This document discusses strategies for gamma sterilization of pharmaceuticals. It describes gamma sterilization as having benefits over other sterilization methods like being a low-temperature process without leaving residues. The key steps are determining product tolerance to radiation through testing, setting the minimum sterilization dose using methods outlined in industry standards to achieve the desired sterility assurance level, and validating the dose through additional testing. Proper characterization of the product before and after irradiation is important to ensure no degradation occurs from the sterilization process.
Parvovirus Filtration Best Practices - 25 Years of Hands-On ExperienceMerck Life Sciences
In this webinar, you will learn:
- how to measure filter performance and capacity,
- how to optimize filter virus removal capability,
- and avoid potential pit-falls
Detailed description:
This webinar will cover all aspects of parvovirus filtration best practices: process development/ optimization, pilot scale-up, and validation and explain the important connections between these activities. The rationale for the recommended best practices will be explained by discussing the underlying mechanisms that control filter performance.
Polymer based drug delivery systems for parenteral controlled release: from s...Merck Life Sciences
This webinar, presented by two world-class experts in polymer based parenteral controlled-release drug delivery technologies, will provide insights into formulation technologies from small molecules up to biologics.
There is an increasing interest in long-acting injectables as drugs administered through injection help to increase patient compliance due to reduced frequency of administration while providing the same therapeutic efficiency. Depending from the nature of the drug, the optimum polymer technology is to be selected.
Prof. Dr. Mäder focus on how to select the appropriate PLA/PLGA polymer for small drug molecule applications. He will provide an overview of drug delivery systems, most important formulation techniques and appropriate characterization methods along with application examples.
Alternative polymer systems are required for peptide and protein controlled-release formulations. Dr. Rob Steendam introduces InnoCore´s SynBioSys® biodegradable polymer system demonstrating excellent safety, control over release kinetics and effective preservation of structural integrity and bioactivity of biologics. InnoCore Pharmaceuticals and SynBioSys® multi-block polymer introduction, challenges in development of controlled-release formulations of biological therapeutics including various examples and development and cGMP manufacturing at InnoCore are key elements of his presentation.
In this webinar, you will learn:
• drug delivery systems
• most important formulation techniques
• appropriate characterization methods along with application examples
Amorphous formulations for bioavailability enhancement risks and opportunitie...Merck Life Sciences
Watch the presentation of this webinar here: bit.ly/39Rd5Xd
Amorphous formulations provide unparalleled solubility advantages. However, physical stability of the molecule in the formulation is crucial for success. Join this webinar to learn the advantages and risks of amorphous formulations and strategies for ensuring stabilization of challenging compounds.
Solubility is a major challenge in the development of oral solid dosage forms. Amorphous formulation with polymeric solid dispersions have been the technology of choice to enhance solubility. However, this approach may have some downfalls when considering the ability to successfully stabilize compounds, especially poor glass former compounds with high propensity to re-crystallize. This webinar will examine amorphous stability from a theoretical perspective in the context of polymeric solid dispersions and mesoporous silica formulations. Finally, recent data demonstrating the potential of mesoporous silica for superior amorphous stabilization of poor glass formers will be presented.
In this webinar, you will learn
• Why solubility is a critical consideration in development of oral medication
• How the amorphous form can enhance solubility and increase absorption
• Why some molecules are at risk of re-crystallization with typical polymeric amorphous technologies
• How mesoporous silica can reduce the risk of re-crystallization of poor glass formers
Microbiological inspection of mineral water by redox-potential measurement Olivér Reichart
MicroTester as a validated method is suitable for rapid microbiological testing of mineral water, carbonated water, tank and running drinking water and other types of water. The time needed for a reliable detection of microorganisms is of key importance: in water industry the real-time (or at least as fast as possible) monitoring of the microbiological properties of the production is indispensable; in public water supply the essential basis of the epidemiological and public health measures is the fast and reliable result of the microbiological inspection. Beside the most important and most widely inspected microbiological contaminants the most relevant disturbing flora was involved to the validation process as well.
Parvovirus Filtration Best Practices - 25 Years of Hands-On ExperienceMerck Life Sciences
In this webinar, you will learn:
- how to measure filter performance and capacity,
- how to optimize filter virus removal capability,
- and avoid potential pit-falls
Detailed description:
This webinar will cover all aspects of parvovirus filtration best practices: process development/ optimization, pilot scale-up, and validation and explain the important connections between these activities. The rationale for the recommended best practices will be explained by discussing the underlying mechanisms that control filter performance.
