November 2016

To know which sterilization method to choose, it depends on your bioburden, desired SAL and the dose your product can handle. The number of test samples will greatly impact your decision. Since products are required to undergo a sterilization audit every three (3) months, you may want to choose a method that requires less samples to cut down on scrapping product and testing costs.

If your product can withstand at least 15 kGy, VDmax method is your best bet since it requires the lowest number of samples. Dosing at this range is also the most cost effective when sourcing sterilization vendors. Here are some suggestions for samples sizes.

1. VDmax15-35 (≈ 46 samples total)
   1. Typical for a bioburden of 1.5 CFU or higher. Options are for 15-35 kGy in increments of 2.5 kGy. Refer to AAMI TIR33:2005, another guidance document that has tables for additional VDmax testing other than 15 and 25 kGy, shown in ISO 11137-2.
2. Method 1 (≈ 120 samples total)
   1. Used if you’re trying to achieve a low sterilization dose (≤15 kGy).
      • B/F = 6 samples
      • Bioburden = 10 samples
      • Sterilization Validation = 100 samples sterilized at verification dose.
   2. Used to achieve a SAL lower than 10^-6 (i.e., 10^-5, 10^-4, 10^-3, etc.)
      • B/F = 6 samples
      • Bioburden = 10 samples
      • Sterilization Validation = 30 samples (10 samples from 3 lots) sterilized at verification dose.
3. Method 2a or b (≈ 540 samples)
   1. Used for product with very low sterilization dose and a low bioburden during initial processing.
   2. Used to determine lowest dose possible and is ideal for radiation-sensitive product.
   3. Rarest method of testing.
      • 9 doses at 60 samples/dose.
      • Doses are between 2-18 kGy
      • 540 samples tested!

A dose audit consists of the same number of samples minus the B/F samples.

In short, avoid Methods 1 & 2 unless you have a valid justification for using them. Also keep in mind that the tightest tolerance a sterilizer can achieve is ±10%, typically achieved at costly R&D facilities.

Validating sterility is one of the most important steps in the validation process. It ensures that your product is free from viable organisms. Any compromise in sterility can result in infection or even death. In most situations a sterility assurance level (SAL) of 10^-6 is preferred (i.e. a 1 in a million chance of a non-sterile unit). This SAL is not absolutely necessary, though, depending on your requirements and product capabilities.

So what standards must you follow? ANSI/AAMI/ISO 11137 is the main guidance for the sterilization of health products. Like most standards, it is broken into two parts: 11137-1 & 11137-2.

ANSI/AAMI/ISO 11137-1 describes the overall requirements needed for the development of the sterilization process. Think of it as a general overview of the processes involved, including establishing dose, equipment validations, sterilization audits, and maintenance of equipment.

ANSI/AAMI/ISO 11137-2 describes the different types of validation methods, including VDmax 25, VDmax 15, Method 1, and Method 2. Each of these methods consists of three steps:

1. Bacteriostasis/Fungistasis (5 day test)
   1. Determines if the product contains inhibitory properties (e.g. antibiotics) or chemicals that can inhibit or mask the growth of microorganisms in the sample.
      • Refer to USP <71> for methods.
2. Bioburden (12 day test)
   1. Determines population of viable organisms in the product in the form of colony forming units (CFU).
      • Test methods are detailed per ANSI/AAMI/ISO 11737-1
   2. Includes all components labeled sterile NOT just the product.
   3. Establishes the verification dose to achieve 10^-2 SAL, based on tables provided in the standard.
3. Sterilization Validation (14 day test)
   1. Samples are dosed at the verification dose and samples are tested for bioburden.
      • Test methods are detailed per ANSI/AAMI/ISO 11737-2
   2. Depending on the method, zero (0) samples or two (2) samples can test positive for the product to pass the validation.

Medical devices are grouped into specified areas, and the FDA has provided guidances for nearly all of them. Sterile packaging is no different, and it too has its own guidance – ISO 11607.  Want your medical device packaging to perform efficiently, safely, and adequately? Follow ISO 11607.

There are two parts to ISO 11607. ISO 11607-1 deals with the basic attributes of the packaging system. Think materials, medical device, packaging design, conditioning, and sterilization methods. ISO 11607-2 describes validation requirements, covering mainly IQ, OQ, and PQ of the packaging equipment and process.

ISO 11607-1 Testing Requirements:

1. Material Characterization
   • Do the materials suit their use (i.e., temperature, pressure, sterilization, biocompatibility, etc.)?
2. Performance Testing:
   • How does the packaging/product assembly respond to stresses imposed by the manufacturing and sterilization process and the handling, storage, and shipping environment?
     1. Package Integrity Testing: ASTM F2096:2002
     2. Package Strength Testing: ASTM F88:2000
     3. Distribution Testing: ASTM D4169:2001 or ISTA 2A

3. Stability Testing:
   • Does the packaging maintain integrity over time?
     1. Accelerated Aging: ASTM 1980:2002
     2. Real Time Aging

Ensure that the packaging meets all requirements. It is so easy to overlook variables such as compatibility with sterilization, storage temperatures, and distribution. Keep in mind that these tests are expensive, so experience in the initial design is essential.

ISO 11607-2 Testing Requirements

1. Installation Qualification (IQ)
   1. Evidence that equipment has been provided and installed to spec
2. Operation Qualification (OQ)
   1. Proof that installed equipment operates within predetermined limits when used as intended.
3. Process Qualification (PQ)
   1. Evidence that the equipment, as installed and operating as intended, consistently performs in accordance with predetermined criteria.

A seamless integration (IQ) of the equipment to your facility is crucial. A design of experiments protocol will nail down the optimal operating parameters of your equipment (OQ).  Challenging the equipment to meet typical processing conditions and exposing the equipment to the minimum and maximum processing parameters will ensure the efficiency of your process (PQ).