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Mass spectrometry in freeze-drying: Motivations for using a bespoke PAT for laboratory and production environment

San Jose, May 19, 2018

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Abstract

Mass Spectrometry has commonly been used in the semi-conductor industry where maintaining a clean environment with minimum contaminants under high vacuum is crucial for successful manufacturing. Since the technology’s early usage for pharmaceutical manufacturing in the 1980 s, particularly in the freeze-drying environment, much has changed. The focus of the current work is aimed at asking some key questions regarding the maturity of the technology, its challenges and importance of having an application-specific instrument for quantitative process analyses applied to freeze-drying. Furthermore, we compare the use of mass spectrometers in early installations from the ’80s with recent experiences of the technology in the production and laboratory environments comparing data from different MS technologies. In addition, the manuscript covers broad application of the technology towards detection of and sensitivity for analytes including silicone oil and Helium. It also explores the option of using MS in detecting water vapor and nitrogen concentration not just in primary drying, but also in secondary drying. The technology, when purpose built, has the potential for use as a robust, multi-purpose PAT tool in the freeze-drying laboratory and production environments.

Graphical abstract

AMS1300 bespoke PAT Freezedrying

 

 

Abbreviations

CM : capacitance manometer
FBRM : focused beam reflectance measurement
Fluorescence : fluorescence spectroscopy
GC–MS : gas chromatography-mass spectrometry
ICP-MS : inductively coupled plasma-mass spectrometry
Laser Headspace : NIR laser measurements tuned typically for oxygen or carbon dioxide
LC-MS : liquid chromatography-mass spectrometry
MIR : mid infrared spectroscopy
MS : mass spectrometry
MTM : manometric temperature measurement
NIR : near infrared spectroscopy
RGA : residual gas analyzer
RTD : resistance temperature detector
TDLAS : tunable diode laser absorption spectroscopy
SIMS : secondary ion mass spectrometry
TOC : total organic carbon content
Turbidity : sensor to measure the amount of light (NIR) scattered from particulates in suspension
UV : ultraviolet spectroscopy
WFI : water for injection

1. Introduction

Freeze-drying involves removal of solvent such that the molecular structure of the active ingredient of the drug is least disturbed, thus providing a dried drug product that is quickly and completely rehydrated upon addition of the solvent. The process requires freezing on temperature controlled shelves of a freeze-dryer. The heat transfer fluid circulating through the shelves is often a silicone-based oil which can withstand temperatures down to −55 °C to −60 °C and on heating to 121 °C. It is imperative that the circuit remains completely closed at all times since the oil itself is not sterile. Service life of freeze-dryers can sometimes exceed three decades. A simple preventative maintenance operation of the shelf hoses can risk batch contamination unless materials and connections are carefully chosen. A typical freeze-dryer cycles through large local thermal stresses with operating temperatures ranging from −50 °C to 121 °C and pressures ranging from 5 Pa (37.5 mTorr) to 0.2 MPa (1500 Torr). Moreover, the shelves of a freeze-dryer move during Clean in Place/Sterilize in Place (CIP/SIP) cycles, loading/unloading, and stoppering of vials. Although rare, failed preventative maintenance operations or even the thermal or mechanical stresses could lead to micro cracks that eventually leak silicone oil. Initially, these cracks are too small to be observed during preventative maintenance or by the human eye. Coupled with the value of the products manufactured in each batch of a freeze-drying cycle, testing product integrity is of paramount importance.

Mass spectrometry (MS) is a powerful detection technique that allows sensing species concentrations down to ppm levels of contaminants in a closed environment. Here we investigate the possibility of using mass spectrometry and applying it towards contaminant detection and freeze-drying process analysis. While freeze-drying and PAT tools used for the same purpose remain the core scope of the manuscript, the authors would like to bring to the attention of the reader the different PAT tools used both upstream and downstream of the freeze-drying unit operation. The following section covers a range of PAT tools used in aseptic manufacturing.

1.1. A brief overview of some PATs used in support of aseptic manufacturing

Process Analytical Technology (PAT) as described by the Food and Drug Administration (FDA) – a definition:

The FDA considers PAT to be a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality. It is important to note that the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner [1].

Fig. 1 provides a summary of some of the different PAT tools used at various stages of aseptic processing and manufacture. For the sake of brevity as the article is centered on mass spectrometry, we only briefly touch on some of those tools used immediately before, during and after lyophilization.

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