Gammapak Sterilizasyon

GAMMA PROCESSING TECHNOLOGY: AN ALTERNATIVE TECHNOLOGY FOR TERMINAL STERILIZATION OF PARENTERALS

ABSTRACT:' This paper will outline the advantages of utilizing gamma radiation as a means for terminally sterilizing parenterals and other pharmaceutical products. The factors which must be evaluated in order to qualify a product for radiation sterilization will be detailed. It will also compare the characteristics of this method with other technologies currently available. The highest SAL can be achieved by combining a knowledge of the microbial quality of the raw materials, and the manufacturing environment with a formulation designed to promote the most radiation stable from of the product.

This paper presents an overview of Gamma Radiation Processing for terminal sterilization as applicable to pharmaceutical products. It focuses on the unique capabilities of gamma radiation and how they may best be applied to pharmaceutical products. There is a growing need by, and pressure on, the pharmaceutical industry to find and use alternative terminal sterilization technologies. Each technology has its own particular capabilities. It is the manufacturer's responsibility to select the most appropriate technology for the task.

In this context, i.e., the use of "new" technologies, Gamma Radiation Processing is being more actively investigated now than at any other time. This renewed interest has come at a most appropriate time because the increased use of radiation processing to sterilize medical devices has led to the development of more efficient and economical irradiation equipment and processes. It has also generated new scientific data. The positive experience of the medical device industry should be a "signpost" for the pharmaceutical industry.

Many pharmaceutical raw materials and finished products are currently being successfully sanitized and terminally sterilized using gamma radiation. However, other raw materials and finished products have not been successfully treated. The primary reason for this is a lack of knowledge; knowledge of how an irradiation facility operates, and of the effects of gamma radiation on many products. Once these topics are more fully understood by the pharmaceutical industry, many more raw materials and finished products will be found compatible with gamma irradiation.

The reader is directed to the following references for a comprehensive overview: G. Jacobs (1); B. Gordon et al (2). In addition, "Radiation Processing Technology for Pharmaceuticals and Cosmetics: A Bibliography" (3) contains some 400-plus references to the effects of irradiation on pharmaceuticals, excipients, containers and closures. A copy of the bibliography and any referenced papers can be obtained from the author.

Gamma radiation processing is defined as the exposure of a product to ionizing radiation in a controlled manner. This controlled exposure ensures that the specified dose of radiation is delivered to the product. The specified dose is that which will reduce the bioburden to the desired level while at the same time minimizing the effect on the product. By controlling the time spent in the irradiation chamber we control the exposure of the product.

Gamma radiation's unique capabilities are used to provide consistently performing raw materials and finished products. How they may best be applied to pharmaceutical raw materials and finished products is the subject of this presentation.

The ability of gamma radiation to penetrate any existing packaging material permits the selection of the most appropriate packaging to protect the raw material or product. There is a very large selection of radiation resistant packaging materials on the market today.

Novel forms of packaging such as dual chamber syringes or vials may be used. New drug delivery systems such as liposomes or monoclonal antibodies, can also be successfully irradiated. Because there is no need to consider the diffusion of a gas into or out of the product, multiple packaging layers can be employed.

Gamma radiation processing with its single variable, time, makes validation very easy. Time is the only variable as Co(XJ (Cobalt 60) decays at a fixed rate. Once the total number of curies installed and the required dose is known, only the timers, which control the dwell time of the carrier/tote at each position around the source rack, need to be set. This is in direct contrast to gas and steam sterilization where a vacuum system, gas/ steam mixture and the uniformity of heat/ gas within the treatment chamber must be monitored. Similarly, for electron beam, the power variables (i.e., voltage, current) and the rate of movement of the transport system must be strictly controlled and monitored throughout the irradiation process.

The dosimetry system used means results are available within minutes after treatment. As this indicates the dose delivered to the product, there is no need for sterility testing. There are also no 'residuals' with gamma radiation processing. The product can be shipped directly to the customer. Gaseous treatment methods frequently require a lengthy post-exposure time to remove residual gas. Byproducts of the reaction of the gas are left behind. These byproducts at worst can be toxic (4), and can sometimes cause sensitivity reactions in patients. These residues have been detected for up to 7 days (5), and sometimes even longer.

Two papers have recently been published demonstrating the ability of gamma radiation to reduce endotoxins (6, 7). This is a unique feature associated with gamma radiation, and does not occur with electron beam irradiation or steam or gas sterilization, which should further encourage the use of gamma radiation processing.

