SterilizationStrategies forGamma Sterilization ofPharmaceuticalsby Ruth Garcia, Betty Howard, Rose LaRue, Glenn Parton, an...
Sterilizationmigration test, which deter mines                                                          Radiation Steriliz...
Sterilizationdose exceeds the prescribed verifica-        Should positives occur, another dose-         lation is not nece...
Sterilization   A radiation dose of 11.9 kGy ±            e.g., a spike in bioburden number or      and TIR 27) and are de...
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Strategies for gamma sterilization of pharmaceuticals(2)


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Strategies for gamma sterilization of pharmaceuticals(2)

  1. 1. SterilizationStrategies forGamma Sterilization ofPharmaceuticalsby Ruth Garcia, Betty Howard, Rose LaRue, Glenn Parton, and John WalkerSteris Isomedix Services (Mentor, OH) Sterility is desirable not only for medical devices, but also to ensure the safety of parenterals or injectable drugs. Various methods of reducing microbial load in drugs and parenterals are available. crucial step in pharmaceu- • No residue like EtO leaves behind. include potency, efficacy, stability, bio-A tical production is steril- ization. There are many sterilization methods to choose from, such assteam, sterile filtration, ethylene oxidegas (EtO), electron beam (E-beam),and gamma radiation. Each technique • • • More penetrating than E-beam. Low-temperature process. Simple validation process. The first aspect to consider when sterilizing with gamma is product tol- erance to the radiation. During use of compatibility, and chemical accept- ability. Per guidelines under the International Conference on Harmo- nization (ICH), known as Technical Requirements for Registration of Pharmaceuticals for Human Use, it is recommended to use high-performancehas aspects that make it suitable or this type of radiation, high-energy liquid chromatography (HPLC), massunsuitable for the sterilization of a photons bombard the product, caus- spectrometry, or gas chromatographyparticular product. ing electron displacement within. to characterize and compare different For example, EtO, while being a These reactions, in turn, generate analytical aspects of irradiated prod-highly effective method, leaves behind free radicals, which aid in breaking uct versus nonirradiated product.potentially hazardous residuals and can- chemical bonds. Disrupting microbial A qualified laboratory should per-not reach products in airtight packages. DNA renders any organisms that sur- form package testing. It is often recom-E-beam, while being one of the fastest vive the process nonviable or unable mended to have an aerosol challengemethods of sterilization, cannot pene- to reproduce. performed on the product and pack-trate well into dense product or bulk However, these high-energy reac- aging. This test entails placing thepackaging of some products. In addi- tions also have the potential to disrupt packaged product inside an aerosol PHOTO COURTESY STERIS ISOMEDIX SERVICES (MENTOR, OH)tion, the product complexities of hetero- bonds within the pharmaceutical for- chamber and exposing it to high levelsgeneous components often require mulation, to weaken the strength of of bacterial spores. The product isextensive product qualification. Gamma packaging materials, and to cause then subjected to a sterility test, whichradiation can cause certain product and changes in color or odor in some shows whether or not the packagingpackage materials to degrade. materials. For these reasons, drug maintains a sufficient barrier. manufacturers should perform pre- In addition, at least one physicalGAMMA BENEFITS qualification Dmax (maximum dose) challenge should be performed on the Gamma radiation does have some testing, whereby the drug and its pack- packaging, if applicable. These in-significant advantages over other aging are subjected to a high dose of clude the peel test to determine themethods of producing sterile product. gamma radiation and then evaluated amount of pressure needed to openThese benefits include: for stability and functionality. the seal; the burst test to determine the Usually, the manufacturer will be amount of pressure needed to burst• Better assurance of product sterility the party responsible for drug testing. the package and to locate areas of than filtration and aseptic processing. Parameters to characterize typically weakness in the package; and the dye
