Pages: 63
Annexes: 1, Pages: 1