n 1668, Francesco Redi, an Italian physician and biologist, published a book entitled Experiments on the Generation of Insects
challenging the theory of “spontaneous generation” of maggots from dead flesh or, in a more general way, of putrefying matter.1
Under the theory of spontaneous generation, the widely held belief at the time, microorganisms were formed without reproduction from parents. Redi prepared jars with raw meat, some he left open and others he covered with corks or with “very fine Naples veil” to avoid flies entering the jars to deposit their larvae. Maggots only appeared in uncovered jars. Redi’s experiments were a cornerstone of the scientific work that allowed Louis Pasteur, Joseph Lister, Robert Koch, and others to understand the true nature of microorganisms. But what was also remarkable, Redi conducted probably the first scientific experiments with containers covered with a porous lid and he worked with a control, in this case with uncovered jars, to prove his hypothesis, an innovative concept at the time. The veil used was a barrier to flies, and allowed air to enter, important to counter the arguments of those believing that air was required for life to develop. The veil was probably not a good microbial barrier, but by challenging the theory of spontaneous generation, the concept of protection for preservation became possible. It took however two additional centuries to finally root out this ancient theory.
In 1745-1748, John Needham, a Scottish clergyman and naturalist, showed that broth still shows microbial growth when conserved in a hermetically sealed container after being boiled, although the boiling should have destroyed all forms of life. Critics pointed out that he may have recontaminated the broth during transfer to the container.1
Another Italian, Lazzaro Spallanzani at the University of Reggio Emilia, repeated these experiments during 1765-1767 in sealed glass flasks using a special procedure to avoid recontamination. Spallanzani concluded that the elements at the source of putrefaction could be killed by sufficiently long boiling. He also proposed that these elements can move through air and the hermetic sealing protects from recontamination. He even showed that the liquid could not be preserved in flasks with an integrity issue. His opponents claimed that his hermetically sealed flasks did not allow air to enter, which was believed at the time to be an essential requirement (ER) for life.1
But it was Louis Pasteur who finally gave the mortal blow to the theory of spontaneous generation with his famous swan neck flask experiments during the period of 1859-1865 (see Figure 2.2
, chapter 2
). His flasks had a thin and long tub neck shaped like the neck of a swan. Air could enter, but particulates would not get into the flask as they settled somewhere in the S-shaped neck of the flask. Pasteur filled the flasks with a meat broth, sterilized them through boiling, and could demonstrate preservation of these liquids for weeks or months unless the bulb was tilted such that some liquid could reach the bottom of the S-shaped neck where particulates with microorganisms had settled. Microorganisms would also develop when the neck was broken off such that the surrounding air could enter freely into the flask. With his experiments, Pasteur demonstrated that a torturous path could be an effective barrier to microorganisms, a concept still in use today. He also showed the limitations of the swan neck tortuous path. When the flasks were violently shaken such that air would rush in, then it was possible of observe microbial growth. He even demonstrated that the air of Paris was more contaminated than mountain air at 850 m or even 2000 m above sea level (see Vallery-Radot1
In the 19th century, Louis Pasteur, Robert Koch, Joseph Lister, and many others set the basis for moving into modern medicine with the increasing knowledge of microbiology. Sterilization at the point of use with carbolic acid and heat was the first approach without any preservation means. As packaging emerged to preserve the microbiological state, it was mainly based on metal or glass containers. During the 19th century, a lot of research focused on the preservation of foods.
François Nicolas Appert2
invented the process of food bottling and was awarded by Napoleon in 1810 who was keen to have a method to preserve the food for his armies. The effective and simple method was widely adopted in a short time span. Preservation was first done in glass bottles and later in tin cans invented by Peter Durand. The process of bottling was further improved by Dr Rudolf Rempel who filed a patent in 1892 to close and vent sterilization containers. His patent was the basis for Johann Carl Weck to create the company Weck GmbH, which still marketing their Weck preservation bottles today.3
The limitations of boiling for sterilization became quickly apparent. It took until 1879 for the first autoclave for medical purposes to be introduced by Charles Chamberland in Paris, although Denis Papin had already developed a precursor in 1679. Using this equipment, Pasteur demonstrated that steam sterilization was particularly effective to kill microorganisms. Steam sterilization presented a problem that any packaging had to be porous to allow the steam to reach the packaged devices. In 1890, Curt Schimmelbusch4
filed a patent for sterilization containers, the so-called Schimmelbusch drum (Figure 41.1
), and he recommended the steam sterilization of wound dressings in his famous book published in 1892 with the support of Prof Dr E. von Bergmann. Schimmelbusch4
described the preservation of sterilized wound care products in sterilization drums as well as preservation of surgical catgut ligatures in special containers. The same year, Aesculap (in Germany) created the first rigid sterilization containers responding to the needs of military hospitals. Originally, they were equipped with valves or sliding vents replaced in the 1930s with reusable filters.