A successful gamma radiation processing program encompasses three basic elements. They are Product Qualification, Equipment Qualification and Process Qualification. All three combined form an integral part of the Process Validation Document.

A product qualification program demonstrates the effects of ionizing irradiation on the product. The most important outcome of product qualification is the determination of the product's Maximum Tolerated Dose. In addition, the Maximum Process Dose and the Minimum Process Dose will also be set.

The Maximum Tolerated Dose is that dose of radiation which is just below that which induces an unacceptable change in the analytical profile of the pharmaceutical. It may be possible to select a radiation dose at which no radiation-induced changes in the analytical profile can be detected. It is important in the initial product qualification steps to test the product using widely separated radiation doses. This will quickly assess the ability of the product to withstand radiation and to "zero-in" on the most appropriate radiation dose for further testing.

One of the doses chosen should be approximately three times the "expected" dose. This will help to identify the type and nature of the breakdown products to expect at lower doses. Thus, analytical techniques can be adjusted or developed to assess the concentrations of those products produced using the process dose. Control samples should always be included to separate the effects of changes due to transportation or storage from those due to radiation.

It is also important to do "real-time" studies as opposed to accelerated aging studies. Radiation processing deposits energy into molecules. Some molecules have crystal lattices which can store the energy. This energy will slowly dissipate and may be a source of product failure with time.

Accelerated aging causes a proportionately more rapid loss of this energy which can often give a false indication of the true shelf-life of the product. This can be especially true of certain plastics which may form part of the finished product. Bear in mind that these problems are not new, unique or difficult to solve. The medical device industry has been down this path often. Most, if not all of the problems that the pharmaceutical industry will encounter have been solved. Many good laboratories/consultants are available to avoid "reinventing the wheel."

The Maximum Process Dose is determined by judgment. It is usually set below the Maximum Tolerated Dose to ensure that the product is not overexposed. It is dependant upon the product loading, and the physical parameters of the irradiator, such as source strength.

A third factor is the Minimum Process Dose. The Minimum Process Dose is determined by the product loading pattern, density, and the operating characteristics of the irradiator. What is sought is that the desired degree of product sanitization/sterilization will occur at this Minimum Process Dose. The ratio of the Maximum Process Dose to the Minimum Process Dose is known as the Dmax/Dmin Ratio. This ratio is the key to successful radiation processing. The closer the ratio is to 1, the less risk there is that the product will experience a radiation dose close the Maximum Process Dose. This in turn means that the product will undergo less radiation induced change. In "normal" operating conditions with material densities around 0.2-0.4 g.cc-1 this ratio is 1.2-1.4. Knowing that there is a need for a tighter ratio (e.g., 1.1), the experienced irradiation operator can position the material to achieve this goal.

It is important to know what treatments have been applied to raw materials before subjecting them to radiation processing. If a microbial limit specification exists, there is a high probability that heat, steam, gas or radiation has been used to treat the material to achieve the specified microbial limit. Each process will affect the material in a different way. Heat or steam may create degradation products which are more sensitive to radiation than is the original material. Ethylene oxide can leave residues which are activated by radiation. Prior radiation exposure may cause the product to exceed the maximum dose limit if it is retreated as a final product.

Radiation processing is especially suited to reducing the bioburden on incoming raw materials. This reduces the bioburden on the manufacturing process and reduces the radiation dose that needs to be applied to the finished product. By specifying radiation processing for every lot of raw materials, consistent performance properties are assured.

A consistent raw material and a consistent product mean a more cost effective process (less manipulation no rework) and hence a more competitive product.

There are certain cases where a raw material may need to be supplied as a sterile product. For example, an antibiotic powder which is to be supplied to a contract packager. In such instances, the material can be double or triple-bagged before being sterilized. This will facilitate bringing the material into the clean room manufacturing area.

It is particularly important to know the bioburden by species, not just by number. This applies to the raw materials as well as to the manufacturing area for the finished product. Accurate historical data and ongoing data must be collected to facilitate validation of the radiation dose selected.

The radiation sensitivity of the bioburden, as contained in the product, should be confirmed first. This must be done to detect any radio protective effect that the product might have on the bioburden. It may also show heightened sensitivity, which could be used to reduce the radiation dose or increase the achievable SAL.

