There are several inhalation drug products available on the market. All of them have some advantages and disadvantages. Based on your opinion, which is the best for the end-user-patient?
The best device or device class of inhalation drug products for the end-user-patient depends on several circumstances:
- Indication
- Dose
- Mobility
- Coordination of the patient
- Handling
- Cost of goods
This is not an exhaustive list.
For the traditional indications of inhalation drug products like treatment of Asthma attacks I think pMDIs and pre-metered, multi-dose DPIs would be the best classes of devices and for the maintenance treatment of Asthma and COPD all mobile devices would be feasible.
For children and elderly patients, I think pMDIs with spacer, breath-actuated pMDIs, Soft-mist inhalers and nebulizers would be the best devices due to the de-link of the coordination activities between actuation and inhalation and easy handling of the devices. For adults, all device classes would be feasible, preferably with device connectivity for feedback on inhalation for pMDIs and nebulizers during and/or after application.
For other indications like bacterial infections, pulmonary arterial hypertension, and applications of biological and biotech compounds pre-metered, single-dose DPIs and nebulizers would be the best choices.
Orally inhaled and nasal drug products are generally categorised as high-risk dosage forms. Why?
Due to safety considerations related to the route of administration (i.e., drug administered directly into the lung) and high probability of packaging component interaction with the formulation (i.e., compounds which could leach out of the plastic and elastomer materials). In addition, the formulations for nebulizers must be sterile which needs a critical manufacturing process (i.e., aseptic process) in terms of safety considerations for the ready-to-use solutions and powders for nebulization.
What are the key aspects of the Control Strategy for API and DP? And then, what are the necessary development steps towards commercialisation?
The control strategy has to be defined throughout the development of a new or reformulated inhalation drug product to ensure the identity, potency, purity and safety of the commercial product. The control strategy should be defined according to the ICH guidelines Q8 “Pharmaceutical Development” and Q9 “Quality Risk Management” starting with the Quality Target Product Profile (QTPP). Based on the QTPP the API will be identified and its characteristics assessed. The suitable excipient(s) and container closure system for pMDIs and DPIs will be chosen for the formulation and manufacturing process development activities. Through evaluations of the development data the Critical Quality Attributes (CQAs) of the inhalation product (e.g., assay, purity, delivered dose uniformity (DDU), aerodynamic particle size distribution (APSD) can be identified, and the CQAs of the active ingredient and excipient(s) can be determined (e.g., potency, purity, particle size and shape). As part of the manufacturing process development the CQAs will be linked to the Critical Process Parameters (CPPs) and In-process Controls (IPCs) of the product in order to control the manufacturing process of the commercial product. The CQAs will be included in the specification for release and stability of the inhalation drug product to ensure adequate quality of the commercial product at release and throughout shelf-life.
The development steps towards commercialization covers:
- Assessment of API characteristics and development risks (incl. QTPP, prototype formulations)
- Formulation screening (incl. selection of formulation / container closure system, evaluation of CQAs)
- Selection of clinical candidate formulation (incl. evaluation and definition of design space)
- Formulation and container closure optimization
- Process development and scale-up (incl. link between CPPs / IPCs and CQAs and definition of control space for manufacturing)
- Technical transfer to commercial production site and manufacturing process validation
The key analytical method, which is delivered dose uniformity (DDU) has different specification approaches for the U.S. and EU. Can you elaborate on the differences in counting tests between US and EU guidelines?
The differences in the specification approaches for the delivered dose uniformity (DDU) using the counting test required by the U.S. and EU regulatory guidance documents are in the sampling / testing regimens and the acceptance criteria of this key performance test.
Sampling/testing regimens (pMDIs and pre-metered, multi-dose DPIs):
U.S.:
- Tier 1 testing: DDU test is performed using 10 inhalers which are tested at beginning (dose 1) and end (labelled dose) of inhaler life (n = 20 individual DDU determinations).
- Tier 2 testing: 20 additional inhalers which are tested at the beginning (dose 1) and end (labelled dose) of inhaler life (in total: n = 60 individual DDU determinations).
EU: Two DDU tests: Intra- and inter inhaler tests
Intra-inhaler test
- Tier 1 testing: DDU test is performed using 1 inhaler which is tested 3 times at beginning (dose 1 to 3), 4 times at middle (doses around labelled dose / 2) and 3 times at end (labelled dose – 2, labelled dose – 1 and labelled dose) of inhaler life (n = 10 individual DDU determinations).
