Liquids

Today, some of the industry’s top pharmaceutical researchers are controlling,micromanaging, and tenaciously refusing to think “outside the box.”And that is exactly how it should be. In fact, these traits are essential to developing state-of-the-art barrier isolation systems because what is controlled is contamination, what is managed is microparticulates, and what is in the “box” is valuable product.

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The number of parenteral products entering development and reaching the market has increased significantly during the past decade. By some estimates as many as half of all investigational new drug applications consist of biopharmaceuticals, the vast majority of which are  anufactured aseptically.Most of these products are proteins and therefore highly susceptible to microbial contamination. In addition, regulatory agencies around the world are devising and enforcing increasingly stringent requirements for environmental and process control in aseptic processing. These factors are creating interest in advanced aseptic technologies that provide superior
contamination control.

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ASEPTIC PROCESSING Cleanrooms all have one common performance criterion: to provide an atmosphere that will protect the product from a hostile environment. Operators in cleanrooms must be trained in various disciplines, practices, and skills. Training must be a dynamic process to meet the job requirements and the demands of contamination control.

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The Aseptic Processing Working Group was formed in December 2002 within the Product Quality Research Institute (PQRI) to provide input on specific topics presented in FDA’s concept paper “Sterile Drug Products Produced by Aseptic Processing.” PQRI is a nonprofit organization designed to provide a neutral environment in which FDA, academia, and industry can collaborate on pharmaceutical product quality– related topics. For this reason PQRI was an appropriate choice in which to form such a group. As designed, it allowed members from FDA, industry, and academia to openly discuss the topics on the basis of science and then provide formalized clarifications and recommendations to FDA for their consideration and incorporation into FDA’s draft guidance on aseptic processing. The working group, totaling 41 members, began its work on23 December 2002 and issued its final report  on 10 March 2003.

On 27 September 2002, FDA released a concept paper regarding aseptic processing. This concept paper (available at www.fda.gov/cder/dmpq) is essentially a working revision of the 1987 industry guideline entitled “Sterile Drug Products Produced by Aseptic Processing,” which was issued jointly by the Center for Drug Evaluation and Research (CDER), the Center for Biologics
Evaluation and Research (CBER), and the Office of Regulatory Affairs (ORA) (1). FDA’s overarching goal is to provide a document that will facilitate industry compliance. The agency’s focus is on the critical control points of sterile processing and risk-based CGMP systems. Ultimately, the final guidance will provide greater clarity by including updated information regarding CGMP expectations for aseptic processing facilities, highlighting the latest scientific
developments in this area of sterile drug quality.

Filtration is an important practice in aseptic processing. Microporous membranes are relied upon because of their relatively narrow pore-size distributions. Traditionally, filters with pore-size ratings of 0.2/0.22
m have been considered “sterilizing grade,” meaning that they are expected to produce sterile effluents. Most drug preparations do result in sterility but not all. Therefore, it has been suggested that 0.1
m–rated membranes should be used to remove smaller organisms more thoroughly by sieve retention. A universal substitution of 0.2/0.22
m–rated filters by 0.1
m–rated filters is considered unnecessary, although contexts exist in which filters tighter than a 0.2/0.22
m can be used advantageously. However, one should consider that the smaller the pore-size designation of the filter, the more restricted its flow rate is, and depending upon the degree of particle loading in the fluid, the smaller the throughput that may be obtained.

In 1976 I was a senior scientist in the pharmaceutical development department of Alcon Laboratories in Fort Worth, Texas. At that time Alcon employed about 250 technical
people. How much that company has grown in the past 25 years! One year later I moved to Memphis to teach and do research at the University of Tennessee College of Pharmacy. I
helped Dr. Kenneth Avis teach summer postgraduate parenteral medications courses, which back then were two weeks in duration (including Saturdays!). Today those courses still exist, although now they are only one week long.

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Sterile products produced in staffed cleanrooms are subject to microbial contamination from the environment in which the process is carried out. The process may be adversely affected by the presence of microorganisms termed “adventitious,” (i.e., contamination incidental to the process) but also by contamination that is an unavoidable consequence of that process. Furthermore, there is no direct method to establish the source of contamination in aseptic processing environments. Contamination may be derived from the process, materials, equipment, operators, or the production environment, but could just as easily be introduced during sampling or the testing of samples (1). The sterility testing of samples from an aseptic process may be considered an entirely separate aseptic process, subject to the same types of adventitious contamination as the aseptic process itself.

Diane J. Burgess, Daan J.A. Crommelin, Ajaz S. Hussain, Mei-Ling Chen
AAPS PharmSci. 2004; 6 (1):
Abstract :This is a summary report of the workshop, organized by the European Federation of Pharmaceutical Scientists in association with the American Association of Pharmaceutical Scientists, the European Agency for the Evaluation of Medicinal Products, the European Pharmacopoeia, the US Food and Drug Administration and the United States Pharmacopoeia, on “Assuring Quality and Performance of Sustained and Controlled Release Parenterals” held in Basel, Switzerland, February 2003. Experts from the pharmaceutical industry, regulatory authorities and academia participated in this workshop to review, discuss and debate formulation, processing and manufacture of sustained and controlled release parenterals, and identify critical process parameters and their control.

Abstract: This is a summary report of the American Association of Pharmaceutical Scientists, the Food and Drug Administration and the United States Pharmacopoeia co-sponsored workshop on "Assuring Quality and Performance of Sustained and Controlled Release Parenterals." Experts from the pharmaceutical industry, the regulatory authorities and academia participated in this workshop to review, discuss and debate formulation, processing and manufacture of sustained and controlled release parenterals and identify critical process parameters and their control. Areas were identified where research is needed in order to understand the performance of these drug delivery systems and to assist in the development of appropriate testing procedures.