  2. 2. Sterilizationmigration test, which deter mines Radiation Sterilization.”whether dye travels through the seals Method 1 encompasses productof the package. If a shelf-life claim is with bioburden up to 1 million colony-desired, most labs will perform accel- forming units (CFUs). It allows forerated aging. Typically, incubation at extremely low and high doses and is55°C for 6.5 weeks equals one year on well known throughout the gammaa shelf (this may vary depending on sterilization industry. The steps arethe drug formulation). These tests are simple and straightforward. First ofperformed on aged products. all, 10 product samples from each of Performing a fraction of or all of three separate production batchesthese tests following a high dose of must have bioburden testing per-gamma radiation will give the manu- Steris’ new JS 10,000 continuous and formed on them. This quantitativefacturer a good idea of product and incremental Cobalt-60 irradiator is ready to measure, or count, of the number ofpackaging suitability for gamma radia- process customers’ products. organisms on the unsterilized producttion. (A high dose is usually considered provides an excellent tool for deter-to be in the 50–60-kGy range or high- ed drug products, are composed largely mining the minimum dose necessaryer, preferably twice the minimum.) of water. Water dissociates as a result for sterilization.Many materials are highly resistant to of exposure to radiation and is a major Bioburden tests should be accompa-radiation. If possible, the manufactur- source of free radicals. These free radi- nied by a determination of recoveryer should choose materials that are cals can cause chemical compromise, efficiency. This allows the laboratoryresistant to the effects of gamma prior so drugs with high water content often to calculate a more accurate biobur-to the initial production phases. respond poorly to irradiation. den number. The average bioburden Performing irradiation on product of each batch and the overall averageHANDLING DEGRADATION in a frozen state can mitigate these of all product units should be deter- If a drug experiences degradation, effects. If the product can be safely mined. If any single-batch bioburdendiscoloration, or any other physical frozen and thawed, the potential exists level is more than twice that of themalady due to the high dose of 50–60 to irradiate it without, or with less, overall bioburden, that batch averagekGy, the manufacturer can begin test- product degradation. Freezing the should be used. Otherwise, the overalling at lower doses. One method drug traps free radicals in the ice crys- average should be used.involves testing at particular intervals, tals, reducing their freedom to move Afterward, the verification or sub-such as at 5 or 10 kGy. For example, a about. This may induce them to lethal dose must be set. Usingdrug that fails at 50 kGy may be stable recombine with each other, rather AAMI/ANSI/ISO 11137 Table B.1,at 40 kGy. then disrupt molecules in the product find the bioburden number equal to or However, some drugs may continue itself. This would possibly improve just higher than that of the exhibit effects from the radiation at drug resistance to degradation during Follow the row to the column labeledextremely low doses. Another test gamma irradiation. Other options SAL 10–2, where the verification doseentails dropping the dose to half of such as freeze-drying and/or using will be found.the original high dose. This would cut free-radical scavengers may also alle- The final phase includes testing forthe range of possible maximum doses viate the degradation effects seen in Bacteriostasis/Fungistasis (B/F) andin half. If the product is stable at the some products. setting the verification dose. The B/Fnew dose, then the max dose will fall test validates the sterility test by deter-somewhere within the top half of the FINDING THE RIGHT DOSE mining whether the product formula-original high dose. If the product is The next step is to set the minimum tion inhibits bacterial or fungalstill showing instability, the max dose sterilization dose, which will provide growth. If inhibition is seen, stepsmust fall in the lower half of the origi- the desired sterility assurance level must be taken to neutralize it. The testnal high dose tested. This method may (SAL). There exist two commonly is required only once in the lifetimereduce the number of irradiations used, industry accepted, validation of a product, but it is recommendednecessary for establishing this infor- techniques, with several variations annually. Without such a test, sterility-mation. All in all, the end product of for special circumstances. The first testing results are meaningless.this testing should be a solid maximum technique for discussion, Method 1, To begin the verification dose exper-tolerated dose for the particular drug is found in AAMI/ANSI/ISO iment, send 103 product units (100 forproduct. 11137:1994, “Sterilization of Health sterility testing and 3 for B/F) to the Many pharmaceutical products, Care Products: Requirements for sterilization provider for irradiation atincluding parenterals and orally ingest- Validation and Routine Control— the verification dose ± 10%. If the
