By Marc Schmidt, Business Development Manager, Pharma, for AAF International, Lothar Gail, Senior Contamination Consultant and Hugo Hemel, MSc, EMEA Marketing Manager for air filter manufacturer AAF International

This article is featured in the September/October 2015 issue of Pharmaceutical Engineering®.

Dry-heat sterilization/depyrogenation may well be one of the most critical steps in the sterile manufacturing process. This paper analyzes the main challenges of high-temperature HEPA filter design and describes a new development that addresses these challenges, promising a more reliable operation and longer life.

Dry-Heat Sterilization and Depyrogenation

Production of sterile medicine has to be carried out in a controlled environment to minimize the risk of product contamination. Regulatory guidance provides information on the area classification required for the various stages of manufacture, thereby preventing severe harm or life-threatening health risks to patients. (Dry-heat depyrogenation is used throughout to refer to both dry-heat sterilization and dry-heat depyrogenation.)

Sterilization

Sterilization is a process that removes living microorganisms, including their dormancy, from materials and objects. The achieved state is called “sterile.”

Depyrogenation

Depyrogenation is a process that removes biological pyrogens from materials and objects. Pyrogens in this sense are substances that cause fever when injected into the body. Of particular interest is the removal of bacterial endotoxins (for example, liposaccharides of the bacterial cell membrane with relatively high temperate resistance), but virus pyrogens and fungal pyrogens also have to be removed.

Dry-heat sterilization and depyrogenation are process steps used for the primary containers to ensure that they are sterile and pyrogen-free before they are aseptically filled and closed, as required by the US Food and Drug Administration (FDA) regulation 21 CFR Part 211.94. For many products, terminal sterilization of the finished filled container is not possible. Therefore, before it is filled, glassware must be sterilized and depyrogenated.

One of the most common methods of achieving sterilization and depyrogenation is through the use of a depyrogenation oven or tunnel; the process requires ensuring that the primary container reaches, and is held at, a high temperature for a defined period of time. Typically a temperature of over 121°C is used to sterilize – that is to say, kill any living organisms; depyrogenation requires higher temperatures in the region of 200°C to 350°C. Depyrogenation is used to reduce endotoxins. Because of the increasing demand for pyrogen-free sterile packaging and fast, safe, and efficient processing, dry-heat depyrogenation is a critical step in the sterile medicine filling process.

Pyrogen-free primary containers were originally required merely for the filling of large-volume containers, but it has now become a requirement for all sterile filling.1 Regulatory authorities require the depyrogenation processes to be validated to demonstrate that a predefined performance is consistently met by the process; the FDA, for example, requires “that the endotoxic substance has been inactivated to not more than 1/1,000 of the original amount (3 log cycle reduction).”2 This demand contributed decisively to the development of safe, fast, and efficient dry-heat sterilization processes, including unidirectional airflow with HEPA filtration.

The Protecting Role of HEPA Filtration

HEPA filtration is used to control the quality of air used for the ovens and tunnels, providing protection from particulate and microbial contamination.
However, the quality of the air supplied relies on the installed filter integrity as well as the seals from the filter media to the filter frame, and the frame to the equipment filter housing these needs to be essentially leak-free; leakage will reduce the quality of the air supplied by the system.

The dry-heat depyrogenation of glassware typically follows a three-step approach: infeed, heating, and cooling. (See Figure 1.) Dry-heat depyrogenation systems are typically located in, and supplied from, a Good Manufacturing Practice (GMP) grade C/D area and feed into a grade A area. (Note: Grades used refer to Volume 4, Annex 1; see Table A.) The regulations require grade A conditions for the whole glassware transportation line between washing and filling; therefore, in these areas any air admitted has to pass through a HEPA filter.3

Schematic representation of a dry-heat sterilization tunnel - PE Magazine

Environmental control requirements in regulations - Dry-Heat Sterilization PE Magazine

The heating process, taking place in the “hot zone,” makes high demands on HEPA filters at temperatures up to 350°C. But even in the “cooling zone,” the installed HEPA filters have to withstand temperatures between 200°C and 250°C in the case of sterilizable cooling sections. Challenges in terms of filter durability and efficiency have to be met to guarantee the sterility of the containers leaving the sterilization tunnel.

