Guidance and Review of New USP 797 Changes

USP 797 published new proposed guidelines for comment. Many of the new standards change/affect the compounding industry. Medizap / SteriTek have read the USP 797 guidelines to develop a position. The goal is to share this position with you.

By being thought leaders, we hope to influence USP 797 guidelines while also building the advocacy and trust of the APC, compounding industry, and all stakeholders affected and defined by this Pharmacopeia regulatory body.

Medizap / SteriTek is uniquely positioned to bring a scientific perspective to the newly proposed guidelines and ensure understanding and use of ISO guidelines for all irradiation validation and ongoing testing since USP 797 omits detailed Irradiation standards. We believe that selecting the Irradiation sterilization modality defaults to ISO regulatory guidelines.

Since 1994 the FDA has accepted and encouraged terminal sterilization for Human and Veterinary Drug Products. The acceptance of terminal sterilization is demonstrated in the Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM), November 1994, Guidance for Industry for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products.

In addition to the new proposed USP 797, the USP supports terminal sterilization methods defined in USP <1222> Terminally Sterilized Pharmaceutical Products-Parametric Release, USP <1223> Validation of Alternative Microbiological Methods, and USP <1225> Validation of Compendial Procedures, USP, General Notices (Alternative and Harmonized Methods and Procedures).

Drug products designated as 'STERILE' are prepared using appropriate validation methods. Whenever possible, sterile drug products are terminally sterilized using an adequately validated and controlled sterilization process (see ISO 11135, ISO 11137, ISO 14160). It is difficult to exclude all microorganisms from a manufacturing and packaging area. Hence, the preference is to utilize a validated terminal sterilization process as this is an active mechanism to destroy any microorganisms on the product following assembly.

The core sterilization standards that have served the industry well are listed in the Table to the left. As discussed above, terminal sterilization is preferred over aseptic processing. The rationale for this preference can be seen in the foundational sterility assurance principles and current realities that permeate these standards as summarized in section 'Foundational Terminal Sterilization Principles and Current Realities.' ISO 14937, sterilization of health care products—General requirements for characterization of a sterilizing agent and the development, validation, and routine control of a sterilization process, provides the general structure for extending these principles to non-traditional sterilization modalities, beyond those for which there is a specific standard.

When terminal sterilization of compound pharmaceuticals is validated per the ANSI/AAMI/ISO 11137 standard series, subsequent dose audit protocols are performed to ensure ongoing process validation, including ISO sterility and bioburden testing. The additional execution of USP <71> sterility tests is not required per ISO regulatory guidelines nor suggested. They do not provide further evidence or higher SAL that supersedes scientific methodology as required in ISO regulations.

Another newly proposed USP 797 section, Chapter 14.2, Pg. 41, 4th Paragraph: “A longer BUD is permitted if sterility testing results are within acceptable limits. The maximum batch sizes for all CSPs requiring sterility testing must be limited to 250 final yield units.” CSP’s terminally sterilized by Irradiation does not require USP 71 sterility testing as an alternate method of sterility testing would be validated in ISO 11137 sterilization process validation with Dose audits and thereby have no limitation of testing to lot size. Also, no FDA audit of terminal sterilization under ISO 11137 has ever sited a lot size restriction.

The FDA has committed to the industry to recognize AAMI, ISO, and ASTM standards to meet the requirements for sterilization of healthcare products and drug products. Below is a list of the recognized AAMI/ISO standards recognized by the FDA concerning Irradiation Sterilization.

Moreover, it’s important to note that ISO separates terminal sterilization into three separate and distinct guidelines: Heat Sterilization, ETO, and Irradiation.

Our Industry Position:

The basis of the confidence for terminal sterilization processes includes the challenge process, the validation approaches, and the ability to reproducibly deliver and demonstrate control of the process.

USP 797 bundles Terminal Sterilization as a group to include Steam Heat, Dry Heat, and Irradiation. We argue that grouping all three sterilization modalities ignores and does not recognize the advantages and disadvantages of each technology and cannot scientifically be rationalized because the Sterility Assurance Level or SAL achieved by Steam Heat / Dry Heat is 10-4 vs. SAL achievable by Irradiation is 10-6.

Even though all three forms sterilize a drug product in their final primary packaging, Steam, and Dry Heat terminal sterilization process validations are proven through biological indicators. Sterilization processes are validated either using a biological indicator (BI) or using the product's natural bioburden. If BIs are used, it must be demonstrated that they provide a challenge to the sterilization process greater than the natural bioburden of the product.

If product natural bioburden is used, it must be shown that the more highly resistant bioburden organisms are considered appropriate in the sterilization validation approach.

Terminal Sterilization via Irradiation is proven and documented under ISO 11137 + ISO 11737. Proof of sterility under ISO requires a full sterilization process validation to be performed and continued sterilization process validation with Dose Audits for sterility and bio-burden testing.

The ISO 11137 standard for radiation sterilization provides bioburden-based validation methods. Sub-lethal radiation dose(s), based on the level of product bioburden, is applied to the product to determine if the natural product bioburden has resistance to radiation lethality equal to or less than the SDR. All this to say, a specific radiation dose is defined that will provide to the product the desired assurance of sterility, e.g., 10−6 SAL.

In our opinion, only Irradiation terminal sterilization has a proven SAL and validated testing methodology that should allow for a BUD set by Stability Testing. This is due to the scientific and empirical evidence of the technology and approach to validate and ensure the ongoing sterility of products when following ISO-defined guidelines. Terminal sterilization by Dry/Steam Heat has a higher probability of affecting the potency of a drug; in addition, the equipment validation and ongoing maintenance allow for more margin of error in delivering the safest drug product. Dry/Steam Heat terminal sterilization must comply with USP 71, and sample sets pulled from production lots have received a full sterilization dose. In comparison, Irradiation must follow ISO 11137 and requires validation and ongoing testing on a product that has received a sub-lethal or verification dose for sterilization and still prove sterile. That is to say, the required hurdle or bar to show a sterile drug product is exponentially higher.

Therefore, overall, our position is that if terminal sterilization by Irradiation is selected, then USP 71 does not apply. If USP 71 does not apply, the newly proposed USP 797 limit of 250 units per lot does not apply. We also propose that if Category 3 requires Stability Testing under a proven scientific method and Irradiation is chosen as the sterilization modality, then extension or reduction of the CSP BUD be allowed and used instead of the newly proposed Category 3 standard table.

In conclusion, the sterility assurance industry, as represented by contract suppliers such as Medizap / SteriTek, needs to be included and recognized at USP forums and allow input into guiding the evolution of regulatory guidelines to ensure discussions about the sterility assurance challenges the industry is facing are represented. Patients around the world need innovative medical compounded drug products being developed that are delivered at the highest safety profile. We need to ensure that scientific advances in sterilization technology be applied and used according to ongoing and improving Pharmacopeia regulations and push for harmonization of global standards (ANSI/AAMI/ISO) benefiting all drug manufacturers represented across the global footprint.

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