  3. 3. Sterilizationdose exceeds the prescribed verifica- Should positives occur, another dose- lation is not necessary.tion dose by more than 10%, then the setting method must be used. The organism most commonly usedproduct must be sacrificed and new Also contained in AAMI 11137 is for radiation challenge is Bacillusproduct irradiated. If the dose is lower an alternative validation procedure pumilis. It was once believed that thisthan 90% of the prescribed dose, the referred to as Method 2. Method 2 organism was highly resistant to gam-remainder of the testing may be per- provides for dose setting based on ma. However, many organisms natu-formed and a failing test would allow the actual radiation resistance of rally occurring in medical products arefor a retest. microorganisms as they naturally more resistant to radiation than The product should then be sent to occur on a product. Of the methods B. pumilis, rendering this a poor surro-the laboratory for sterility testing and cited, it can provide the lowest possi- gate organism. If no alternative exists,B/F testing. If two or fewer sterility ble minimum dose. It is not used as however, this method may be accept-tests turn positive, the product has frequently as Method 1 or VDmax, able. A D10 value (D value) of anpassed the validation, and the next due to more sample requirements and organism, in this case, is the amount ofstep is to find the sterilization dose. associated costs. radiation (quantity of kGy) necessaryManufacturers should follow the same Method 2 uses incremental dose to reduce the bioburden level by 1 log.row in Table B.1 from which the verifi- data to select a verification dose. An example of a published D valuecation dose was taken, to the column Groups of samples from three produc- for B. pumilis is 1.7 kGy. Some cautionmarked SAL 10 –6. This is the mini- tion batches are irradiated in dose should be taken in using a published Dmum sterilization dose. The product increments up to the point where an value, as D values can vary dependingnow qualifies to be irradiated at a SAL of 10 –2 can be determined. A on the technique used to determinerange from the minimum dose to the Method 2 validation starts with the them and/or the inoculation substrate.maximum dose determined during the random selection of 280 samples Also, D values, or the resistance of anhigh-dose materials testing. (Method 2A) or 260 samples (Method organism to gamma radiation, can The second type of validation is 2B) from each of three production change over time, analogous to antibi-commonly known as VDmax. Found in batches of product. Samples are then otic resistance in microorganisms.AAMI TIR 27:2001, “Radiation Steril- designated in groups of 20 samples for However, if this is the method to beization, Substantiation of 25 kGy,” this each dose increment. Method 2A uses used, the following is an example ofmethod requires fewer products and nine increments in 2-kGy increments, the calculation for determining mini-results in a minimum sterilization dose and 2B uses eight doses at 1-kGy incre- mum sterilization dose.of 25 kGy. However, only products with ments. All samples are tested for sterili-1000 CFU or less qualify. ty. After the results of sterility tests Inoculation with 10 6 (1,000,000 The first step of this process is iden- are known, a series of calculations organisms):tical to that of Method 1. Bioburden described in AAMI 11137 (sectiondata from 10 products from each of B3.4.2) a verification dose (D*kGy) is SAL = 10–6three separate production batches determined. 106 to 10–6 = 12 log reductionshould be collected. Using Table 2 of An additional 100 samples from the D value 1.7 kGy × 12 log reductionthe TIR, the bioburden number equal batch designated from the initial sterili- = 20.4 kGyto or just greater than the product’s ty tests are irradiated at the verification 20.4 kGy = 10–6 SAL doseaverage bioburden is found. The sub- dose and tested to confirm sterility. Fol-lethal dose is found by following the lowing these sterility tests, a steriliza- The following calculation deter-row to the column labeled “Verifica- tion dose is calculated using the mines the necessary verification dosetion dose” (SAL 10–1). Send 13 product equation appropriate to the specific for 10 products to show the efficacyunits (10 for sterility testing and 3 for method chosen (2A or 2B). of the above 20.4-kGy sterilizationB/F) to the sterilizer for irradiation at In extreme circumstances in which dose:the verification dose ± 10%. Once the all efforts to neutralize bacteriostaticirradiation is complete, send the prod- agents have been exhausted and other Log bioburden – log (1/#samples)]ucts to the laboratory for sterility test- sterilization methods are unsuitable, × d-value = verification doseing. If one or fewer sterility tests turn dose setting can be done with inocula- Log 1,000,000 – log (1/10)] × 1.7 =positive, the product can be irradiated tion of the product. The practice of verification doseat a minimum dose of 25 kGy. If two inoculation, commonly used in the [6 – (–1)] × 1.7 = verification dosepositive sterility tests occur, a retest past, is not currently recommended [6 + 1] × 1.7 = verification doseshould be performed on 10 additional unless it is impossible to collect natural 7 × 1.7 = verification doseproducts. This time, no positives are bioburden data from the product. For- 11.9 kGy = verification doseallowed for substantiation of 25 kGy. tunately, in most cases, product inocu-
  4. 4. Sterilization A radiation dose of 11.9 kGy ± e.g., a spike in bioburden number or and TIR 27) and are designed to pro-10% is applied to 10 product units, shift in organism types. If neither of vide a guideline that encompasseswhich are then sent to a lab for sterility these is the case, there is possibly an the latest in industry knowledge andtesting. If no more than one test out of increase in the radiation resistance of requirements.10 turns positive, the sterilization dose, the organisms. Each method has advantages andin this example, 20.4 kGy, is validated. A dose audit failure requires a dose disadvantages, and care must be used Finally, whichever method is used, augmentation. The augmentation in selecting a method that best fitsthe manufacturer must verify the dose amount is found in the dose-setting the needs and limitations of theevery 3 months in an experiment table used in the original validation. product being evaluated. Theseknown as a Quarterly Dose Audit. To Beyond all of this, the dose audit methods can provide an acceptabledo this, 10 samples must be sent to the should also include manufacturing and straightforward means of sub-laboratory for bioburden testing. environment monitoring, such as stantiating dose selection for pharma- Furthermore, every organism cul- water testing, air sampling, and con- ceutical products.tured during the bioburden test tact agar plates. Although regular Following this guidance will aid inshould be identified, at minimum environmental monitoring is recom- the successful validation of any radia-with a colony morphology and gram mended at shorter intervals, such test- tion-stable pharmaceutical product forstain. Simultaneously, repeat the orig- ing quarterly meets the minimum gamma radiation sterilization. Theinal verification dose experiment for requirements. ideal time for considering the methodwhichever method was used during The AAMI dose-setting methods of sterilization is at the concept stage,the original validation. For example, described here are only recommenda- so that gamma-compatible materialsif Method 1 determined the original tions and do not exclude other dose- can be chosen and the effects on prod-sterilization dose, then the Method 1 setting procedures that may be uct safety and efficacy can be consid-verification experiment must be deemed more appropriate by their ered. With the variety of materialsrepeated. The original verification users. The AAMI methods are widely currently available, many pharmaceu-dose, or a dose augmented from a accepted in North America. When ticals and most packaging materialspast dose audit, is the dose that must properly applied, they have been can satisfactorily withstand the rigorsbe used. accepted by regulatory groups as valid of gamma processing. The quarterly bioburden samples dose-setting procedures.serve as a trend-analysis tool. A new AAMI guidelines are regularly Steris Isomedix Services provides technicalverification dose should not be deter- reviewed and updated through collab- support during all of these processes, includingmined from new bioburden data. oration by industry experts (the latest research, turnkey validations, special projects,Should a product fail a dose audit, the drafts under consideration are 11137- and technical information. ■bioburden data may hold valuable 01, 02, and 03, which will encompassclues as to why the failure occurred, the methods cited here in 11137:1994 STERIS Isomedix Services provides contract sterilization, microbial reduc- tion, and materials modification services to medical device manufacturers, pharma- ceutical, biotechnology, and industrial customers. Through a network of North American facilities, we deliver state-of-the-art Gamma, EtO, and E-beam processes as part of a complete managed program that emphasizes exceptional process quali- ty, efficient turnaround, and optimum cost containment. For more information about STERIS Isomedix Services please call (877) 783-7470 or log onto Reprinted from Pharmaceutical & Medical Packaging News, May 2004 • Copyright © 2004 Canon Communications LLC