The revision of Annex 1 is requiring a major effort from the life sciences industry; from setting up new processes, to training staff, to managing noncompliance, the industry needs to adapt particularly to the new requirements regarding contamination control strategy and the essential elements needed to develop a robust sterility assurance system.
One of the most discussed processes concerns autoclaving and the risks associated with it.
We talked about it with. Tim Sandle, a microbiologist, author and science journalist, known as one of the leading experts in the field.
Evaluation of the impact of the new Annex 1 in pharmaceutical production
Our interview opens with an assessment of the overall impact of the new Annex 1 on contamination control strategies in the pharmaceutical industry. Dr. Tim Sandle, the new revision of Annex 1 is distinguished by a "holistic" view of contamination control. What are the most immediate consequences of this new approach?
Many facilities have developed approaches to contamination control, but the Annex's call is to bring it all together to provide a holistic overview that covers the structure, rationale, nonconformities, as well as the level of risk and corrective actions in relation to them.
A contamination control strategy is a system that considers all the integral elements of pharmaceutical manufacturing. It is best implemented using quality risk management principles and supporting risk assessments for contamination control and monitoring (the detectability of the contamination event).
As a management ethic, processes, equipment, facilities and production activities must be conducted according to risk management principles that provide a proactive means of identifying, scientifically assessing and controlling potential quality risks.
Each facility's strategy varies, but common themes include: microbial contamination, cleaning and disinfection, ensuring sterility, facility design, and chemical and particulate contamination.
Outside of microbial contamination, other forms of contamination may result from mixing errors, damage to primary or secondary packaging, distribution problems, and environmental fluctuations. In general, the focus should be on reducing the probability of contamination and the potentials for cross-contamination. This requires scientific and technical procedures and controls.
The format should be that of a linked document or series of documents developed to reflect the site-level strategy for minimizing contamination control.
It is important that the strategy be a living document and that it be updated in relation to change controls, process development, recurring deviations, and other quality documents.
Challenges in sterilization processes
What challenges does the pharmaceutical industry face in sterilization processes with respect to the requirements of the new Annex 1?
Perhaps the most significant change concerns the sterilization of equipment used for aseptic processing. The 2017 draft stated that critical direct-impact surfaces had to be sterilized (such as the fill manifold or cap cup); with the 2020 revision, however, direct and indirect contact parts are required to be sterilized. This could pose a challenge for facilities that have both isolators and RABS devices.
There is a specific update for freeze-dried products in terms of freeze dryers (or freeze dryers). These are freeze dryers that are manually loaded or unloaded. In this case, freeze dryers must be sterilized before each load.
Other important points in Annex 1 include the requirement that the feed water of a pure steam generator (clean steam) be adequately purified to achieve the required chemical and endotoxin levels as assessed by the monitoring and pharmacopeia testing requirements of water for injectables. Regarding the chemical requirement, steam used as a direct sterilizing agent must not contain additives at a level that would cause contamination of products or equipment. This part of the process must be validated. The steam must also consistently meet the parameters for non-condensable gases, dryness value (dryness fraction) and overheating.
The Annex also specifies that each sterilized item must be inspected for damage, integrity of packaging material, and moisture upon removal from the autoclave. Any item found to be unfit for purpose, damaged, or showing evidence of a "wet load" must be removed from the production area and an investigation conducted.
The issue of wet loading is the most worrisome factor. When steam enters the autoclave chamber and comes in contact with the product, it is important that the steam collapses (condenses) onto the product. In this way, heat is transferred to the load. However, the formation of water must be discharged through condensate management or re-vaporized to avoid contamination of the product. Removal of excess water is important to avoid isolation of the load from vapor.
Attention should also be paid to pressure and its relationship to temperature. Since autoclaves destroy microorganisms by direct contact with steam at the required temperature and pressure for a specific time, pressure control is important. Poor pressure control can cause variations in steam velocity.
Critical issues in autoclave sterilization
What are the main critical issues in the processes of autoclave sterilization?
Some of the main problems concern the reasons for cycle failure. Understanding these is important to control critical issues. One of these is load design. Many companies use a matrix approach, in which the worst load configurations are validated to allow other load combinations to be used without being subjected to validation. In this case, attention must be paid to the design of the matrix to identify and take into account everything about the load that may affect the inlet vapor distribution or that may affect temperature uniformity. The evaluation must also take into account anything that may remove heat from the chamber and affect temperature uniformity.
Often the matrix is based on mass. However, there are other factors that can affect sterilization. These include the shape of the equipment, where narrow pipes or tubes pose a particular challenge in terms of steam penetration (the center of the length of the tube is the most difficult point to sterilize); while as for the worst location inside a bottle, flask, or cylinder, the worst case is the center near the bottom of the container.
