Significant time and money is invested by medical device manufacturers to ensure that their products meet product performance needs and FDA guidelines. Choosing the appropriate polymer is critical for successful introduction of combination products, (a drug eluting stent/drug inhaler) to market. Physical ageing is an essential test, critical for documenting expiration dates for combination medical products. This test helps manufacturers decrease the time required for testing prior to device commercialization. To speed up the process, manufacturers perform accelerated ageing studies to determine physical ageing. Scientific evidence supports the fact that material exposure to an elevated temperature for a short period of time ages the combination device to the same extent as would be observed at room temperature for a longer period of time. Effectively observing the effects of time through accelerated ageing studies on the product/package combination can decrease the time taken to introduce a product to the marketplace.
Material ageing information, including physical, thermal and optical performance over time, is imperative for ensuring product integrity to meet stringent FDA validation requirements, including evidence of sterility and whether a product is fit to use over its life cycle.

Physical ageing is a process of molecular relaxation that occurs in all amorphous polymers held at temperatures below their Tg temperature. Ageing has been observed in PVC, PS and PC, as well as in copolyester polymers. When a polymer is rapidly cooled to below its Tg, which occurs in all commercial melt phase processing techniques, it freezes into a non-equilibrium conformation with excess free volume. In an attempt to attain equilibrium, the molecular chains rearrange themselves into a more dense structure, reducing the free volume of the system. Although this densification is difficult to detect, it directly affects thermodynamic and mechanical properties that are easier to measure and can, therefore, be used to track the extent of ageing over time.
The effect of physical ageing on thermal and mechanical properties can often be modeled as linear with the log of ageing time. The ageing process proceeds more quickly at higher temperatures closer to the polymer's Tg. These trends are consistent with other similar viscoelastic molecular relaxation processes, such as rheological behavior. As with other relaxation processes, time and temperature can relate through the principle of time-temperature superposition. Molecular motions that occur over a given period of time at one temperature are equivalent to motions that occur over a longer time period at lower temperatures. Simply stated, an elevated temperature acts as a catalyst for the rate of motion.

Copolyester plastics possess excellent final application properties such as long-term clarity and toughness. Utilizing accelerated ageing testing on copolyesters in combination medical products helps manufacturers to capitalize on these benefits. The ASTM guideline suggests using an accelerated ageing (Q10) factor of 2.0 as a conservative estimate for ageing the device. The guideline also states that materials such as PVC, PC and copolyester have a unique Q10 factor. Other Q10 factors can and should be used if they are derived from proper research and experimentation.
To assist OEMs and medical device manufacturers in determining the proper Q10 factor, Eastman Chemical Company conducted a number of trials to induce accelerated ageing on Eastar� 6763. Testing this copolyester, which can be used for a wide range of medical devices and rigid medical packageing, illustrated how well the material's physical characteristics are maintained during the ageing cycle. Through this process, it has been shown that using the wrong Q10 factor can drastically alter the outcome and reliability of accelerated ageing testing.

For example, if a medical device manufacturer wishes to age a package made of a sheet of Eastar Copolyester 6763 by five years (43,800 hours) at 60�C prior to performing shipping validation testing with the Q10 set at 2.0, they will inadvertently age the material well past the intended time frame. Using the ASTM equation (t23=tT*Q10^((T-T23)/10) leads the manufacturer to deduce that the accelerated ageing time duration will be 3,370 hours (140 days). Experimentation has shown that this process ages the copolyester almost 2,000 years. Based on this error, the product would not withstand additional testing.
However, by using the correct Q10 value for copolyester and taking relative humidity and ageing temperature into consideration, the accelerated ageing testing can be accurately completed in just 92 hours at 50�C with reliable results. Through extensive experimentation, Eastman has determined that the Q10 factor for Eastar Copolyester 6763 is 9.8.

Due to time-temperature superposition, it is possible to generate data as a function of time at different temperatures and then shift the data together on one common master curve. Eastman conducted numerous tests to determine the mechanical and thermal properties of copolyesters as a function of ageing time and temperature.
Time-temperature superpositions were performed on the data generated from these experiments to create master curves for each material. These times and temperatures (Table) can be used to perform "accelerated ageing� experiments. A product is aged at an elevated temperature for a short period of time to simulate ageing at a lower temperature for an extended period of time.

Ageing Temperature	Stimulated Age/ Accelerated Ageing Time(Hours)
	approx.   165 years	approx. 17 years	approx.   20 months	approx. 12 months	approx . 7 months	approx.  3 weeks	approx. 2 days
23�C	1,400,000	150,000	15,000	8,800	5,100	500	48
30�C	290,000	30,000	30,000	1,800	1,000	100	10
40�C	30,000	3100	300	180	110	10	1.0
50�C	3,000	310	31	18	11	10	-
60�C	310	32	3.1	1.9	1.1	-	-
65�C	99	10	0	0.6	-	-	-

The testing concludes that Eastar� Copolyester provides the required properties to ensure product integrity for a minimum of five years if good manufacturing practices are followed during extrusion, package design, forming, and sterilization, and if the packaged device is stored at room temperature under normal conditions and humidity levels.

For example, using the Q10 factor of 9.8 for copolyester, 1 hour at 60�C is equivalent to 96 hours at 40�C or 4,650 hours For example, using the Q10 factor of 9.8 for copolyester, 1 hour at 60�C is equivalent to 96 hours at 40�C or 4,700 hours at 23�C. Likewise, one hour at 40�C equals 48 hours at 23�C. Therefore, if manufacturers wanted to simulate the performance of a package after ten years of life (87,600 hours) at 23�C, it should be aged at either 50�C for 180 hours or 60�C for 19 hours. This ageing protocol reasonably represents the lifetime of a typical copolyester application.
Ageing copolyesters at higher temperatures for longer periods of time is not generally recommended. For example, ageing for 250 hours (ten days) at 60�C is equivalent to ageing for 1,200,000 hours (133 years) at room temperature 23�C. Ageing for this length of time or longer at 60�C may over-age the material and provide an unrealistic expectation of properties and ageing at standard room temperature conditions.
The recommended conditions for copolyesters are to perform ageing at 50�C and 50% relative humidity. At these conditions, 18 hours are equivalent to one year of actual ageing at room temperature 23�C. Therefore, 92 hours of ageing at accelerated conditions are equivalent to five years of actual ageing at room temperature 23�C.

The polymer used in a combination product must ensure integrity over a long period of time. For this purpose, accelerated ageing testing is performed to understand and determine a product's expiration date. Proper testing is essential to maximize the benefits of copolyester or any other polymer material used to create a product and package that both meets regulatory guidelines and can be administered successfully.

Courtsey :Glenn Petrie, Eastman Chemical Co.