Effects Of Gamma On Packaging Material

Gamma Radiation Processing: Effects on Packaging Materials Abstract This paper will highlight the need for selecting appropriate plastic polymers for packaging materials. Gamma radiation processing is becoming an important means for the terminal sterilization/sanitization of many end-user products. These range from medical devices through pharmaceuticals, cosmetics and foods. The physical changes that occur with irradiation are well documented. However, the potential chemical interactions between the plastic polymer and what it contains are less well known. An understanding of these reactions is essential for both the development of new polymers and of appropriate packages. This paper will identify the factors which should be evaluated to qualify a packaging material for radiation sterilization. HISTORICAL PERSPECTIVE The selection of a plastic resin for a pharmaceutical or medical device package has largely been a matter of marketing or transportation requirements, or for bonding to a material which will allow the free passage of a sterilant gas into and out of the package without allowing bacteria or viruses to enter. In addition, the matter of costs is a constant focal point. The need for increasingly large amounts of product information on the label is another challenge. It is almost to the point where a magnifying glass is needed to read it. Last but probably most important, is the maintenance of seal integrity to preserve function and sterility. With the development of gamma radiation processing, and resins which will withstand gamma radiation processing, more packaging options are open to the manufacturer today than ever before. Breathable materials are no longer required as there is no sterilant gas to get in or out of the package. Barrier materials to control humidity are possible as there is no need to change the atmospheric environment for gamma radiation processing. This is a feature, unique to gamma radiation processing. It can provide opportunities to reduce the volume of packaging materials while providing greater visual recognition of contents. It will also provide greater assurance of the maintenance of sterility throughout transportation, storage and subsequent use. However, the development of newer gamma radiation stabilized resins requires a knowledge of the additives used to achieve these properties (1-3). This in turn will provide better understanding of how the components of the resins will respond to radiation. There is a saying at Nordion that runs along these lines: "You will have better products after gamma radiation processing than you would have if you didn’t use the process." The reason for this, of course, is that the investigation of this technology forces you to understand more about your product(s) and manufacturing process than you ever thought you needed. For example, are you aware that standard injection molding techniques can rob a polymer resin of 80 to 90% of its elongation properties. A resin with 600% elongation (according to the manufacturer), ends up after molding with only 50% elongation. No wonder it reacts poorly to gamma radiation processing, or results in an unreasonable number of product failures under normal conditions. This can be attested to by the number of product recalls listed in the "Gray Sheets" for loss of sterility due to package failure. This is a very costly failure in more ways than one! ATTRIBUTES OF PACKAGING FOR CONSIDERATION The attributes that need to be considered for all types of packaging have been grouped for discussion under the following topics: Materials, Seals, Adhesives, Rigors of Use/Shipment and Marketing Materials. Some are listed for the sake of completeness and thus there is only a brief discussion; others warrant more discussion.

Page 1 of 7

MDS Nordion – Gamma Radiation Processing: Effects on Packaging Materials

www.mds.nordion.com

Materials Medical Devices Materials for medical device packaging need to have the following properties. • easy to handle • provide good visibility • be easily manufactured • provide moisture/climate barriers • be bondable to themselves or other materials Pharmaceuticals In addition to all of the above considerations, the pharmaceutical manufacturer is primarily concerned with the impact of additives and their breakdown products on the active drug in the package. These are not new (4-7). The migration of free radicals, from a plastic, to the surface and their reaction with a pharmaceutical is a major concern (8). While technologies exist to coat the surfaces of plastics with a thin film of glass (as silicon), to reduce the potential for product/package interaction (9) this process is not widely used on a commercial basis. It is important to have available plastics, whose surfaces will not interact with the pharmaceutical. This is important not only for tradition pharmaceuticals, but also for the vast majority of new classes of pharmaceuticals such as monoclonal antibodies, liposomes and other biotechnology-derived products. These products are very sensitive to their external environment. New techniques for irradiating pharmaceuticals are also emerging. They include treating the pharmaceutical in the frozen state (14), or as a lyophilized powder (15). This sterilization step puts additional stress on a plastic. If the product can be safely frozen and thawed, or lyophilized, the potential exists to provide a much greater range of terminally sterilized pharmaceuticals.

