Opinion Review Article | Open Access | Published 20th December 2023
Containers, closures and measurements to support the assurance of sterility
Tim Sandle, BPL Pharmaceutical Microbiologist & Contamination Control Consultant. Author, journalist, lecturer, editor, and scientist. | EJPPS | 284 (2023) | Click to download pdf
The sterile condition can only exist within barriers that protect it from the non-sterile general environment. An essential prerequisite to the maintenance of sterility is for the product or that part of the product which is required to be sterile to be isolated by containment within a material impermeable to microbial penetration. Containment systems must be specified in great detail with regard to the physical properties that may affect their resistance to microbiological penetration.
While integrity tests (both deterministic and probabilistic) are well described, what of the physical measures and associated controls during manufacturing?
Containment systems need to be specified in great detail in terms of the physical properties that affect resistance to microbiological penetration. For example, with stoppered vials dimensional specifications need to include the internal diameter of the neck opening and its depth, the internal and external diameters of the flange, and the concentricity of the flange, the neck and the body of the vial. Any angularity of the flange versus the vertical centre line of the vial must be specified; so must the physical finish of the surface of the flange and internal neck bore to ensure satisfactory mating with the closure.
Closures must be specified in terms of diameters, depth, thickness and elasticity. These various measures must be assessed during manufacturing and through the shelf-life.
Controls during manufacturing
In routine manufacture, the assurance of the microbiological integrity of containment systems is obtained through measurement and monitoring of critical physical characteristics. Deciding which characteristics of components and filling and sealing processes are critical to containment system integrity demands a detailed and thorough understanding of the sealing mechanism and those factors of design, assembly and processing that may affect microbiological integrity.
Although these differ for particular containment systems, the integrity of containments systems relies only on some essential principles: Thermal fusion processes, mechanical forces, adhesion, and electrically based processes.
For ampoules (either glass or plastic), sealing is by thermal fusion. These types of containers in particular require 100% integrity testing since there are few measurable and controllable container characteristics of assurance of integrity. With plastic ampoules the process of forming and sealing is complex and lends itself to establishment of process limits which may be validated, controlled and monitored. With glass ampoules this is less so.
With glass vials sealed with rubber stoppers, the dimensional characteristics of the individual components must be specified and carefully controlled. In particular, in relation to the “interference fit” between the neck of the vial and the “shank” of the stopper. Control is essential under all conditions to the maintenance of integrity. Control must extend to the mechanical forces which place the rubber stoppers and keep them in place – these are provided by aluminium “over-seals”, “caps” or “crimps”.
The force a compressed rubber stopper exerts against the vial is termed Residual Seal Force and it can be measured as an in-process test for samples of sealed vials and can be considered a critical characteristic of this type of containment system.
Although ampoules and vials are the most commonly encountered containment system for sterile products there are numerous others (syringes, infusion fluid bags, modified vials, etc). Each must be individually considered for determination of critical characteristics.
Control during the product shelf-life
As well as initial determinations, sterile pharmaceutical dosage forms must also remain sterile throughout their shelf-lives. It is expected that all new containment systems should be validated against microbiological penetration. However, microbiological challenge tests using media filled containers are independent of the dosage forms which may be held within the containment systems.
This places limitations on the applicability of the data obtainable from microbiological challenge techniques using media-filled containers because containment systems filled with media are not subject to the same chemical stresses as containment systems filled with pharmaceutical products. Moreover, it would also seem reasonable to assume that different pharmaceutical dosage forms might have different effects on particular containments systems.
For instance, elastomeric closures (e.g. rubber stoppers) “age” in the first six months after manufacture. Even if closures are not used until this period has elapsed there is still the possibility, at least in principle, that the composition of a closure could change as a result of chemical reaction with the dosage form such that after some period of time the containment system could no longer maintain microbiological integrity. This explains why this linkage needs to be verifiable through shelf-life. Several approaches have been taken to establishing these factors.
Tim Sandle is the author of the book Sterility, Sterilisation and Sterility Assurance for Pharmaceuticals: Technology, Validation and Current Regulations, published by Elsevier: https://www.sciencedirect.com/book/9781907568381/sterility-sterilisation-and-sterility-assurance-for-pharmaceuticals