June Edition of ISPE’s Journal of Pharmaceutical Innovation Publishes Groundbreaking Scientific Papers

The first scientific papers outlining the progress made on ISPE’s Product Quality Lifecycle Implementation (PQLI) initiative are being published in the June 2008 issue of the Journal of Pharmaceutical Innovation. Written by experts representing the global pharmaceutical manufacturing industry, these papers present practical scientific and technological approaches to implementing ICH documents that address Pharmaceutical Development, Quality Risk Management, and Pharmaceutical Quality Systems.

In addition to PQLI Innovations, the June edition will feature research on acoustic experiments and surface decontamination effectiveness, and a case study that proposes a method for determining the criticality of a process parameter.

The issue is available to ISPE Members on Springer’s electronic information platform SpringerLink.

Editorial: Introducing PQLI Innovations from ISPE’s Product Quality Life Cycle Implementation (PQLI) Initiative
by Dr. James K. Drennen III

PQLI Key Topics - Criticality, Design Space, and Control Strategy
by Thomas Garcia, Graham Cook, and Roger Nosal

This paper gives an overview of progress made by the ISPE PQLI initiative - a global industry-led initiative aimed at facilitating the implementation of ICH Q8, Q9, and ultimately Q10 guidance. Through this initiative ISPE is spearheading the effort to help industry begin to define areas where they will be able to provide the technical framework for the implementation of key elements of Quality by Design (QbD) - a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management. Three topic areas, Design Space, Criticality, and Control Strategy were selected for specific focus and discussion, and this paper gives an overview of progress in these three areas.

PQLI Definition of Criticality
by Roger Nosal  and Tom Schultz

This paper describes progress made by the Criticality Task Team within the ISPE PQLI initiative. It aims to provide a concise, coherent, and universal approach for determining criticality for parameters, material attributes, conditions, and quality attributes. The work also clarifies the risk based distinctions governing the assignment of criticality to provide consistency and facilitate the adoption and implementation of Quality by Design (QbD) principles in the development of pharmaceutical manufacturing processes. The application of the concept of criticality presented in this paper aligns with the principles of ICH Q8, Q9 and Q10 guidelines.

PQLI Design Space
by John Lepore and James Spavins

This paper describes progress made by the Design Space Task Team within the ISPE Product Quality Lifecycle Implementation (PQLI) initiative. It is intended to provide approaches to the rational development of Design Space, as well as background on Design Space, its historical origins and how it fits within the wider PQLI initiative. The focus of this paper is on the technical elements of Design Space development.

PQLI Engineering Controls and Automation Strategy
by Ray Bolton and Stephen Tyler

This paper discusses the development of engineering controls and automation strategy required to practically implement a Control Strategy within a Quality by Design environment. It describes the relationship to the ISPE PQLI Control Strategy model, and covers operating philosophy, record keeping, data management, and alarm strategy. Engineering and automation controls may include measurement technologies for equipment parameters (off-line, at-line, in-line or on-line), univariate or multivariate process models and control models, engineering or plant procedural controls and automation systems. Concepts from ANSI/ISA S95 standards are applied.

PQLI Control Strategy Model and Concepts
by Bruce Davis, Line Lundsberg, and Graham Cook

This paper describes an approach and technical process for developing and implementing a Control Strategy, which is a planned set of controls, derived from current product and process understanding that assures process performance and product quality. Development of a Control Strategy requires a structured process, involving a multi-disciplinary team of experts, linking pharmaceutical development to the manufacturing process, and engineering controls of process equipment. The PQLI Control Strategy Team has proposed a Control Strategy Model that facilitates understanding and that may be used a cross-functional communication tool. This paper concentrates on the techniques and principles involved in developing the early Control Strategy rather than the operational implementation of the strategy.