As medicine continued to make progress internationally, Fred Kilmer, pharmacist in New Brunswick, New Jersey, saw the potential of offering ready-made packaged sterile dressings, which he described in 1897 in an article entitled “Modern Surgical Dressings.”5
The sterile glass jars were filled aseptically under well-controlled conditions and become the key product for the success of Johnson & Johnson. At the beginning of the 20th century, sterile packaging was still very basic, for example, Charles E. Parker6
specified packaging in his catgut ligature and suture patent of June 3, 1902, as follows: “wrapping or container of paper or similar material which is permeable to sterilizing fluids, but will exclude dust or any solid carrier of infection.” Parker’s description included all the essentials, but engineered microbial barrier materials were not yet available. He included a drawing, which showed an object wrapped in plain paper. The development of the prefilled syringe, combining primary packaging and drug delivery mechanism is an equally fascinating story. Johann Sigismund Elsholtz was one of the first to investigate ways of intravenous (IV) injection in 1667. Literature7
lists several inventors for the syringe working independently in the middle of the 19th century, namely, Alexander Wood (1817-1884), a Scottish physician, and Charles Gabriel Pravaz (1791-1853), a French surgeon. Robert Koch came up with a sterilizable syringe in 1888 and Becton, Dickinson and Company introduced the disposable syringe.7
In 1939, Erhard9
of E.R. Squibb and Sons, filed a patent for a “hypodermic unit,” which led to the development of the famous “morphine syrette” adopted by the US army during World War II. The design was simple and battlefield compatible; it consisted of a toothpaste-like squeezable metal container with a seal that was pierced by a wire in the attached hypodermic needle before the medication could be administered into the patient. In first aid kits, the syrette was protected with a hard fireboard tube. This innovative device combined the delivery system, packaging, and protection for extreme situations with simplicity and great usability to allow for administration in adverse and difficult conditions.
FIGURE 41.1 Schimmelbusch drum.
In the 1940s, the US military commissioned Drs Charles A Phillips and Saul Kaye to develop an efficient biological decontamination process.10
Their work at Fort Detrick, Maryland, on ethylene oxide (EO) established the scientific foundations for the introduction of EO as a gaseous sterilant. The EO sterilization, also in addition to the use of radiation, enabled the introduction of sterile medical devices made of materials that were not compatible with the high temperatures of steam sterilization. More and more single-use disposable medical devices emerged, and with that the need for appropriate packaging. Fabrics and medical paper were the most used material initially, joined by film packaging and later by DuPontTM
Sterile packaging over the many years of its history has developed into an extremely diverse sector covering medical devices, combination products, and pharmaceuticals, addressing professional health care users as well as patients in a variety of situations such as home health, health care facilities, and military applications. The complexity of sterile packaging has grown with the emergence of sophisticated devices, sensitive drug products, new sterilization modalities, and aseptic processing technologies as well as with the development of sophisticated clinical procedures. Packaging continues to evolve with the
introduction of new drug delivery and device technology, to enable productivity improvements, the adoption of new materials and manufacturing technologies, the inclusion of active elements to control atmosphere, and the integration of microchips for smart functions, and to address changing regulatory requirements. But the fundamental aspects, discovered by the pioneers, are still true today.
INTENDED USE, FUNCTIONS, AND REQUIREMENTS FOR STERILE PACKAGING
There are a broad range of sterile packaging types to package devices, combination products, or drugs. Before reviewing these in detail, it is worthwhile considering the intended use, typical functions, and key requirements for sterile packaging.
The preferred and the lowest risk method to provide a sterile health care product is to package first and then sterilize the contents in the package (referred to as terminal sterilization). For drugs or devices that cannot be sterilized, aseptic processing is another option (see chapter 58
). But even in this case, the various components including the packaging should be sterilized before filling the drug or device packaging operation. Packaging needs to allow for and must be compatible with the selected sterilization process(es). As an example, gaseous sterilization modalities require porous packaging for penetration of the gaseous sterilizing agent and evacuation of any residues. Packaging materials need to be able to withstand the specific sterilization process being applied in a way that the properties of the material stay within required limits and there are no chemical or other reactions that could lead to detrimental impacts on the product (safety and efficacy) or limited stability and performance of the packaging over the shelf life.