The orientation of the equipment is also important and affects the ability of the element to drain freely. If there is uncertainty about what constitutes the worst case, initial work can be undertaken thermometrically (heat penetration evaluation test); this allows data to be collected on heat distribution, and study of what is "hard to heat" is generally recommended. In the case of liquid loads, the viscosity of the liquid should be taken into account, as this can affect heat penetration.
Another factor is the type of material, such as elastomers and stainless steel. If these types of materials are used in combination, balancing of both may be necessary for the worst case. However, if in practice the materials are sterilized separately, there may be two types of worst-case loads.
Materials: the risks of medical paper and the advantages of Tyvek®
Let's talk about packaging materials: despite the strong presence of cellulose, many continue to use medical paper. What are the risks and how do you need to address them with the new Annex 1?
Packaging materials, used to wrap the items to be sterilized, are probably one of the most important elements of the sterilization process. Packaging provides a protective barrier for the sterile item and prevents its recontamination. When used in the aseptic process, packaging must be low particle generation.
Medical paper, which is cellulose-based, is not suitable for higher-grade cleanrooms, mainly because of the potential release of fibers. Annex 1 emphasizes that products must be free of visible particulate matter. Non-autoclaved cellulosic paper is also susceptible to microbial contamination, given the range of microbes capable of hydrolysis of cellulose.
An alternative is Tyvek® and Tyvek®/PET-PP. Tyvek® material consists of continuous, strong fibers of pure high-density polyethylene, has low particle release, and is free of inherent contaminants that could pose a risk in critical environments. Tyvek® retains its dimensional stability and integrity and maintains its tensile strength, microbial barrier, and air permeability necessary to enable effective sterilization.
To make the right choice, the packaging must be well designed and have sufficient porosity to allow steam to pass through the packaging. In addition, the packaging must be water-repellent to ensure a sterile "field." In addition, the packaging material must not change significantly during sterilization or release substances that can interfere with the action of steam.
Validation of autoclave loading
The new requirements in Annex 1 will force pharmaceutical manufacturers to review autoclave load validation processes.
Validation must be carefully designed to avoid failures (or failures with revalidation). The Annex provides for a greater level of detail and investigation. Failure to inactivate biological indicators is usually due to inadequate air removal rather than inadequate temperature and time conditions.
Sometimes revalidation failures can be attributed to the use of biological indicators with much higher D values than those used for initial validation (if the biological indicators used for revalidation have much higher strength than those used for initial qualification. This could occur, for example, if initial qualification was performed using a biological indicator with a D value of 1.5 minutes and revalidation was performed using a biological indicator with a D value of 3.0 minutes).
Problems can also arise due to changes in load models. The way load models are evaluated, such as mass versus complexity and configuration of items, as in the case of pipes.
One problem will be the need to more carefully evaluate the quality of pure steam. There is also a materials aspect, in that before any sterilization process is adopted, the suitability of the product or equipment must be evaluated to ensure that it is suitable for the desired sterilization conditions.
Criticality of washable products
How do you evaluate the use of washable products and what, if any, are the critical issues with this type of choice?
The main problem with washable products is the number of times they can be processed and the impact this has on the durability of the item. Integrity problems and particle release are two areas of concern, along with other forms of structural weakness and discoloration. This relates not only to the washing process, but also to sterilization: both are aggressive processes that can affect the material. The choice of water, the type of sterilization process, and the parameters surrounding it are important choices to make, to avoid damage and prolong the reprocessing cycle.
It is important to make a careful assessment and establish an appropriate maximum retreatment time.
Conclusions
We want to end this interview with a quote from the new Annex 1.
§8.60 The items to be sterilized, other than products in sealed containers, should be dry, wrapped in a material which allows removal of air and penetration of steam and prevents recontamination after sterilization. All loaded items should be dry upon removal from the sterilizer. Load dryness should be confirmed by visual inspection as a part of the sterilization process acceptance.
The choice of packaging systems becomes of utmost importance for proper alignment with the requirements of the new Annex 1. Indeed, as is clear from the text, and from the same interview with Tim Sandle, the success of the sterilization cycle depends on several factors closely related to the selection of the packaging material: only a low degree of particle release, an anti-microbial barrier of maximum effectiveness, a bill that allows uniform steam penetration, and not least resistance to tearing and puncture can ensure a proper autoclave cycle.
Tim Sandle is a pharmaceutical microbiologist, author and science journalist. He is a recognized biologist and holds a bachelor's degree with honors in applied biology, a master's degree in education and a doctorate from Keele University.
Interview by Cristina Masciola - Marketing & Communication Manager AM