Challenges to Be Met

Various studies have shown that performance improvement issues dominate the priority list of the pharmaceutical industry. Challenges related to reducing time to market, increasing manufacturing throughput, quality requirements on cleanliness, complying with applicable regulations, and reducing costs are of high concern. The performance of a dry-heat depyrogenation tunnel has a direct influence on all these critical issues.

The degree to which a depyrogenation tunnel is able to retain the quality of the treated glassware in an effective, efficient, and repeatable manner is dependent on the performance of the HEPA filtration.4

Unidirectional airflow with HEPA filtration is the most common approach used to address the various challenges of dry-heat depyrogenation.5 Final filtration of the circulated air stream enables a faster and more simultaneous heating up of the glassware. However, the air filter must withstand integrity challenges caused by large variations in operating temperature during heating and cooling (i.e., system start-up and shutdown). Process contamination and the resulting unscheduled downtime from the bypass of unfiltered air, leaks, or shedding of particles has to be prevented. Limiting particle shedding can be particularly critical in cases of temperature fluctuations that arise from emergency shutdowns or the interruption of power supply. In addition, the heating and cooling rates of HEPA filters need to be carefully controlled, as excessive heating/cooling rates can cause filters to shed particulates.

Controlling the challenges during exposure to high temperatures and frequent heating and cooling cycles for a HEPA filter is not an easy job. Grade A conditions are being stipulated and must be demonstrated.

High-Temperature HEPA Filtration

Considerations for Selecting the Right Solution

Several characteristic requirements for high-temperature HEPA filters can be identified that directly influence the productivity of a depyrogenation tunnel. From various in-depth interviews conducted with tunnel manufacturers and pharmaceutical end users, three HEPA filter requirements have been found most critical in especially the hot zone of a sterilization tunnel: high stiffness (to reduce flexing of the filter, which would reduce its life), durability of construction (for long operational filter life), and efficiency performance.

High stiffness and durability of construction should assure that the integrity of the HEPA filter is retained during elevated temperatures for the life of the filter. Filter design and material selection should be such that degradation does not occur and thermal expansion and contraction do not create stress cracks. Integrity breaches, caused by stress cracks, should be avoided at all times as these might result in bypass, particle shedding, and process contamination. It should be noted that, although the scope of this article is on the impact of the applied separators and sealant, particles may also shed from the filter media itself when the binding agent burns off and glass fibers are released. New filters are usually leak tested after they have been installed cold; then they are “burned in” through an initial heating cycle to ensure that any volatile content is removed and the media reaches a stable condition.

Compliant efficient performance that meets the vendor specifications for the HEPA filter should be confirmed through the filter test certificate and be maintained through its operational life. A stable downstream efficiency is to be retained during multiple heating and cooling cycles, whereby the particle counts are compliant with the Grade A specifications as shown in Table A.

Missed parts two and three?  Catch up now:
Air Filtration Challenges & Answers for Dry-Heat Sterilization Tunnels Part 2
High Temperature HEPA Filter – Dry-Heat Sterilization Tunnels Part 3

Want to read part two right now?  Join ISPE today to get exclusive access to this article and more member benefits including full access to Pharmaceutical Engineering Magazine®.  In February, the ISPE Training Institute will be conducting an HVAC training focusing on the common issues and problems in the operation of a facility and maintaining readiness for cGMP inspection.  Sign up today!

References
1. Forbert, R., L. Gail, and U. Pflugmacher, “Neues Verfahren zur Bestimmung der Inaktivierung von Endotoxin bei der Trocken-Hitze-Sterilisation,” Pharmazeutische Industrie, 67 (5), 2005, pp. 592–597.
2. United States Pharmacopeia, General Chapter <1211>, “Sterilization and Sterility Assurance of Compendial Articles.”
3. EudraLex Volume 4: Guidelines for Good Manufacturing Practices for Medicinal Products for Human and Veterinary Use, Annex 1: “Manufacture of Sterile Medicinal Products,” ec.europa.eu.
4. PDA Technical Report No. 3: “Validation of Dry Heat Processes Used for Depyrogenation and Sterilization,” revised 2013, www.pda.org.
5. Wegel, S., “Kurzzeit-Sterilisationsverfahren nach dem Laminar-Flow-Prinzip,” Pharmazeutische Industrie, 35 (11a), 809 (1973).

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