Polymer based drug delivery systems for parenteral controlled release: from s...Merck Life Sciences
This webinar, presented by two world-class experts in polymer based parenteral controlled-release drug delivery technologies, will provide insights into formulation technologies from small molecules up to biologics.
There is an increasing interest in long-acting injectables as drugs administered through injection help to increase patient compliance due to reduced frequency of administration while providing the same therapeutic efficiency. Depending from the nature of the drug, the optimum polymer technology is to be selected.
Prof. Dr. Mäder focus on how to select the appropriate PLA/PLGA polymer for small drug molecule applications. He will provide an overview of drug delivery systems, most important formulation techniques and appropriate characterization methods along with application examples.
Alternative polymer systems are required for peptide and protein controlled-release formulations. Dr. Rob Steendam introduces InnoCore´s SynBioSys® biodegradable polymer system demonstrating excellent safety, control over release kinetics and effective preservation of structural integrity and bioactivity of biologics. InnoCore Pharmaceuticals and SynBioSys® multi-block polymer introduction, challenges in development of controlled-release formulations of biological therapeutics including various examples and development and cGMP manufacturing at InnoCore are key elements of his presentation.
In this webinar, you will learn:
• drug delivery systems
• most important formulation techniques
• appropriate characterization methods along with application examples
Amorphous formulations for bioavailability enhancement risks and opportunitie...Merck Life Sciences
Watch the presentation of this webinar here: bit.ly/39Rd5Xd
Amorphous formulations provide unparalleled solubility advantages. However, physical stability of the molecule in the formulation is crucial for success. Join this webinar to learn the advantages and risks of amorphous formulations and strategies for ensuring stabilization of challenging compounds.
Solubility is a major challenge in the development of oral solid dosage forms. Amorphous formulation with polymeric solid dispersions have been the technology of choice to enhance solubility. However, this approach may have some downfalls when considering the ability to successfully stabilize compounds, especially poor glass former compounds with high propensity to re-crystallize. This webinar will examine amorphous stability from a theoretical perspective in the context of polymeric solid dispersions and mesoporous silica formulations. Finally, recent data demonstrating the potential of mesoporous silica for superior amorphous stabilization of poor glass formers will be presented.
In this webinar, you will learn
• Why solubility is a critical consideration in development of oral medication
• How the amorphous form can enhance solubility and increase absorption
• Why some molecules are at risk of re-crystallization with typical polymeric amorphous technologies
• How mesoporous silica can reduce the risk of re-crystallization of poor glass formers
Microbiological inspection of mineral water by redox-potential measurement Olivér Reichart
MicroTester as a validated method is suitable for rapid microbiological testing of mineral water, carbonated water, tank and running drinking water and other types of water. The time needed for a reliable detection of microorganisms is of key importance: in water industry the real-time (or at least as fast as possible) monitoring of the microbiological properties of the production is indispensable; in public water supply the essential basis of the epidemiological and public health measures is the fast and reliable result of the microbiological inspection. Beside the most important and most widely inspected microbiological contaminants the most relevant disturbing flora was involved to the validation process as well.
Technology Trends in Bioprocessing PurificationMilliporeSigma
This presentation reviews current trends in bioprocessing purification and includes key considerations for continuous processing and connected polishing for monoclonal antibodies. Topics include:
• Market trends and the evolution of next-generation processes
• Intensified capture processing
• Continuous virus inactivation
• Connected flow-through polishing
To learn more about this topic or collaborate with our technical experts, schedule an in-person or remote visit at our M Lab™ Collaboration Centers: www.emdmillipore.com/mlab
David A. Weil, Ph.D, senior applications scientist with Agilent Technologies, presented "Identification of Potential Bioactive Leachables and Extractables from Plastic Lab Ware by using GC and LC Separation Methods linked with MS Detection."
MicroPRO, A Rapid Microbiology Method Based on Flow Cytometryguest32bcc5
The MicroPRO is a rapid microbiology method based on flow cytometry to detect presence/absence of bacteria, yeast and molds in pharmaceutical and cosmetic products in 24 hours. It can also detect these micro-organisms quantitatively in 5 minutes in water and swabs.