- Tier 2 testing: 2 additional inhalers which are tested 3 times at beginning (dose 1 to 3), 4 times at middle (doses around labelled dose / 2) and 3 times at end (labelled dose – 2, labelled dose – 1 and labelled dose) of inhaler life (in total: n = 30 individual DDU determinations).
Inter-inhaler test
- Tier 1 testing: DDU test is performed using 10 inhalers of which 3 inhalers tested at beginning (dose 1 to 3), 4 inhalers at middle (doses around labelled dose / 2) and 3 inhalers at end (labelled dose – 2, labelled dose – 1 and labelled dose) of inhaler life (n = 10 individual DDU determinations).
- Tier 2 testing: 20 additional inhalers of which 3 inhalers are tested at beginning (dose 1 to 3), 4 inhalers at middle (doses around labelled dose / 2) and 3 inhalers at end (labelled dose – 2, labelled dose – 1 and labelled dose) of inhaler life (in total: n = 30 individual DDU determinations).
Acceptance criteria (pMDIs and pre-metered, multi-dose DPIs):
U.S.:
- Tier 1 testing: (I) Mean of 10 individual determinations separately at the beginning and end of inhaler life must be within ± 15 % of target delivered dose (TDD) and (II) 90 % of individual determinations (18 of 20) must be within 80 to 120 % of TDD and none outside of 75 to 125 % of TDD.
- Tier 2 testing: (I) Mean of 20 individual determinations separately at the beginning and end of inhaler life must be within ± 15 % of target delivered dose (TDD) and (II) 90 % of individual determinations (54 of 60) must be within 80 to 120 % of TDD and none outside of 75 to 125 % of TDD.
EU: Two DDU tests: Intra- and inter inhaler tests
- Tier 1 testing: (I) Mean of 10 individual determinations must be within ± 15 % of target delivered dose (TDD) and (II) 90 % of individual determinations (9 of 10) must be within 75 to 125 % of mean and none outside of 65 to 135 % of mean.
- Tier 2 testing: (I) Mean of 30 individual determinations must be within ± 15 % of target delivered dose (TDD) and (II) 90 % of individual determinations (27 of 30) must be within 75 to 125 % of mean and none outside of 65 to 135 % of mean.
The main differences of acceptance criteria between U.S. and EU highlighted in bold.
How has the Next Generation Impactor influenced the testing process?
The time for the Aerodynamic Particle Size Distribution (APSD) tests using Next Generation Impactors (NGIs) is significantly shorter compared to the APSD tests applying Andersen Cascade Impactors (ACIs). This shorter time for testing is mainly caused by a shorter set-up time of the NGI between APSD tests. Due to the NGI technology the cup tray with the removable impaction cups can be exchanged between successive APSD tests so that a new test can be started in parallel to the extraction of the drug deposited on the impaction cups from the previous test. This is significant different from the handling of the ACI as this cascade impactor has to be fully disassembled, the drug deposited on the collection plates has to be extracted, the impactor parts (i.e., stages and plates) have to be cleaned and dried, the filter material has to be replaced and the ACI has to be assembled prior the next ACI test and thus, the set-up time between APSD tests is much longer compared to the tests by NGI.
Furthermore, for APSD testing of DPIs different flow rates (30 to 90 L/min) are needed which have an impact on the aerodynamic particle size cut-off diameters of the impactor stages. For NGIs tabulated particle size cut-off diameters of the stages are available (USP <601>) depending on flow rates between 30 and 90 L/min that can be used for the APSD tests while for ACIs the stage configuration has to be adjusted to the specific flow rate (USP <601>, Table 3a) and therefore, additional ACI stages are needed.
During the development of generic inhalation drugs, there are key steps that are crucial. Can you briefly describe them?
The following key steps for a successful development of generic inhalation drugs should be considered:
- Understand the performance characteristics of the originating product, perform originator / RLD benchmarking studies.
- The product development should be based on QbD principles (ICH Q8) and risk-based approaches (ICH Q9).
– Define Quality Target Product Profile (QTPP) for the generic product – set development specification.
– Perform formulation / device DoEs – define design space for product manufacturing.
- Conduct PK BE and PD BE studies (EU not mandatory) according to the guidelines.
- Perform in vitro BE studies according to the guidelines.
- Perform primary stability studies and conduct drug product characterisation (DPC) studies.
- Define control strategy for the commercial product – set final specifications.
- Submit ANDA / MAA with the FDA / EU authorities.
- Conduct manufacturing process validation.