Seals Packaging seals, in addition to all of the specific requirements for each type of product as detailed below, must also provide evidence of tampering, i.e., evidence of intactness from time of manufacture to point-of-use. Pharmaceuticals There are two good sources of information for pharmaceutical septa. The first is a very good study published by the PDA (16). The second is a technical brochure published by Stelmi (17). Both deal with the effects of gamma radiation on various elastomeric formulae. The work done by the PDA was at higher doses than are normally used for parental products. Medical Devices Seals should not shed fibers onto the operating field due to separation at the wrong junction. The package must not be sealed so tightly it cannot be opened except with a crowbar, because the adhesive has formed a strong crosslinked bond. The package must not have gaps in the seal where contamination can enter thus compromising the sterility of the product. These packages may need to be able to withstand not only gamma radiation but also the rigors of EtO sterilization which include high humidity and high vacuum. Too often package integrity becomes compromised with this last technology. However, there are products which cannot commercially be sterilized in any other way at the moment. I would like to draw your attention to two articles by Don Barcan. In the first article (18), he describes a very simple yet elegant test for seal strength, which measures the stress strain curve. It is a variation on the tensile tester which measures only the maximum force generated during separation of the seal. Barcan states: "Because ¼peak values of seal strength can be misleading and do not provide complete information about the seal separation,.¼an alternative technique that measures seal strength in terms of stress/strain curves has been developed". This equipment uses a digital force gauge with output connected to either an x-y plotter or a computer programmed to calculate average Page 2 of 7

MDS Nordion – Gamma Radiation Processing: Effects on Packaging Materials

www.mds.nordion.com

seal force. Samples are shown in the following figures. Figure 1 shows the three main features of the stress/strain curve; the Preliminary area (normally called the peak seal strength), the Sustaining area and the Concluding area. In Figure 2, the materials’ peel characteristics remained virtually unchanged through 50 kGy . After 100 kGy the peak value dropped but the sustaining value was higher, apparently caused by minor cross-linking -- an example of a very stable and consistent heat-sealing system. Figure 3 shows that the seal strength improved up to 25 kGy (similar shape, higher values), but above 50 kGy the concluding seal strength dropped off. This indicates an initial crosslinking followed by chain scission. Figure 4 presents curves for a very poorly performing combination of materials. Figure 5 takes a little more interpretation, but if one looks closely at the width of the peak, it becomes obvious that the seal is failing with increasing radiation dose. Lastly, Figure 6 provides an example of increasing strength towards the Concluding area of the seal. However, the performance with increasing radiation dose is again rather poor. One might reasonably accept 25 kGy, and perhaps even 50 kGy (note the effect of cross-linking in the increase in preliminary (peak) strength). However, by 100 kGy the preliminary strength is poor. These five examples show that "there is more to understanding seal strength than peak values" (18). The design of a sterile medical package should include stress/strain analysis. This will help in selecting the right materials, the right vendor and the right process conditions. The second article (19)covers many of the same areas we are addressing here, but with greater detail.

Adhesives The most difficult area to address is the area of adhesives. They must have the right degree of tack, holding and release for the package to provide the degree of functionality and protection required for the product. The choice of adhesive is also dependent upon the type of sealing equipment in use. Pharmaceuticals This application encompasses what is best termed the ‘gray area’. It involves the intimate coupling of both pharmaceutical and device. Examples would be the ‘patch’-type drug delivery system used for hormone replacement therapy or for providing a substitute for nicotine. Here the device is both the drug package and to some degree the delivery system. The package must have a special type of adhesive which protects the drug during routine handling, yet will stick to the skin without causing dermal reactions. Now this is one tough adhesive problem. In addition, while these drugs/devices are meant to be applied to the intact dermal surface, this may not always be the case. Therefore they must also have some degree of sterility. Because the drug is contained in a viscous base for timing of delivery, gamma radiation is the method of choice for sterilizing these products. Gamma radiation has the potential to adversely affect the adhesive if care is not taken in selecting the appropriate adhesive formulation. Medical Devices Both curing and polymerization of pressure sensitive and other types of adhesives involves intentional exposure to ionizing radiation. The impact of this exposure on adhesives, while incidental, must be anticipated to ensure satisfactory performance. There are four main areas where adhesives are used namely, Packaging, Assembly, Delivery and Labeling. When the cross-linking process is controlled, it leads to a useful increase in the cohesive force. Excessive crosslinking can lead to embrittlement and loss of tack. Simple chain scission will lead to loss of cohesive strength. For additional information, the reader is referred to the article by Fries, presented at Radtech’88 (20). According to Fries adhesives can be functionally classified as follows: • Laminating • Heat Seal • Cold Seal • Pressure Sensitive Pressure Sensitive adhesives are further divided into the Hot Melt PSAs where hold falls off with increasing radiation dose and the Acrylic Solution PSAs where the hold increases with increasing radiation dose). It is to be noted that these observations are for gamma irradiation only. Fries refers also to electron beam effects on various types of adhesives. Page 3 of 7