Package Integrity, Microbial, and Other Barrier Functionalities
The ability to exclude microbial contamination from the packaged product is a key feature of sterile packaging for the maintenance of sterility after sterilization or aseptic processing until the point of use. For preservation of sterile contents, packaging needs to maintain integrity over the shelf life and through the challenges of transportation and handling. In many cases, packaging must also shield the product from environmental impacts such as from oxygen or humidity while maintaining a set atmosphere inside. Porous materials for gaseous sterilization modalities should allow air to enter and exit while retaining particulates and airborne microorganisms. Air will pass typically through the porous structure of the sheet in a meandering pattern around fibers or filaments, representing a tortuous path with given microbial barrier properties, a concept originally demonstrated as effective by Pasteur. Porous materials are also used to allow packaging to adapt to changes in atmospheric pressure, important for large packages, or if transportation includes airfreight and significant changes in altitude.
The packaging, that is in direct contact with the product, is identified as primary packaging in pharmaceutical applications, whereas the medical device industry has introduced the terminology of sterile barrier system to identify the minimum package that minimizes the risk of ingress of microorganisms and allows aseptic presentation of the sterile contents at the point of use.11
The sterile barrier system is considered an essential accessory to a sterile device.
Protection of the Product and Its Sterile Barrier System
Packaging must protect the health care product from physical hazards, like shocks, vibration, compression of transport, distribution, and storage as well as from any harmful environmental elements like ultraviolet (UV) light, electromagnetic fields, temperature, or chemical products. To cope with these adverse conditions, packaging systems are often composed of various protective packaging layers, or secondary and tertiary packaging, including means for transportation like pallets or containers. If packaging alone cannot guarantee the protection, special conditions must be maintained like a temperature-controlled supply chain (cool or cold chains).
Biocompatibility Aspects and Interactions With the Health Care Product
Packaging can be in direct contact with a health care product, or during use, it may even come into contact with the patient. Biocompatibility, toxicity aspects, chemical compatibilities, potential leachables, and the risks of adverse impacts on the health care product from such interactions need to be understood. Leachables are chemical entities from materials in direct or even in indirect contact with the product that migrate to the product and as such contaminate it. Leachables could come from plastics and their antioxidants; from residual catalyst respective impurities; or from glass, metals, or any packaging materials. Further sources include printing inks used for labeling, label adhesives, paperboard, and cardboard boxes used for protection and from products used to treat pallets (eg, preservatives; see chapter 69
). Leachables can lead
to effectiveness alterations of a drug product, inactivate active ingredients, or react with ingredients to form new chemical compounds that have further undesirable secondary effects. Packaging constructs could also bind components of a drug product to change it. Packaging is considered compatible with a health care product if its safety and intended use is not compromised and in case of a drug product if its efficacy is within required limits.12
At the point of product use, packaging will be opened, removed, or the product will be dispensed, administered, or used. There are several functions and requirements for product usability that can impact packaging:
Identification of the product
Reading the information on the label, cautions, use-bydate information, required storage conditions, etc
Opening the package
Aseptically removing the sterile health care product or administering the drug
Aseptically handling components in an aseptic filling process
All aspects in the list earlier may have an impact on patient safety. Labels help with identification not only of the product but also design features like transparent web materials or windows in cardboard box allow for visual identification of the product. Label readability is important to support health care personnel that must deal with an increasing complexity under often stressful conditions. The use of symbols is preferred to increase label readability and to eliminate the need for multiple languages of internationally distributed products.
The packaging design must allow for appropriate aseptic technique to remove the sterile device to minimize the risk of cross-contamination and infection. Aseptic presentation after opening is ideally performed by two people, one to open the packaging and the other to remove the product from the package without contact with unsterile areas (Figure 41.2
FIGURE 41.2 Aseptic presentation.
Aseptic presentation is defined as “transfer of the sterile contents from their sterile barrier system using conditions and procedures that minimize the risk of microbial contamination.”13
Often, health care acts are only performed by a single health care practitioner and packaging designs need to account for these specific situations. Regulations and standards put increasing focus on usability evaluation of the device, including its packaging, to minimize the risk of adverse events with the patient and to produce evidence that the design allows for easy handling and is safe.
Finally, empty packaging must be discarded properly, avoiding harm to the environment and to users, like unintended sticks from needles, and increasingly prepared for recycling and fed into the appropriate channels. Many jurisdictions have set ambitious goals to improve recycling rates moving to a more circular economy and packaging designs will have to adapt to optimize reuse and recycling possibilities.14