Particle Size Determination and Raman Spectroscopic Evaluation of a Semi-soli...HORIBA Particle
Dr. Robert Lee of Particle Sciences joins HORIBA Scientific to discuss how his company uses the LA-950 particle size analyzer and XploRA raman spectrometer to characterize semi-solid dosage forms.
Ultrasound-assisted Virgin Olive Oil Extraction by Low-scale Industrial MillBeatriz de Almeida
Poster presented at Fats, Oils and Lipids: New Challenges in Technology, Quality Control and Health. 13th Euro Fed Lipid Congress, 2015, Florence, Italy.
This presentation reviews the results of a study in which the authors investigated the effects of poly-diallydimethylammonium chloride (pDADMAC) flocculation and clarification on the performance and longevity of protein A resin.
To learn more about this topic or collaborate with our technical experts, schedule an in-person or remote visit at our M Lab™ Collaboration Centers: http://www.emdmillipore.com/mlab
Simplification of Fed-Batch Processes Using Modified Amino AcidsMerck Life Sciences
Mammalian fed-batch processes to produce biopharmaceuticals, e.g. monoclonal antibodies (mAbs), rely on strategic feeding of nutrients aiming at cell culture longevity and protein yield. At high concentrations and neutral pH, limitations in these bioprocesses arise from the low solubility or stability of some compounds, predominantly amino acids. In current processes, L-cysteine and L-tyrosine are fed separately at alkaline pH, resulting in pH peaks and precipitations. To simplify next generation processes, both amino acids have been chemically modified to enhance their respective stability and solubility profiles.
CHO fed-batch processes were substituted with the derivatives phosphotyrosine di-sodium salt (PTyr) and S-sulfocysteine sodium salt (SSC). Cellular performance as well as stability of the single substances in neutral pH feed were assessed. Lastly, the suitability of modified amino acids in fed-batch processes was confirmed examining critical quality attributes of the produced mAb.
In feed, PTyr solubility was evaluated at 70 g/L with a stability of at least 6 months stored light protected at 4 °C. The derivative was not impacting cellular performance or product quality. In cell culture supernatant, PTyr cleavage was induced by released phosphatases, thus being bioavailable for the cells.
SSC was demonstrated stable for at least 3 months in feed stored light protected at RT. In fed-batch processes, integrating the derivative into the main feed, cell specific productivity was significantly improved compared to the two-feed system. Further, IgG heterogeneity was decreased by reduced fragmentation and trisulfide bond formation of the antibody. Finally, the mechanism of action of SSC was investigated and results pointed out to an anti-oxidative response mediated through an increase in superoxide dismutase enzymes and in total intracellular glutathione pool involved in ROS elimination.
In addition to the simplification of fed-batch processes via the implementation of a single feed strategy, the two derivatives also enable the production of highly concentrated and room temperature stable feeds along with optimized space time yields.
In this webinar you will learn:
• Design of highly concentrated and stable feeds.
• Overcoming issues with unstable or insoluble amino acids.
• Understanding the function of modified amino acids in cellular metabolism and antibody production.
Long acting injectable microparticle formulation - a new dimension for peptid...Merck Life Sciences
Explore the clinical benefits and applications of sustained release drug delivery with this presentation. Access the findings from a technical feasibility study as well as a case study on sustained release microparticle formulation for a sensitive peptide.
Effect of Sterilization on Elastomeric components Used in Pharmaceutical Indu...ijsrd.com
Sterilization (or sterilisation) is a term referring to any process that eliminates (removes) or kills all forms of microbial life, including transmissible agents (such as fungi, bacteria, viruses, spore forms, etc.) present on a surface, contained in a fluid, in medication, or in a compound such as biological culture media. Sterilization can be achieved by applying the proper combinations of heat, chemicals, irradiation, high pressure, and filtration. Several methods are available for sterilization and among all steam & gamma sterilization are most suitable methods for elastomeric components. In this study the effect of steam & gamma sterilization has been compared with non-sterile components. For this comparison EP & USP methodology has been used. Steam and gamma which has been used as a source for sterilization that may affect the molecular chain & crosslink density of elastomeric components. The study on effect of sterilization serves to help understand the potential deterioration of physical and chemical properties, the possible impact to functionality and the potential changes to the extractable/leachable profile as a result of sterilization.