MDS Nordion – Gamma Radiation Processing: Effects on Packaging Materials

www.mds.nordion.com

In addition, there have been new advertisements for improved color for acrylics and more data on radiation effects on acrylics has recently been published in Medical Design & Device Technology.

Rigors of Shipping The effect of irradiation on adhesives, seals and other packaging components needs to be tested under the rigors of shipping conditions. These could include, for example, sitting in the trunk of a car in a parking lot on a hot summer’s day where temperatures can reach 80oC+. Likewise exposure to extreme cold, hot arid and hot wet climate conditions are also required. Perhaps there is no single package that’s right for all environments. It may mean different packages for different markets!! Not that novel an idea as goods are often packaged differently to reflect cultural/usage patterns. Marketing This is one of the hardest areas to tackle. Packaging is often called upon to meet very unusual conditions. The packaging must of course be aesthetically pleasing, provide maintenance of sterility and inspire confidence in the product -- all at a competitive price. Fortunately as more manufacturers design for radiation processing, the volume of gamma/radiation stable materials is increasing and the price is decreasing. In addition, many of the newer plastics are also more environmentally friendly. This also helps in the marketing and acceptance of new products and their packaging (21). A problem encountered with polyolefin type products is the odor that is generated after exposure to ionizing radiation. It has been described as a "rancid" smell and appears to be dose related. The larger the dose, the stronger the smell. While it is noticed primarily by the nurse who opens the medical "kit" it has also been a problem for products like milk or milk substitutes packed in the "TetraPak" format. This odor may come from the linoleic or soy bean oils used as lubricants. A possible replacement might be mineral oil, or another synthetic lubricant which would impart no odor after receiving a radiation dose of 50 kGy. The replacement would also need to be inert to the pharmaceutical product. It is our current understanding that this problem has been addressed and is now resolved for the "TetraPak" package. THE VALIDATION PROGRAM Successful gamma radiation process validation encompasses the three basic elements of any validation program(22). They are Product Qualification, Equipment Qualification and Process Qualification. All three combine to provide a validated process. The validation of an irradiation process is product and process specific. Details of gamma radiation processing validation for pharmaceuticals can be found in a paper published by the author in the J. Parenteral Sci. (23). Packaging Materials Qualification The medical device manufacturer is concerned about the ability of the material to be sealed, how that seal responds to radiation, and can the package actually be opened after being irradiated. The pharmaceutical manufacturer is concerned about product/package interactions (24,25). This paper addresses only Product qualification, where the product is the packaging material. Packaging Qualification in addition to any and all of the attributes discussed above also involves testing for the following: • physical changes • chemical changes • extractables • lubricants • stabilizers In the end, the most important outcome of product qualification is a determination of the Maximum Tolerated Dose and the setting of the Maximum or Minimum Process Dose. For pharmaceuticals we set the Maximum Process Dose: for medical devices the Minimum Process Dose.. The difference is due to the sensitivity of pharmaceutical products to irradiation. Generally speaking, pharmaceuticals are more sensitive to irradiation than are medical devices. Thus, greater care needs to be taken to ensure that the Maximum Tolerated Dose is not exceeded. The Page 4 of 7

