Mathematics of Terminal Sterilization - Probability of Survival Approach vs Overkill Approach

Why Should You Attend:

Since there are so many different interpretations of regulatory statements and because different agencies have different philosophies, and there are those who need a deeper comprehension of the sterilization design relative to microbiological impact, this course will:

• Discuss the definition of ‘sterile’
• Elaborate how to get there by describing different sterilization methods
• Discuss various approaches for the validation of a sterilization process using moist heat as template
• List requirements for routine monitoring and control of sterilization
• Review causes for FDA issuing Warning Letters for inappropriate sterilization development, validation and on-going assessment of the process

This webinar will address such essential process questions and also discuss lethality, the different elements that affect D-value and Z-value, and how to calculate the probability that a defined cycle is going to give the Sterility Assurance Level (SAL) and Probability of a Non-Sterile Unit (PNSU) needed to ensure that none or maybe one in a million patients might have a problem due to sterility issues.

Areas Covered in the Webinar:

• Survivor curves to determine D-values and Z-values
• Linear regression used to calculate the edge of failure
• Fraction negative studies
• Correction factors associated with heating and cooling
• Cold spot determination - product and chamber - TD and HP
• Calculation of process lethality
• Biological indicators to be used and how to make the selection
• Laboratory studies needed to support sterilizer studies
• Identification of elements in the process that can affect D-value

Who Will Benefit:

• Manufacturing operations personnel
• QA/QC professionals
• Formulation ,product and process development personnel
• Regulatory affairs professionals
• Research and development personnel
• Sterility assurance team members
• Technical operations personnel
• Validation professionals

Instructor Profile:

Jerry Dalfors has over 40 years of business administration, consultative, technical and managerial experience in the development and manufacture of highly regulated biopharmaceutical products including injectables, biologics, medical devices, and oral dosages. He has held various management positions with several major pharmaceutical and biotechnology companies in the US.

He has worked with or assisted more than two dozen companies in: establishment of controlled document/quality systems; FDA briefing and submittal documents; project management of multimillion dollar projects including design, start-up and validation to assure fast track FDA approval by maintaining strict regulatory compliance during all phases of engineering, construction, commissioning and validation; and writing numerous submission documents for product, process and facility approval/licensing which also requires the development of quality systems including customer complaint management, deviation management, CAPA and associated site wide employee training.

Each of his projects have been received and accepted by the FDA and other regulatory agencies. Mr. Dalfors is considered an expert in almost all aspects of the biopharmaceutical and medical device industry and has trained many FDA field inspectors on a variety of topics. His projects have corrected and prevented clients from receiving a 483 and he has assisted several clients with Warning Letter remediation, while none of them have received a 483 under his guidance.

Topic Background:

Different microorganisms in different environments during sterilization have different resistance to the destructive principles that causes the organism or spore to die (lethality). The chemical environment causes significant variance in the death rate of a microorganism. Very dense cell walls, spore coats, or slime layers outside the cell can severely limit the ingress of what is being used to sterilize the product.

General principals used to kill microorganisms, such as steam and dry heat which, cause denaturization of macromolecules, dissociation of tertiary and secondary structures, and protein agglutination along with destruction of molecular arrangements in the cells caused by radiation. The generation of free radicals causes destruction and re-arrangement of chemical bonds in macromolecules. Chemical disinfection or sterilization causes modifications of macromolecules depending on the agent used.

Heat sterilization is a probability function dependent on heat exposure, the number of microorganisms, and the heat resistance of the microorganisms. Current regulations expect the sterilization process to provide a level of assurance of at least 1 x 10-6 probability of survival (non-sterility) for terminally sterilized parenterals and medical devices. Since regulations require that we generate in our sterilization processes a PNSU, how do we use D-values and Z-values to calculate the probability and determine that there are no risks in the products due to lack of sterility? How do we calculate and monitor these different variables in order to generate the required SAL and PNSU based on the bioburden that may be contaminating the product from an API or the process?

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