Selecting an appropriate dosage form, e.g., lyophilized product, microencapsulated product, frozen product, oil-based emulsion, or including radical scavengers (8-11) or buffers to compensate for pH changes will improve the ability of the product to withstand radiation processing. The elimination of water (other than that of crystallization), greatly improves the stability of the material to irradiation (12, 13).

Hand-in-glove with formulation is product testing. It is important to understand how the product reacts to radiation. The analytical techniques must also be established and validated. Ideally, they should be the same as those currently used to assess the efficacy/safety of the product. Knowledge of the product breakdown products will assist in arriving at the best formulation. It must be strongly emphasized that no unique radiolytic products have been found in irradiated drugs (14). The breakdown products found after irradiation are identical to those found during manufacture of the drug or are metabolites of the drug.

Once the basic response of the drug is understood, it should be further tested in its final packaging to detect. any potential product-packaging material interactions. There are changes known to occur, for example, in the lubricants used for plastic packaging materials, which: may affect the properties or stability of the irradiated. product (15).

Raw Materials: For several years now the author has had various groups undertake specific studies designed to illustrate the effects, or lack thereof, of gamma radiation on specific bulk materials. The original materials selected were starch, talc, gelatin, and bentonite. These materials are widely used in both the pharmaceutical and cosmetic industries (16). Recently, the effect of radiation on StayRx, Avicell, and Lactose were examined, as they are widely used in tableting. The results of these studies are available in detail from the author. In short, no changes in the V.S.P. or tableting properties of these materials were found after exposure to 25 kGy of radiation (17).

Other materials which have been investigated privately include anaesthetics, antibiotics, methyl and propyl-parabens, methylcellulose and hydroxymethylcellulose, povidone, and mastitis products (oil suspensions). Some have been treated as solutions, others as the dry or lyophilized powder. To be sure, some products have shown changes at higher radiation doses (25 kGy). However, with few exceptions, the correct dose for every product and manufacturing scenario has been found.

Biologicals: Radiation processing is ideally suited to treat these very sensitive materials (18-20). Because many of these products come from microbial or viral processes, it is necessary to ensure that no viable organisms are present in the product. Radiation is currently the only technology available to achieve this result without severely damaging the product. Modest doses of radiation will inactivate most viruses (21-25), and certainly kill any bacteria present.

Enzymes: Contrary to popular opinion, enzymes can be successfully irradiated. Information is available on the irradiation of certain enzymes in solution, although this is less common. The most stable forms are as a lyophilized powder, frozen solution, or suspension (e.g., insulin) (26).

Finished Product (Other than Biologicals): This class represents the largest area available to radiation processing (27). The ability to treat a product in its final container, after aseptic assembly, provides the highest degree of sterility assurance possible. This cannot be done with gaseous treatments.

The second step is the qualification of the irradiation equipment available for use. Normally, this will be done or provided by the operator of the irradiation equipment or by the manufacturer of the equipment. In the event that the irradiation equipment is to be operated by the pharmaceutical manufacturer or raw material supplier, this documentation should already be available. It need only be reviewed to ensure that a particular irradiator / facility will deliver the dose required within the specified maximum and minimum limits.

Equipment qualification focuses on four discrete topics: suitability of the design, correctness of installation, operation, and maintenance. The most important outcome of equipment qualification is the determination of the Minimum Process Dose while respecting the Maximum Process Dose. This documentation will be a part of the Validation Program Documentation. "

Ionizing radiation may be generated by an isotopic source such as Cobalt 60, electron beams, or X-rays generated from electron beams striking a suitable target. There are significant differences among the three source types which affect the validation of the process. For instance, gamma radiation from Cobalt 60 is delivered slowly over a period of minutes to hours. An electron beam machine usually delivers the same dose in a fraction of a second. It is imperative that a product be independently qualified for the specific type of radiation that will be used. This article will address only the use of Cobalt 60 as the radiation source.

Process qualification for the irradiation of pharmaceutical products should include, but is not limited to, a consideration of the following subjects: sterilization approaches, dose distribution determination, product loading patterns, biological challenge reduction studies, cycle interruptions, and product temperature control. These subjects will be addressed in the following paragraphs.

Sterilization Approaches: Three basic approaches can be employed to determine if the Minimum Process Dose will provide sufficient sterilization for the existing product bioburden. They are Overkill, Bioburden-Based, and Species-Specific Bioburden.

