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Microbiology Sampling For Regulatory Testing Of Inhalable Devices

What are non-sterile processes?

Non-sterile processes are methods or procedures undertaken in an environment where bioburden is controlled to safety levels based on product attributes, route of administration, and target patient population. Non-sterile processes contrast to sterile processes, in which the bioburden is essentially eliminated. Microbiology testing methods, microbiology sampling for testing labs, and drug device microbe requirements for inhalable drugs and inhaled nasal products. 

What are examples of common medical products manufactured in non-sterile environments?

  • Metered-dose and dry powder inhalants (inhalable drugs)
  • Nasal sprays
  • Optics
  • Vaginal suppositories
  • Topicals
  • Rectal suppositories
  • Oral liquids (aqueous)
  • Liquid-filled capsules
  • Oral tablets and powder-filled capsules

The inhalable drugs and devices are common non-sterile products that require microbiology and biocompatibility testing prior to release in the United States.

What are the challenges with aseptically sampling inhalable products?

Inhalable nasal products and inhalable drugs are stored in special containers that protect powder or liquid from contamination during storage. These special containers must also allow the user to easily release the product into the nasal passage or lungs during product use. Without unique methods for product sample collection, sufficient quantities of inhaled products for microbiology testing methods or other regulatory assessments are difficult to obtain without external contamination.

How do you determine the sample size for regulatory microbiology testing?

Ten drug product containers that can provide at least a gram of product are sampled for each microbiological test. The product within individual containers can be pooled to obtain enough product for testing.

What types of inhaled products are there?

Inhaled and nasal drug products (INDPs) are separated into two primary categories: low-content INDPs and high-content INDPs. Low-content INDPs are filled with less than one hundred milligrams of powder or liquid per unit. An example of a low-content INDP unit would be a pre-metered inhaler. High-content INDPs are multidose devices filled with more than one hundred milligrams of liquid or powder per unit. Examples of high-content INDPs are metered-dose inhalers that release aerosols for inhalation and multidose nasal sprays.

Picture of different inhalable devices.

What are sampling methods for low-content inhaled and nasal drug products?

Inhalable drug testing may be performed on the unpackaged bulk dry powder, unpacked bulk liquid, or the finished product. Thus, testing unpacked bulk liquid or powder formulations may be ideal for low-content inhalable and nasal drug products because it is easier to obtain a larger representative sample of the product. Testing bulk product is easier since it saves time and prevents accidental microbial contamination during test sample collection. However, if bulk testing is performed instead of testing the finished product, the filling and packaging processes the bulk powdered or liquid product would experience must be cGMP validated to prove microbial contamination is not occurring. Only finished products may be used for regulatory testing if the validation does not occur. Generally, between one and ten grams or milliliters of the bulk product will be used for lab microbiology testing.

What are sampling methods for high-content inhaled and nasal drug products?

There are four primary microbiology testing lab methods for sampling high-content inhalable drugs (high-content INDPs): the automatic actuation method, the room temperature method, the chilling method, and the traditional method. All four methods are described in further detail below. Be aware of any flammability hazards with inhalable products prior to utilizing these sampling methods and use aseptic techniques when possible to minimize microbial contamination during sample collection.

Automatic Actuation Method

The contents of inhalers can be gathered using automatic actuation. With this method, the product is collected using equipment to trigger the release of all aerosolized material within an inhaler. The release is often triggered by twisting or pressing the packaging device containing the powder or liquid product. For inhalers containing multiple doses, all doses must be released and collected. The aerosolized product released is collected on a sterile filter.

Room Temperature Method

The room temperature method is also used to collect the product from inhalers. First, the inhalers are disinfected and placed into a controlled (ideally aseptic) environment. Then a needle apparatus or similar device is used to empty the contents of the aerosol container into a sterile vessel. If the inhaler’s propellant isn’t antimicrobial, the aerosol’s contents can be used for microbial testing directly. Otherwise, the contents must be left at room temperature to allow the propellant to evaporate. A microbiologically inert, sterile gas may be blown over the aerosol’s surface to remove any residual propellant.

Chilling Method

The chilling method is used to collect an aerosolized product. First, disinfected aerosol containers are placed in dry ice, a dry ice slurry, or a cryo freezer long enough for the contents to liquefy. The containers are then aseptically opened, and the product contents poured into a sterile vessel. Alternatively, cooled products can be poured over a sterile membrane filtration unit. The collected product can then be diluted as needed for testing. For hydrofluoroalkane-based products, the product contents are poured into sterile vessels surrounded by dry ice. Sterile, filtered compressed air can be used to evaporate off any propellants used with liquid or dry bulk products.  

Traditional Method

Traditional methods for product sample collection that are described in USP 61 and USP 62 can be used for multidose nasal spray containers. This is because multidose nasal sprays are often stored in containers with easy access to the liquid material. Indeed, a nasal product can be obtained through unscrewing or de-crimping packaging tops.

Summary

Overall, inhalable products are common non-sterile products. These items require microbiology and biocompatibility testing before release in the United States. Inhalable nasal products are stored in special containers that protect powder or liquid from contamination during storage. These special containers must also allow the user to easily release the product into the nasal passage or lungs during product use. Without unique methods for product sample collection, gathering sufficient quantities of inhaled products for microbiology or other regulator testing is difficult. Inhaled and nasal drug products (INDPs) are separated into two primary categories: low-content INDPs and high-content INDPs. Samples from high-content INDPs can be obtained using an automatic actuation method, room temperature method, chilling method, or traditional method. In contrast, bulk liquid or powder may be assessed for low-content INDPs with GMP-validated filling and packaging processes. All in all, ensure you choose a contract testing organization that can support you with appropriate microbiology testing and sample collection for your unique medical device or product needs.

Ethide Labs is a contract testing organization specializing in Sterilization Validations and Microbiology Testing. Ethide Labs also offers Sterility Testing, Bioburden Testing, EO Residual Testing, Bacterial Endotoxin Testing, Cytotoxicity Testing, Environmental MonitoringPackage Integrity Testing services for medical device companies and allied industries. Ethide is an ISO 13485 certified facility. 

References

United States Pharmacopeial Convention. <61> Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests. Rockville, MD, USA. 2021. (USPC <61>).

United States Pharmacopeial Convention. <62> Microbiological Examination Of Nonsterile Products: Tests For Specified Microorganisms. Rockville, MD, USA. 2021. (USP <62>).

United States Pharmacopeial Convention. <610> Alternative Microbiological Sampling Methods For Nonsterile Inhaled And Nasal Products. Rockville, MD, USA. 2021. (USPC <610>).

United States Pharmacopeial Convention. <1115> Bioburden Control of Non-Sterile Drug Substances and Products. Rockville, MD, USA. 2021. (USPC <1115>).

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