MDS Nordion – Gamma Radiation Processing: Effects on Packaging Materials

www.mds.nordion.com

greater range of tolerated doses for medical devices means that there is a larger ‘sterilization window’ for them than for pharmaceuticals. This ‘sterilization window’ is referred to as the Dmax/Dmin ratio. The closer this value is to one, the greater the degree of optimization of the sterilization process. For pharmaceuticals, the Maximum Process Dose is arbitrarily set at a dose below the maximum tolerated dose taking into account dosimeter error, so that the maximum tolerated dose will not be exceeded during processing. The minimum dose is that achieved through product loading and the characteristics of a given irradiator design. From a knowledge of the bioburden species, and the Dmin the Sterility Assurance Level (SAL) which will be achieved with the selected dose can be determined. This last point is very critical. It means that the SAL achieved from an aseptic or barrier process cannot be combined with an SAL from another process to achieve an SAL of 10-6. That is, it cannot be ‘topped up,’ with sufficient gamma radiation, or other sterilization methodology. The SAL from an aseptic process measures the Number of Contaminated Units, but tells us nothing about how many organisms are in that contaminated unit. The SAL for a medical device, on the other hand, tells us how many organisms there are per unit as measured by colony forming units (CFUs).. DIFFERENCES BETWEEN PHARMACEUTICALS AND MEDICAL DEVICES PHARMACEUTICALS MEDICAL DEVICES Small Dmax/Dmin Window Dmin determines SAL SAL from aseptic process is Number of Contaminated Units

Larger Dmax/Dmin Window SAL determines Dmin SAL, as determined by AAMI, is the Number of Organisms per Unit

For Medical Devices, the Minimum Process Dose is established based on the product bioburden and the degree of sterility assurance required. The Maximum Process Dose is determined by the density of the product, the load configuration and the physical limitations of the irradiator. Because of the large tolerance for radiation inherent in most plastics, the processing window is relatively large. Some consideration needs to be given to the possibility of resterilization. Therefore, when testing various materials or designs, be sure that the product is exposed to 2 or 3 times the maximum dose expected to be received during routine processing. A product qualification program will also suggest the impact any physical or chemical changes will have on the shelf life of the package. Accelerated aging studies for shelf life determination, can speed up the development process. However, it is the belief of this author that it is too early in the development of radiation sterilization of pharmaceuticals, to rely solely on such studies. Real time studies are preferred. Accelerated aging studies, if used, should be initiated simultaneously with real time studies. They may prove to be an indicator of future trends. During shelf life studies frequent sampling early in the program will help to establish any trend. What has been observed to date, is an initial drop in the level of the active ingredient, followed by a paralleling of the normal degradation curve (26). SUMMARY The needs of the pharmaceutical industry are varied and complex. The importance of the raw materials used in plastics cannot be overemphasized. Only when all the ingredients are known, can the effects of exposure to gamma radiation be predicted with any accuracy. Knowing the potential reactants allows the skillful formulator to add or delete the correct ingredients to offset any potential radiation effects. It is often helpful if information regarding the extractables, and their composition, can be provided. A confidentiality agreement may be required in some cases. Often these studies will encompass stability or shelf-life determinations. However, it is possible to market a drug with a six month shelf life while additional stability data is generated. The use of the correct package for the final pharmaceutical product is also important for product qualification, stability studies and process validation. The use of controlled environments, for the production of the packages and Page 5 of 7