Case Study: The Use of Routine Process Capability for the Determination of Process Parameter Criticality in Small-molecule API Synthesis
by Kevin D. Seibert, Shanthi Sethuraman, Jerry D. Mitchell, Kristi L. Griffiths, and Bernard McGarvey

During the development of a pharmaceutical chemical process, it is vital to establish a control strategy that will ensure the process performance and fitness for use of the active pharmaceutical ingredient (API), which in turn is essential to the drug product performance and its fitness for use. As part of the control strategy, it is very important to understand and establish critical elements of the process, one of which is the establishment of the critical process parameters that impact the critical quality attributes (CQAs) of the API. In this paper, we are proposing a method for determining the criticality of a process parameter and whether it should be listed in the common technical document as critical. By using routine process control capability across a variety of operating conditions and equipment configurations, a risk-based approach is used to identify parameters that could have a potential of impacting the CQAs of the API. Beyond establishing criticality, and understanding the operational variability, the knowledge gathered from these approaches can also be used to facilitate the efficient mapping of a multivariate design space.

Research Article: Monitoring of High-shear Granulation using Acoustic Emission: Predicting Granule Properties
by Michelle K. Papp, Chetan P. Pujara, and Rodolfo Pinal

Sound in the ultrasonic (20 to 1,000 kHz) range emitted during high-shear granulation was recorded and analyzed using multivariate techniques in order to assess the relationship between variations in the physical properties of the obtained granules and the evolution of acoustic emissions taking place during their formation. The acoustic signal analysis was preformed on two different granulators. A four-component model was obtained from the analysis and was capable of predicting the particle size distribution of the granules based on a 13 sieve cut measurement covering the range of 53–1,180 μm. The average error of prediction was less than 2%. Acoustic emission also proved useful as a predictor of granule moisture content. The final granule moisture content could be predicted with a root-mean-square error of prediction of 5.76% and 1.9% in the two different granulators evaluated in this investigation. The acoustic signals emitted during wet granulation contain the information necessary to make quantitative assessments of the changes in water content, particle size, and the particle size distribution of the granules produced by the process.

Research Article: The Influence of Humidity, Hydrogen Peroxide Concentration, and Condensation on the Inactivation of Geobacillus stearothermophilus Spores with Hydrogen Peroxide Vapor
by Beatriz Unger-Bimczok, Volker Kottke, Christian Hertel, and Johannes Rauschnabel

The study presented here examined the factors influencing the effectiveness of surface decontamination with hydrogen peroxide vapor. The impact of relative humidity and hydrogen peroxide gas concentrations was investigated and compared to a dew point analysis of these various sterilant atmospheres. For this purpose, a series of different H2O2 decontamination cycles were developed and tested for antimicrobial effectiveness using biological indicators inoculated with greater than 106 spores of Geobacillus stearothermophilus. The results indicate that an increasing concentration of hydrogen peroxide in the gas phase and higher humidity levels result in a faster inactivation of the test organisms. The higher the H2O2 gas phase concentration was, the more independent the inactivation effect from the humidity level. At lower H2O2 concentrations, the same kill was achieved with higher humidity. Subvisible condensation was found to be necessary for short inactivation times, but condensation in the visible range did not further enhance the sporicidal activity. The molecular deposition of water and hydrogen peroxide on the target surface represents the determining factor for microbial inactivation, whereas the hydrogen peroxide concentration in the gas phase is of secondary importance.

Research Letter: Real-time Acoustic Elastic Property Monitoring of Compacts during Compaction
by Ilgaz Akseli, Christopher Libordi, and Cetin Cetinkaya

A non-destructive, real-time acoustic technique for determining elastic properties of compacts during compaction is presented. An acoustic time-of-flight study was conducted, and the extraction of the linear elastic properties of calcium carbonate compacts was demonstrated. To verify the results of the acoustic experiments, a uniaxial compaction investigation was also carried out using a computer-controlled press with an instrumented die. Good agreement between linear elastic properties determined using both acoustic experiments and compaction force-displacement data was observed. This technique has the potential to be used as a real-time compaction monitoring tool.