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The delivery device and drug form should be considered when choosing a test method for identifying and measuring particulates.
Orally inhaled and nasal drug products (OINDPs) are formulated as either solutions, suspensions, or dry powders that are delivered using devices such as nebulizers, metered dose inhalers (MDIs), or dry powder inhalers (DPIs). One of the critical quality attributes of an inhaled drug product is the amount and size of foreign particles in the product. “Foreign particles-including glass, stainless steel, or different types of polymers-can come from any step in the manufacturing process or from the source materials,” notes John Bak, PhD, principal scientist at PPD Laboratories’ GMP Lab. Manufacturers must develop appropriate tests to identify and measure these particles so that they can be eliminated or maintained below a certain level. Pharmaceutical Technology spoke with Bak to learn best practices for developing these tests.
PharmTech: What FDA or United States Pharmacopeia (USP) guidance documents are used to develop appropriate tests for foreign particulate matter in inhaled products?
Bak (PPD): Current guidance documents that are available include:
Although the requirement to do particulate matter testing is included in these documents, no techniques or guidelines for specifications are given. It is up to the applicant to develop and justify the choices made.
USP <788> Particulate Matter in Injections (4) and its specifications are specifically for parenteral products and are not appropriate for OINDPs. The testing procedures can be used to help develop an appropriate test, but not the specifications.
While FDA and USP provide little guidance, there have been some position papers published to fill the gap. Two papers by Blanchard et al., ‘Foreign Particles Testing in Orally Inhaled and Nasal Drug Products’ (5) and ‘Best Practices for Managing Quality and Safety of Foreign Particles in Orally Inhaled and Nasal Drug Products, and an Evaluation of Clinical Relevance’ (6), describe the types of tests that can be done and a rational means of setting product specifications specifically for OINDPs.
The means of setting specifications proposed in the paper (5) is to use the US Environmental Protection Agency National Ambient Air Quality Standards (NAAQS) for particles with < 10 µm aerodynamic diameters. A small percentage (1–5%) of the allowable exposure is suggested for the maximum daily exposure due to the use of the product.
The first article (5) also has a survey of the commonly used techniques for testing for particulate contamination along with each technique’s strengths and weaknesses.
PharmTech: What factors should be considered when deciding upon a testing strategy?
Bak (PPD): Based upon the recommendations of these two articles (5,6) and our experience, when looking at a strategy to test a product under development, the device used for delivery (e.g., nebulizer, MDI, or DPI), the location of action (e.g., nasal or pulmonary), the state of the formulated drug (e.g., solution, suspension, or dry powder), and the testing strategy (e.g., delivered dose or extracted formulated drug product procedures), all impact choices that are made as far as the technologies used, the test method validation strategies applied, the robustness of the resulting procedure, and the cost of the ongoing testing for stability and release.
The first step in putting together the strategy is to harvest the particles from the drug product, drug substance, excipients, and delivery devices and analyze them using microscopic techniques that allow chemical identification, such as Fourier Transform infrared (FTIR) microscopy, Raman microscopy, and scanning electron microscopy with energy dispersive X-ray probe (SEM/EDX), to elucidate what the common contaminants are and identify their sources so they can be eliminated or reduced in the manufacturing process. In addition, a toxicological assessment can be performed to ensure that no particularly harmful materials are present. Special consideration is given to the < 10 µm particles because they are respirable and therefore present the highest risk from exposure.
Understanding the particulate profile and having it be reasonably stable from lot-to-lot demonstrates control of the manufacturing process with respect to particulate contamination in the drug product. When this level of understanding is established, the use of faster and less-expensive techniques to monitor the level of particulate contamination is warranted. Light obscuration is the most common technique used for monitoring.
PharmTech: What are the considerations for choosing to collect and analyze particles using the delivered-dose technique or analyzing the drug product extracted from the device or container?
Bak (PPD): The delivered-dose technique sounds better because it simulates the actual exposure the patient receives. These techniques, however, tend to be difficult to implement because of their poor precision, which requires higher-skilled analysts and thereby increases the cost of testing. In addition, the incidence of atypical and out-of-specification result investigations is increased with the associated delays. If a justification can be made to use material extracted from the device or container, the routine testing for stability and release is typically more robust and trouble-free.
Delivered-dose techniques for particulates often can be created by modifying methodology used in delivered-dose uniformity testing. A sufficient amount of material is collected, and then any solid drug substance or solid excipients are dissolved using an appropriate particle-free solvent. If no other solids are present, a compatible suspending solvent is added instead. The solvent is then well mixed to suspend the captured particulate contamination and tested by light obscuration or other techniques. This approach allows the use of the same or similar devices that analytical teams are used to working with, for instance, those described in USP <601> Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders-Performance Quality Tests (7) and USP <1601> Products for Nebulization-Characterization Tests (8).
When extraction techniques are used, the testing is usually simplified. For nebulizers, the blow-filled vials are opened and the liquid pooled. The pool is then tested by light obscuration or another technique. For DPIs, the powder is extracted as appropriate. For instance, blister strips are cut open and the powder pooled. The powder is then dissolved in an appropriate solvent. The remaining particulate matter is then suspended in the solution and it is tested. For MDIs, the material is extracted by cutting open the frozen can or by dispensing into a container that catches the drug product. If needed, any solid excipients or drug substance is then dissolved in a particle-free solvent. The resulting solution has the particulates suspended and is then tested.
Light obscuration typically is preferred for analyzing the resulting test solutions. If visible light microscopy is used, the solutions are filtered, and the remaining particulate contamination is counted. The magnification should be set high enough that the < 10 µm particles are clearly visible. Techniques based on USP <788> often undercount particles in the 2–5 µm range because at 100x magnification specified in USP <788> (4), these particles are difficult to see against the background of a filter membrane. Light obscuration testing, on the other hand, has good sensitivity to particles in the 2–5 µm range.
PharmTech: What are the most significant challenges in developing appropriate tests for foreign particulate matter?
Bak (PPD): Typically, the most challenging part of developing the testing is to find a solvent that dissolves the drug substance and the excipients at the same time, while minimizing interfering artifacts like microbubbles. The second most significant challenge is cleaning the equipment in a particle-free environment to control laboratory contamination of the samples.
PharmTech: What is typically required for validating these analytical methods?
Bak (PPD): We typically recommend that the < 10 µm particles be validated as a quantitative impurity test, since they present the highest risk because they are respirable. The range of analysis is demonstrated from the limit of quantitation to 120% of the product specification along with any demonstrations of method robustness indicated from the method development. The ≥ 10 µm and ≥ 25 µm particles also can be validated in the same manner, or be shown to have impurity-limits compliance, because they present less risk and are monitored more from a product quality standpoint than a safety risk.
1. USP, USP 40 Supplement 2 <5> Inhalation and Nasal Drug products-General Information and Product Quality Tests (2017).
2. FDA, Guidance for Industry-Nasal Spray and Inhalation Solution, Suspension and Spray Drug Product-Chemistry, Manufacturing and Controls Documentation (CDER, 2002).
3. FDA, Draft Guidance for Industry-Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products (CDER, 1998).
4. USP, USP 40 Supplement 2 <788> Particulate Matter in Injections (2017).
5. J. Blanchard, et al. Pharm. Res. 21 (12) 2137-2147 (2004).
6. J. Blanchard, et al. Pharm. Res. 24 (3) 471-479 (2007).
7. USP, USP <601> Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders-Performance Quality Tests (2014).
8. USP, USP 40 Supplement 2 <1601> Products for Nebulization-Characterization Tests (2017).