Technology Trends in Bioprocessing PurificationMilliporeSigma
This presentation reviews current trends in bioprocessing purification and includes key considerations for continuous processing and connected polishing for monoclonal antibodies. Topics include:
• Market trends and the evolution of next-generation processes
• Intensified capture processing
• Continuous virus inactivation
• Connected flow-through polishing
To learn more about this topic or collaborate with our technical experts, schedule an in-person or remote visit at our M Lab™ Collaboration Centers: www.emdmillipore.com/mlab
David A. Weil, Ph.D, senior applications scientist with Agilent Technologies, presented "Identification of Potential Bioactive Leachables and Extractables from Plastic Lab Ware by using GC and LC Separation Methods linked with MS Detection."
MicroPRO, A Rapid Microbiology Method Based on Flow Cytometryguest32bcc5
The MicroPRO is a rapid microbiology method based on flow cytometry to detect presence/absence of bacteria, yeast and molds in pharmaceutical and cosmetic products in 24 hours. It can also detect these micro-organisms quantitatively in 5 minutes in water and swabs.
Particle Size Determination and Raman Spectroscopic Evaluation of a Semi-soli...HORIBA Particle
Dr. Robert Lee of Particle Sciences joins HORIBA Scientific to discuss how his company uses the LA-950 particle size analyzer and XploRA raman spectrometer to characterize semi-solid dosage forms.
Ultrasound-assisted Virgin Olive Oil Extraction by Low-scale Industrial MillBeatriz de Almeida
Poster presented at Fats, Oils and Lipids: New Challenges in Technology, Quality Control and Health. 13th Euro Fed Lipid Congress, 2015, Florence, Italy.
This presentation reviews the results of a study in which the authors investigated the effects of poly-diallydimethylammonium chloride (pDADMAC) flocculation and clarification on the performance and longevity of protein A resin.
To learn more about this topic or collaborate with our technical experts, schedule an in-person or remote visit at our M Lab™ Collaboration Centers: http://www.emdmillipore.com/mlab
Simplification of Fed-Batch Processes Using Modified Amino AcidsMerck Life Sciences
Mammalian fed-batch processes to produce biopharmaceuticals, e.g. monoclonal antibodies (mAbs), rely on strategic feeding of nutrients aiming at cell culture longevity and protein yield. At high concentrations and neutral pH, limitations in these bioprocesses arise from the low solubility or stability of some compounds, predominantly amino acids. In current processes, L-cysteine and L-tyrosine are fed separately at alkaline pH, resulting in pH peaks and precipitations. To simplify next generation processes, both amino acids have been chemically modified to enhance their respective stability and solubility profiles.
CHO fed-batch processes were substituted with the derivatives phosphotyrosine di-sodium salt (PTyr) and S-sulfocysteine sodium salt (SSC). Cellular performance as well as stability of the single substances in neutral pH feed were assessed. Lastly, the suitability of modified amino acids in fed-batch processes was confirmed examining critical quality attributes of the produced mAb.
In feed, PTyr solubility was evaluated at 70 g/L with a stability of at least 6 months stored light protected at 4 °C. The derivative was not impacting cellular performance or product quality. In cell culture supernatant, PTyr cleavage was induced by released phosphatases, thus being bioavailable for the cells.
SSC was demonstrated stable for at least 3 months in feed stored light protected at RT. In fed-batch processes, integrating the derivative into the main feed, cell specific productivity was significantly improved compared to the two-feed system. Further, IgG heterogeneity was decreased by reduced fragmentation and trisulfide bond formation of the antibody. Finally, the mechanism of action of SSC was investigated and results pointed out to an anti-oxidative response mediated through an increase in superoxide dismutase enzymes and in total intracellular glutathione pool involved in ROS elimination.
In addition to the simplification of fed-batch processes via the implementation of a single feed strategy, the two derivatives also enable the production of highly concentrated and room temperature stable feeds along with optimized space time yields.
In this webinar you will learn:
• Design of highly concentrated and stable feeds.
• Overcoming issues with unstable or insoluble amino acids.
• Understanding the function of modified amino acids in cellular metabolism and antibody production.
Long acting injectable microparticle formulation - a new dimension for peptid...Merck Life Sciences
Explore the clinical benefits and applications of sustained release drug delivery with this presentation. Access the findings from a technical feasibility study as well as a case study on sustained release microparticle formulation for a sensitive peptide.