The Overkill approach has traditionally been used by the medical device industry. It is used when the product to be sterilized can withstand radiation doses in excess of 25 kGy (i.e., no adverse effect.s). A 25-kGy dose is generally accepted as the Minimum Required Dose to sterilize medical supplies instead of determining the Minimum Required Dose by other means. Irradiation 1 time and loading parameters are adjusted to assure that I all parts of the product receive the minimum dose and I that the product's maximum tolerated dose is not r exceeded. Bioburden and radiation resistance data using this approach have not usually been required. This a approach is relevant to the pharmaceutical industry in minimum dose of 25kGy effectively sterilizes pharmaceutical products. This approach is simple, but it ignores the low bioburdens associated with parenteral products and it ignores the product's sensitivities, if any, to radiation. It also ignores the desirability of economic savings which would be achieved if a lower radiation dose could be used.

The Bioburden-Based approach is the basis of the AAMI Guidelines (28). In this approach, the process is validated to prove that the product's bioburden is similar in nature to that assumed for the AAMI calculations. AAMI methods 1, 2 and 3 are eloquently detailed in those guidelines. The reader is strongly encouraged to obtain a copy, because an understanding of this approach is necessary before attempting the SpeciesSpecific Bioburden approach. The Bioburden-Based approach is particularly relevant where the microbial population is known and in control. It often results in the determination that a significantly lower dose than 25 kGy is acceptable to sterilize/sanitize the product. The reader is also directed to the following references which supplement the AAMI guidelines (29-33).

Note: The reader should understand the critical difference between SAL for medical devices and pharmaceuticals. The SAL for medical devices is the probability of a single organism surviving on 10-⁶ devices. For pharmaceuticals it is the probability of finding a contaminated unit in 10⁶ units. or this reason an SAL of 10-³ from a media fill cannot be combined with a radiation dose deemed to provide an SAL of 10-³ to give an overall SAL of 10-⁶. The SAL from AAMI is an absolute number: the number of organisms surviving on 106 devices. The SAL from a media fill is a measure of the rate of contamination. The two cannot be combined.

The Species-Specific Bioburden approach is particularly suited to the pharmaceutical industry. It is applicable for those products which are very sensitive to irradiation and therefore have a low Maximum Process Dose. It relates the delivered radiation dose to the most resistant organism in the bioburden population found in the manufacturing area. This population should be significantly skewed in the direction of radiation sensitive organisms. It is helpful if the product can be manufactured in a Class 100 or better facility. This would result in a much lower dose of radiation being needed to achieve sterilization.

Dose Distribution Determination: A dose distribution study is conducted to determine the distribution of the radiation field throughout the product when processed in the actual production system. This study, usually done only once, identifies the maximum (Dmax) and minimum (DmiJ dose positions for a given product in the product transport mechanism of the irradiation facility. Knowing the exact location of the Dmax and Dmin positions permits routine process control monitoring to be done. This monitoring is done with dosimeters. They measure the amount of radiation delivered to the product. Dosimeters are "read" using an optical density measurement device.

The dose distribution study must be performed according to written procedures, and the results must be documented. A competent irradiation facility Quality Assurance person routinely plans and conducts these studies. The data will be collated into a dose-mapping profile which identifies the location of the Dmax and Dmin positions, the dose ratio, and the expected variation. A dose distribution study must be performed for each product loading pattern and each product size.

Product Loading Patterns: The manner in which the product is loaded into the irradiator's product transport mechanism is critical to achieving the required Dmax and °min, and therefore the required microbial kill. A detailed 'map', called a loading pattern, of how to place the product in the transport mechanism is a part of the process validation documentation.

Biological Challenge Reduction Study: A biological challenge reduction may be performed to ensure that the product does not demonstrate a radioprotective effect on the microbial population in the product. The specifics of the biological challenge selected for the study should consider product lot-to-lot variation in the bioburden (species and number). A worst-case bioburden challenge using B. pumilus is acceptable if the product can withstand a minimum radiation dose of 25 kGy.

In all other cases the microorganism with the highest D₁₀ value occurring in the natural population, as found by sampling, should be used.

The biological challenge should be performed at a sub-lethal dose using one of the AAMI methods as a guideline. Biological challenge tests may be conducted simultaneously with dose distribution study. The placement of the biological challenges should be defined in writing. The biological challenges should be located as close as possible to the Dmin position. They should also be placed as close as possible to any dosimeters if conducted concurrently with dose distribution studies.

A minimum of three test runs should be performed. Records of the organism type, 010 value, number of organisms, lot number, placement, and growth results should be available.

