Novel Cleaning-in-Place Strategies for Pharmaceutical Hot Melt Extrusion.

Martin Spoerk,Amrit Paudel,Jesús Alberto Afonso Urich,Johannes Khinast,Carolina Patricia Alva Zúñiga,Josip Matić,Kathrin Reusch,Klaus Nickisch,Johannes Poms,Karin Eggenreich,Ioannis Koutsamanis,Simone Eder,Raymar Andreína Lara García,Andreas Berghaus,Yorick Relle

doi:10.3390/pharmaceutics12060588

Abstract

To avoid any type of cross-contamination, residue-free production equipment is of utmost importance in the pharmaceutical industry. The equipment cleaning for continuous processes such as hot melt extrusion (HME), which has recently gained popularity in pharmaceutical applications, necessitates extensive manual labour and costs. The present work tackles the HME cleaning issue by investigating two cleaning strategies following the extrusion of polymeric formulations of a hormonal drug and for a sustained release formulation of a poorly soluble drug. First, an in-line quantification by means of UV–Vis spectroscopy was successfully implemented to assess very low active pharmaceutical ingredient (API) concentrations in the extrudates during a cleaning procedure for the first time. Secondly, a novel in-situ solvent-based cleaning approach was developed and its usability was evaluated and compared to a polymer-based cleaning sequence. Comparing the in-line data to typical swab and rinse tests of the process equipment indicated that inaccessible parts of the equipment were still contaminated after the polymer-based cleaning procedure, although no API was detected in the extrudate. Nevertheless, the novel solvent-based cleaning approach proved to be suitable for removing API residue from the majority of problematic equipment parts and can potentially enable a full API cleaning-in-place of a pharmaceutical extruder for the first time.

Highlights

In the pharmaceutical industry, proper cleaning of production equipment is of paramount importance in order to prevent cross-contamination of drug products [1,2] and avoid equipment malfunctions [3]
The present study aims at closing these gaps by analysing various cleaning procedures for a hot melt extruder by means of conventional swab and rinse tests and in-line UV–Vis spectroscopy
The extraction procedure for ibuprofen in the water/ethanol mixture was complete, since already after 10 h of extraction 100% of active pharmaceutical ingredient (API) were recovered from the cleaning polymer

Summary

Introduction

Proper cleaning of production equipment is of paramount importance in order to prevent cross-contamination of drug products [1,2] and avoid equipment malfunctions [3]. Two approaches exist to control the cleaning processes: cleaning validation and cleaning verification (CV) [3]. Cleaning validation is a documented process that assesses the effectiveness and consistency of pharmaceutical equipment cleaning for a large number of compounds manufactured at the respective site [4]. It is an extensive multi-functional programme, which considers the entire manufacturing process. CV confirms the effectiveness of the cleaning procedure and is applied when no established equipment cleaning procedure exists [3], e.g., during manufacturing products for phases I and II of clinical trials

Methods

Results

Conclusion