Effect of Sterilization on Elastomeric components Used in Pharmaceutical Indu...ijsrd.com
Sterilization (or sterilisation) is a term referring to any process that eliminates (removes) or kills all forms of microbial life, including transmissible agents (such as fungi, bacteria, viruses, spore forms, etc.) present on a surface, contained in a fluid, in medication, or in a compound such as biological culture media. Sterilization can be achieved by applying the proper combinations of heat, chemicals, irradiation, high pressure, and filtration. Several methods are available for sterilization and among all steam & gamma sterilization are most suitable methods for elastomeric components. In this study the effect of steam & gamma sterilization has been compared with non-sterile components. For this comparison EP & USP methodology has been used. Steam and gamma which has been used as a source for sterilization that may affect the molecular chain & crosslink density of elastomeric components. The study on effect of sterilization serves to help understand the potential deterioration of physical and chemical properties, the possible impact to functionality and the potential changes to the extractable/leachable profile as a result of sterilization.
Safer cosmetics through in vitro science - XCellR8 presentation to Cosmetics ...Susie Lee-Kilgariff
How to develop safer cosmetics through in vitro science. This presentation was given to the Cosmetics Business Regulatory Summit 2018 by Dr Carol Treasure of XCellR8. It includes case studies of in vitro safety tests for skin sensitisation, advice on testing finished products and progress on a new model to predict mildness to skin.
Safer cosmetics through in vitro science. XCellR8 presentation to Cosmetics B...Dr Carol Barker-Treasure
In vitro methods for key aspects of cosmetic safety, including skin and eye irritation and skin sensitisation, are now in widespread use for regulatory safety testing around the world. In many cases, they are now established as the default rather than the alternative approach, so it’s timely to ask, “where next?”
In vitro technologies offer so much more than basic regulatory compliance, and when used wisely, can provide the competitive edge, from ensuring that formulations are fully optimised before proceeding to human in vivo studies, to providing detailed mechanistic data for claim support purposes. Importantly, they are a powerful tool to support the current move towards exposure-led safety assessments, enhancing the long-term safety of products and limiting the risk of post-market adverse events.
This presentation, first shared at the Cosmetics Business Regulatory Summit 2018, examines case studies from some early-adopters who are taking the application of in vitro data to the next level and considers the feasibility of applying exciting new techniques to the cosmetics of the future.
Stability Testing Photostability Testing of New Drug Substances and Products-...Trishala Bhatt
The ICH Guideline, Stability Testing Photostability Testing of New Drug Substances and Products-Q1B addresses the recommendations for photostability testing, an integral part of stress testing. This document is an annex to the Parent Guideline and focuses on evaluating the intrinsic photostability characteristics of new drug substances and products.
Zagro aims to help farmers improve farm hygienic practices to control and prevent disease-causing microbes. Through its Zagro Farm Hygiene Program, they introduce a range of disinfectant products that are independently proven to be effective and can be applied for multiple purposes. View our range of products to see more information about these disinfectants.
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Similar to Strategies for gamma sterilization of pharmaceuticals(2) (20)
Strategies for gamma sterilization of pharmaceuticals(2)
1. Sterilization
Strategies for
Gamma Sterilization of
Pharmaceuticals
by Ruth Garcia, Betty Howard, Rose LaRue, Glenn Parton, and John Walker
Steris 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 as
steam, sterile filtration, ethylene oxide
gas (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-performance
has aspects that make it suitable or this type of radiation, high-energy liquid chromatography (HPLC), mass
unsuitable for the sterilization of a photons bombard the product, caus- spectrometry, or gas chromatography
particular 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 challenge
methods 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 the
packaging 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 levels
geneous components often require mulation, to weaken the strength of of bacterial spores. The product is
extensive product qualification. Gamma packaging materials, and to cause then subjected to a sterility test, which
radiation can cause certain product and changes in color or odor in some shows whether or not the packaging
package materials to degrade. materials. For these reasons, drug maintains a sufficient barrier.
manufacturers should perform pre- In addition, at least one physical
GAMMA 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 the
methods of producing sterile product. gamma radiation and then evaluated amount of pressure needed to open
These 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. Sterilization
migration test, which deter mines Radiation Sterilization.”
