Delivered Dose Uniformity of Inhalation Aerosols and Inhalation Sprays. MDIs.

General Information:

Metered Dose Inhalers (MDIs) are commonly used delivery devices for medications intended for respiratory conditions such as Asthma and Chronic Obstructive Pulmonary Disease (COPD).

It is critical to ensure that the drug is delivered effectively and consistently to achieve the desired therapeutic effects.

The Delivered Dose is the total amount of drug emitted from the device and hence available to the patient. It’s a crucial measure, because it ensures that the patient is receiving the correct dosage that was prescribed.

There are different Pharmacopoeias (official publications containing a list of medicinal drugs with their effects and directions for their use) around the world, and each has its own Guidelines and Methods for testing:

1. European Pharmacopoeia (Ph.Eur.):

   • Requires a total of 10 doses to be collected from a single inhaler.

   • The doses should be spread out over the life of the inhaler: 3 doses at the beginning, 4 in the middle, and 3 at the end. This ensures that the inhaler is delivering a consistent dose throughout its lifespan.

2. United States Pharmacopeia (USP):

   • Requires samples from 10 separate inhalers.

   • For each inhaler, a dose is taken at the beginning and at the end, resulting in a total of 20 determinations.

   • The reason for sampling from 10 different inhalers is to ensure consistency across multiple units of the same product. The beginning and end doses from each inhaler ensure that each individual unit maintains dose consistency throughout its life.

Both methods aim to ensure that the inhaler is delivering a consistent and accurate dose to the patient. However, they approach it in slightly different ways. The Ph.Eur. method tests the consistency of one inhaler throughout its entire lifespan, while the USP method checks for both inter-inhaler consistency (by sampling 10 different units) and intra-inhaler consistency (by sampling the beginning and end of each unit).

When manufacturing or evaluating inhalers, pharmaceutical companies and regulatory agencies might use one or both of these methods, depending on the region and the specific requirements for that drug or device.

 

System:

The system above is suggested for testing MDIs according to USP 38 <601>, using an electrically operated, timer controlled, two-way solenoid valve. This valve is placed in the line between the collection tube and the vacuum pump to control the airflow supplied to the inhaler. This ensures that the inhaler is tested under consistent and representative conditions.

The importance of the two-way solenoid valve arises because it allows for precise control over the volume of air that’s pulled through the inhaler during testing. This mirrors the typical inhalation volume of an average patient, ensuring the test conditions replicate actual use as closely as possible.

The FDA and USP 38 specify that the volume of air sampled should not exceed 2 liters (that is why 2-way solenoid valve is necessary that has a capacity to open and close achieving the exact volume). This volume is considered representative of the average patient’s inhalation volume. 

This ensures that the MDI delivers the correct dose under typical conditions of use.

Therefore, for MDIs, the air flow rate is fixed at an arbitrary rate of 28.3 L of air/min (±5%) or 30 L/min (±5%). This flow rate is important as it simulates the flow conditions during patient use. 

DUSA:

DUSA is a piece of specialized equipment designed to test the delivery of drugs to inhalers. It has aim to capture and quantify the delivered dose from the inhaler, ensuring consistent and accurate dosing for patients. 

Each component of the DUSA serves a specific purpose:

1. 1. Sampling Collection Tube/Container. This container captures the drug emitted from the MDI during actuation. It provides a controlled environment for the drug to be deposited and subsequently analyzed.
   2. Rinsing Caps x 2. After the drug is deposited in the collection container, it may need to be rinsed or eluted for analysis. The rinsing caps facilitate this process, ensuring that the entire delivered dose is accounted for in the analysis.
   3. Filter Holder Cap. Some testing protocols require the drug to be filtered before analysis. The filter holder cap keeps a filter in place, allowing the drug solution to be passed through, separating out any particulates or undesired elements from the drug.
   4. Mouthpiece Adapter with a Membrane. This component allows the MDI to be attached to the DUSA in a manner that mimics how a patient would use the inhaler.
   5. Vacuum Connection. This element is crucial for providing a connection between DUSA and a vacuum pump.

When testing an MDI using the DUSA, it’s essential to follow a standardized protocol, ensuring the MDI is actuated correctly, and the drug is collected, rinsed, filtered, and analyzed in a consistent manner. This helps regulatory bodies and manufacturers ensure that every MDI on the market delivers a consistent, therapeutic dose to patients.

Procedure:

The process provides a clear step-by-step approach for testing the dosage delivered by a Metered Dose Inhaler (MDI) using the Dosage Delivery Unit (DDU) sampling apparatus, ensuring accuracy and consistency of the delivered drug. 

The main steps:

1. 1. Preparation. Prepare the MDI product for use as per the manufacturer’s label instructions. This often involves shaking the product to ensure uniform distribution of the drug, priming (which may involve firing a few actuations into the air to ensure the product is ready for use), and then firing to collect the dose.
   2. Actuation Collection. After the priming actuations, collect the minimum recommended number of actuations as per the testing protocol. This ensures that the sample taken for analysis is representative of the dose a patient would receive.
   3. Disconnection. Once the required number of actuations for each test sample is collected, detach the MDI from the DDU sampling apparatus. Disconnect the vacuum source from the apparatus to stop the airflow.
   4. Assay & Analysis. Assay the contents of the DDU apparatus for the drug. This involves analyzing the drug that has been collected in the DDU to determine its quantity. After each collection, it’s important to rinse the filter and the interior of the collection container using a suitable solvent. This ensures that all the drug deposited during the actuation is accounted for in the assay. Apply a validated analytical method to determine the exact amount of drug in each delivered dose. The resulting data are then reported (the absolute amount of drug delivered in each dose or the amount of drug delivered as a percentage of the label claim).
2.  

The outlined process ensures that the MDI delivers the correct and consistent amount of medication to the patient. Regular testing and quality control are crucial in pharmaceutical manufacturing to maintain patient safety and therapeutic efficacy.

The filter holder base is designed to accommodate 25-mm diameter filter disks (for MDIs). Glass fiber filters can be used.

The introduction of an integrated system by InPharmaTEC streamlines the testing process for inhalation products, such as MDIs and DPIs. By combining critical components—flowmeter, solenoid valve, timer, vacuum pump, differential pressure transducer, critical flow controller (for both, MDIs and DPIs), into one unit, the workflow is indeed simplified, reducing potential sources of error and enhancing efficiency.

Benefits:

1. Efficiency. By merging multiple components into a single unit, the setup and calibration time is likely reduced. This speeds up the entire testing process.
2. Accuracy. A single integrated unit reduces the potential for errors that might arise when connecting multiple separate devices.
3. Consistency. With an integrated system, every test is performed under identical conditions, ensuring consistent results.
4. Ease of Use. Operators only need to become familiar with one integrated device rather than multiple separate components, making training and daily use simpler.
   Space Saving. Combining multiple devices into one means a more compact footprint in the laboratory.

 

At TCR Tecora, InPharmaTEC, our dedication is unwavering towards our customers and patients with respiratory diseases. We recognize the unique challenges they face, and we’ve committed ourselves to deliver innovative and compassionate solutions that enhance their quality of life.
We have meticulously streamlined our processes to ensure that every moment counts, delivering efficient healthcare solutions that prioritize the well-being of those we serve.