MDS Nordion – Gamma Radiation Processing: Effects on Packaging Materials

www.mds.nordion.com

the pharmaceutical, will reduce the bioburden. This, in turn, will reduce the radiation dose required to achieve the desired sterility assurance level. This in its turn will reduce the potential for radical production and interactions. Chemistry is an important tool for predicting the radiation effects on plastics. A better understanding of these effects will encourage the regulatory agencies to accept the use of this technology. No other technology is as easily validated as gamma radiation. No other current technology can provide the same degree of assurance of microbial inactivation, with as few side effects on the product or package. MDS Nordion (www.mds.nordion.com) specializes in radioisotopes, radiation, and related technologies used to diagnose, prevent and treat disease. MDS Nordion is part of MDS Inc. (TSE: MDS, NYSE: MDZ) an international health and life sciences company based in Canada. In many of its products and services, MDS is among the largest and most respected companies in the world. MDS fights disease. The company’s 11,000 employees are working together to advance global health through science, technology and innovation. It does this by providing: laboratory testing, imaging agents for nuclear medicine testing, systems for radiation pasteurization of foods, sterilization systems for medical and consumer products, research services to speed the discovery and development of new drugs, therapy systems for planning and delivery of cancer treatment, analytical instruments to assist in the development of new drugs, and medical/surgical supplies. Detailed information about the company is available at the MDS Web site at www.mdsintl.com or by calling 1-888-MDS-7222, 24 hours a day. REFERENCES 1. Sipos, M.; Adamis, Z.: "The Effects of Radiation Sterilization on Different Types of Plastics," Korhaz-Es Orvostechnika, (Nov) Vol. 28(6): 164-168 (1990). 2. Sparacio, D.A. and Amini, M.A.: "Effect of Gamma Radiation on the Permeability of Ophthalmic Preservatives Through Fluorine Surface-Treated Low-Density Polyethylene Bottles," Influence of Radiation on Material Properties: ASTM 13th International Symposium (Part II). Philadelphia, PA (USA). 1987. 3. Guise, B.: "Plastic Containers," Manufacturing Chemist, (July): 32-34 (1989). 4. Landfield, H.: "Radiation Effects on Device and Packaging Materials," MD & DI, (May): (1980). 5. Duggin, G.: "Drug Packaging," Manufacturing Chemist, (Feb): 37 (1989). 6. Gopal, N.G.S. et.al. : "Radiation Sterilization of Plasticized PVC and Some Pharmaceuticals," Proc. National Symposium on Isotope Applications in Industry, (Feb): 294-308 (1979). 7. Charlesby, A: "Some Reflections on Radiation Research and Technology," Radiat. Phys. Chem. 28 (5-6): 473-477 (1986). 8. Nitrostat: Physicians Desk Reference: p. 1676-1677 (1990). 9. Johansson, K: "Overview of Recent Glass Coatings Developments, Emphasis on Plasma Techniques," Proceedings European Conference on Pharmaceutical and Medical Plastics Packaging’93: p. 11 (1993) ed. Hroar R. Skov. 10. Gordon et.al. : "Sterilization of Parenterals by Gamma Radiation," J. Parenteral Science and Technology 42 (supplement), Technical Report No. 11, (1988). 11. Radiation Processing Technology for Pharmaceuticals and Cosmetics: A Bibliography, ed. Reid, B.D., Nordion International, Inc., 447 March Road, Kanata ON, K2K 1X8 CANADA. 12. McLaughin and N.W. Holm: "Physical Characteristics of Ionizing Radiation," in Manual on Radiation Sterilization of Medial and Biological Materials: Technical Reports Series No. 149, Chapter 1: 5-12, (1973). 13. Antoni, F.: "The Effect of Ionizing Radiation on Some Molecules of Biological Importance," Manual on Radiation Sterilization of Medical and Biological Materials. IAEA, Vienna, STI/DOC/10/149 Chapter 2: 13-36 (1973). Note: for dextrose only see p. 22-27. 14. Soboleva, N.N.: "Radiation Resistivity of Frozen Insulin Solutions and Suspensions," Int. J. of Appl. Radiat. & Iso. 32: 753-756 (1981). 15. Kaupert, N.L.; Mariano, E.E.: "Effects of Sterilizing Radiation Dose on the Amino Acid Composition of Normal Human Immunoglobulin," CNEA (Argentina), v. 486: 18 (1981). 16. Kiang, P.: "Effects of Gamma Irradiation on Elastomeric Closures," Technical Report No. 16, Journal of Parenteral Science & Technology, 46: No.S2, (1992). 17. Merceille, J.P and Le Gall, P.: "Radiosterilization of Rubber Stoppers for Injectable Preparations," Stelmi (France), (Also available from American Stelmi Corp.) Page 6 of 7

MDS Nordion – Gamma Radiation Processing: Effects on Packaging Materials

www.mds.nordion.com

18. Barcan, D.S.: "The Effects of Radiation Sterilization on Package Seal Strength," Medical Device & Diagnostic Industry 16(11):76-79, (1994). 19. Barcan, D.S.: "Selecting Materials for Medical Device Packaging," Medical Device & Diagnotsit Industry, (1995). 20. Fries, J.A.: "Radiation Curing and Sterilization of Adhesives," Presented at Radtech ‘88, April, (1988). 21. Burgess, R.R.: "The Real cost of Sterile Packaging," Medical Device & Diagnostic Industry, Aug , 10-12, (1990). 22. Hoxey: "Validation of Sterilization Procedures," Medical Device Technology (June): 25-27(1991). 23. Reid, B.D.: "Gamma Processing Technology: An Alternative Technology for Terminal Sterilization of Parenterals," PDA Journal of Pharmaceutical Science & Technology, 49 (2):83-89, (1995). 24. Schonbacher, H.: "How Plastics Perform Under Nuclear Radiation," Modern Plastics, (Dec): 64-68 (1985). 25. Miller-Mizia, R.: "The Sterilizability of Polycarbonate and Polyphthalate Carbonate," MD & DI November, 35-37, (1986). 26. Personal Communication

Page 7 of 7