whether dye travels through the seals Method 1 encompasses product
of 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 for
erated aging. Typically, incubation at extremely low and high doses and is
55°C for 6.5 weeks equals one year on well known throughout the gamma
a shelf (this may vary depending on sterilization industry. The steps are
the drug formulation). These tests are simple and straightforward. First of
performed on aged products. all, 10 product samples from each of
Performing a fraction of or all of three separate production batches
these 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 quantitative
facturer a good idea of product and incremental Cobalt-60 irradiator is ready to measure, or count, of the number of
packaging suitability for gamma radia- process customers’ products. organisms on the unsterilized product
tion. (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 necessary
er, 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 recovery
er should choose materials that are cals can cause chemical compromise, efficiency. This allows the laboratory
resistant 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 average
HANDLING 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 bioburden
discoloration, or any other physical frozen and thawed, the potential exists level is more than twice that of the
malady due to the high dose of 50–60 to irradiate it without, or with less, overall bioburden, that batch average
kGy, the manufacturer can begin test- product degradation. Freezing the should be used. Otherwise, the overall
ing 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. Using
drug 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 product.
to exhibit effects from the radiation at drug resistance to degradation during Follow the row to the column labeled
extremely low doses. Another test gamma irradiation. Other options SAL 10–2, where the verification dose
entails 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 for
the range of possible maximum doses viate the degradation effects seen in Bacteriostasis/Fungistasis (B/F) and
in half. If the product is stable at the some products. setting the verification dose. The B/F
new 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 fungal
still showing instability, the max dose sterilization dose, which will provide growth. If inhibition is seen, steps
must fall in the lower half of the origi- the desired sterility assurance level must be taken to neutralize it. The test
nal high dose tested. This method may (SAL). There exist two commonly is required only once in the lifetime
reduce the number of irradiations used, industry accepted, validation of a product, but it is recommended
necessary 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 for
product. 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 at
including parenterals and orally ingest- Validation and Routine Control— the verification dose ± 10%. If the
3. Sterilization
dose 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 used
product must be sacrificed and new Also contained in AAMI 11137 is for radiation challenge is Bacillus
product irradiated. If the dose is lower an alternative validation procedure pumilis. It was once believed that this
than 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 are
for 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 an
passed the validation, and the next due to more sample requirements and organism, in this case, is the amount of
step is to find the sterilization dose. associated costs. radiation (quantity of kGy) necessary
Manufacturers 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 value
cation dose was taken, to the column Groups of samples from three produc- for B. pumilis is 1.7 kGy. Some caution
marked SAL 10 –6. This is the mini- tion batches are irradiated in dose should be taken in using a published D
mum sterilization dose. The product increments up to the point where an value, as D values can vary depending
now qualifies to be irradiated at a SAL of 10 –2 can be determined. A on the technique used to determine
range 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 an
high-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 be
ization, Substantiation of 25 kGy,” this each dose increment. Method 2A uses used, the following is an example of
method 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 (section
data from 10 products from each of B3.4.2) a verification dose (D*kGy) is SAL = 10–6
three separate production batches determined. 106 to 10–6 = 12 log reduction
should be collected. Using Table 2 of An additional 100 samples from the D value 1.7 kGy × 12 log reduction
the TIR, the bioburden number equal batch designated from the initial sterili- = 20.4 kGy
to or just greater than the product’s ty tests are irradiated at the verification 20.4 kGy = 10–6 SAL dose
average 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 dose
tion dose” (SAL 10–1). Send 13 product equation appropriate to the specific for 10 products to show the efficacy
units (10 for sterility testing and 3 for method chosen (2A or 2B). of the above 20.4-kGy sterilization
B/F) to the sterilizer for irradiation at In extreme circumstances in which dose:
the verification dose ± 10%. Once the all efforts to neutralize bacteriostatic
irradiation 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 dose
ing. 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 dose
at a minimum dose of 25 kGy. If two inoculation, commonly used in the [6 – (–1)] × 1.7 = verification dose
positive sterility tests occur, a retest past, is not currently recommended [6 + 1] × 1.7 = verification dose
should be performed on 10 additional unless it is impossible to collect natural 7 × 1.7 = verification dose
products. This time, no positives are bioburden data from the product. For- 11.9 kGy = verification dose
allowed for substantiation of 25 kGy. tunately, in most cases, product inocu-