Treatment Cycle Interruptions: For mechanical, safety or operational reasons, the irradiation treatment cycle could be interrupted. A procedure must be in place to direct the irradiator operator to the appropriate contact person. This person must have Standard Operating Procedures (SOPs) to follow and must direct the irradiation facility operator as to how to proceed. These SOPs must be in place to define how the product will be handled, i.e., allowed to continue, to be restarted, or to be rejected. For products which can sustain microbial growth, define the maximum tolerable duration of a cycle interruption and its point of occurrence in the treatment cycle. (For example, what to do if the interruption occurs before 50% of the dose has been delivered, a cycle interruption occurs, or there is a delay in starting the processing of the product).

Product Temperature Control: Certain products can be sterilized by gamma radiation if they are cooled or frozen before irradiation. One example is insulin (26, 34). Other products are "naturally" temperature sensitive. For both situations, it will be necessary to have documentation stating the acceptable temperature limits upon arrival and the time available for irradiation. It may be necessary to provide cooling of the product before, during, and after the irradiation treatment cycle. The manner in which this is to be done (e.g., dry ice or ordinary ice) and how it is to be loaded with the product, must be specified. This type of information will form part of the process validation documentation.

Raw Materials: At present, there are few regulatory concerns regarding the irradiation of most pharmaceutical raw materials. Raw materials, including excipients, tend to be particularly stable to radiation processing. The product user or supplier must demonstrate that the material being irradiated is usable after treatment; that is, any changes induced are manageable from a formulation point of view.

Colors: The use of FD & C colors is one area that is very strictly controlled. All organic colors are susceptible to some breakdown after exposure to radiation. Many of these organic colors are based on anthracene-type chemistry and may have inherent carcinogenic properties or break down into potential carcinogens. The success of irradiation for products containing organic colors will largely depend upon the dose required to treat the material containing the color. The lower the dose required, the less likely negative effects will be found. Never the less, appropriate testing is required to determine whether the product and/or the color is affected. Thus, the use of organic colors in capsules, for example, may limit the use of radiation processing for these products.

There is none of the above concern for inorganic colors. These materials are essentially stable to irradiation even at high doses.

Preservatives: Very few preservatives, especially in a liquid finished product, will survive exposure to radiation (35). This is an important point to note. Failure to select the correct radiation-resistant preservative will result in the loss of protection of the product from contamination by the consumer. Therefore, if a finished pharmaceutical product which requires a preservative is to be sterilized by irradiation the effect of the irradiation treatment on the preservative must be investigated.

Finished Products: Most dry, finished products (e.g., antibiotics, freeze-dried products), should respond well to irradiation treatment (36). However, since water is the major source of free radicals, many finished products containing water are difficult, if not impossible, to treat without unacceptably damaging the product.

Gamma radiation leaves no residues, and imparts no radioactivity to the product. This makes it one of the safest technologies to use. There are no concerns for personnel contacting irradiated product, or working in a radiation processing facility. The latter is very strictly regulated. Radiation facilities are designed so that radiation levels are not detectable above the normal background radiation in the area in which they are sited. An irradiation facility is also a more pleasant environment in which to work as opposed to facilities using steam sterilization. The heat and noise associated with operating the latter and the need for frequent maintenance can make for a very oppressive work environment.

Gamma radiation has fewer environmental concerns than ETO or Steam. There are no toxic gases emitted which would deplete the ozone layer. There is no disposal problem for the operator of an irradiation facility. The triple-encapsulated rods containing Cobalt 60 (called pencils, because of their shape), are returned to the manufacturer for reuse, recycling, or disposal in a controlled facility. Cobalt 60 decays to inactive Nickel 60 with a half-life of 5.12 years. All of the Cobalt 60 in a pencil (10,000 Ci) will be reduced to background level in 150 years.

Gamma radiation processing offers a unique opportunity to improve upon the microbial cleanliness of the raw materials and finished products of the pharmaceutical industry. By systematically approaching the use of gamma irradiation, many pitfalls of previous trials can be eliminated. Treating all raw materials with a single type of treatment improves formulation; a more consistent final product is manufactured. Gamma radiation is a clean, non-residue-producing technology that is environmentally friendly and safe for the worker and the community.

. Collect data to demonstrate the efficacy of the process and your control over it.

. Appropriately used gamma irradiation can provide a superior product at reduced total cost.

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