Draft guideline modernizes EMA recommendations on quality of inhaled, nasal products

Background

• Delivery of medications by inhalation or the nasal route requires a number of unique quality considerations. Various technologies are used for delivery into the lungs, including nebulizers, metered-dose inhalers (MDI; pressurized and non-pressurized), dry powder inhalers (DPIs) and soft mist inhalers (SMIs). Delivery into the nasal passages, on the other hand, typically employs nasal powders and liquids.
• In 2006, the EMA published a guideline for developers regarding the pharmaceutical quality of these products. That guideline outlined the extensive testing required to ascertain the quality of an inhaled or nasal product, dependent on features of the active ingredient and the delivery technology. Although it primarily discussed the principles for quality assessment for new marketing authorization applications, the considerations also applied to product changes which occur throughout the lifecycle.
• Scientific progress over almost three decades has necessitated an update to the guideline. In 2017, the EMA issued a concept paper on the need to update its guidance based on experience gained, as well as questions encountered during review of marketing authorization applications and scientific advice procedures. The concept paper specified a number of specific gaps in the 2006 guidance that the agency planned to address in a future revision. Examples of these gaps included requirements for dose proportionality, flow-rate dependency, stage grouping and spacer/holding chambers, as well as the use of new abbreviated methods for aerodynamic particle size distribution (APSD).

Now, the EMA has published the long-awaited draft revision to this guideline

• On April 12 – seven years after the release of the concept paper – the EMA published a draft revision to its pharmaceutical quality guideline for inhaled and nasal medicinal products. According to the Executive Summary, the goals of this revised document are multi-fold, and include consolidation of information found in the prior guidance along with questions and answers published elsewhere, as well as incorporation of recent advances in the field and new regulations, such as the medical device regulation (MDR).
• This new guideline specifically excludes certain information. For example, pharmaceutical development study designs and analytical procedures are outside the scope of the guideline, as are inhalation anesthetics and nasal ointments, creams and gels. The EMA also notes that ICH guidelines should be used for more detail on quality aspects such as impurities, process validation and specifications that are not specifically covered in this guidance.
• Quality considerations for inhalation products and nasal products are now covered in two separate sections. The 2006 version of the guideline was subdivided into sections covering drug substance specification, pharmaceutical product development, manufacture, excipients, specifications, container closure system and stability. Within those sections, subsections discussed considerations for inhaled versus nasal products. Now, the draft guideline discusses inhaled products in the first section, with a separate discussion of nasal products in the second section. Additionally, the guideline contains new subsections on therapeutic equivalence, product information and lifecycle management.

First up: Changes to expectations for the pharmaceutical development of inhaled products

• Overall, this section underwent significant revisions, with a number of notable and sizable additions and deletions.
• The first critical parameter: Particle size of the active substance. The draft guidance now notes that the entire micronization process and the in-process controls should be provided in an initial marketing authorization application. Different polymorphic forms (i.e., different structures of the same chemical substance) could affect the quality or performance of the medication and should be specified and/or controlled for according to ICH Q6A. Additionally, this section now notes that microbiological quality control should be considered where applicable. As before, this section states that the particle size should be validated with an appropriate method and included in the active substance specification with acceptance criteria.
• In an extensive section on pharmaceutical development, the EMA now refers to the use of Quality by Design (QbD). In principle, development studies should demonstrate that the formulation and pharmaceutical form, manufacturing process, and container closure system “are appropriate and result in acceptable product performance” and that the labelled dose is delivered consistently and repeatedly during administration. When utilizing QbD, multiple batches of at least 10 inhalers per batch should be tested to account for inter- and intra-batch variability.
• A table lists the pharmaceutical development studies that could be required for an inhaled product, clarifying which studies are relevant to which delivery methods. The delivery technology types covered in this table, which have not changed, include DPIs, preparations for nebulization, and both pressurized and non-pressurized MDIs. Some development studies have been renamed, and the table now includes two additional studies that were not found in the previous version: extractable volume and spray pattern/plume geometry. Footnotes delineating between products that contain drug suspensions or preservatives have been maintained.
• From here, the guideline provides detailed explanations of each of the 22 pharmaceutical development studies listed in the table. While there are two entirely new sub-sections to address the new studies noted above, many of these sub-sections have also been expanded upon or modified in small ways. For example, the sub-section on physical characterization has been modified to note the importance of pre-processing (e.g. micronization) and dissolution testing. And the extractables and leachables sub-section has been expanded to discuss potential carcinogenic risk (as outlined in ICH M7) and refer developers to the “relevant European pharmacopeial monograph, or the monograph of a member state” for the leachable profile of plastic materials.
• APSD has been added to the previous concept of droplet size distribution and is considered a Critical Quality Attribute (CQA). The APSD is a key factor in the ultimate location and extent of deposition of the drug in the lungs. Smaller and rounder particles may travel faster and further than larger and irregularly shaped particles. The EMA advises that the APSD should be fully characterized during development to ensure consistency between clinical and commercial batches; any differences between these batches should be characterized.
• A new sub-section clarifies the importance of APSD for inhalation devices using a spacer or holding chamber. In these cases, the spacer or holding chamber could actually alter the APSD and the delivered dose, a change that must be identified through additional studies. These studies should evaluate the spacer and holding chamber within the context of a standard cleaning schedule (i.e., weekly), and should test the device both before and after this cleaning. Additionally, patient use factors and external factors should be considered in these studies. If the spacer or holding chamber alters the product’s APSD, a clinical study may be needed to determine any impact on therapeutic equivalence.
• EMA expanded its requirements for the determination of the uniformity of the delivered dose. As before, this sub-section notes that a study to “demonstrate the consistency of the delivered dose” through the life of the container (i.e., first to last dose) is required to ensure that the same dose with a uniform particle size is delivered with each application. The EMA now specifies further that the study should use the minimum dose noted in the product information and that at least ten doses should be tested from each container, including doses from the beginning, middle and end of each container for MDIs and DPIs.
• There are multiple additional considerations for both the evaluation of and labelling for priming and re-priming of a container. In the case of initial priming, the EMA has added a note that any studies should account for the different “storage orientations likely to occur in real life settings.” If certain storage orientations significantly alter the delivered dose of a product, then the labelling should reflect this finding. In the case of re-priming – which may be needed after an extended storage period – the EMA now recommends that developers assess the need for re-priming at multiple time points. Product labelling should include clear instructions (for the worst-case scenario) on the need for re-priming, which must include the length of storage after which re-priming is required and the number of actuations required to effectively re-prime the product.
• Small changes were made to the sub-sections on temperature and moisture studies. Here the EMA calls for studies on inhaled products under temperature variations (low temperatures and cycling temperatures) and high humidity, again noting the importance of evaluating the product in various storage orientations. These sub-sections provide guidance on the specific temperatures, humidity levels, and durations of exposure that should be assessed (at a minimum) for all relevant products.
• An assessment of product “robustness” should now also include simulations of the device being dropped. This assessment should specifically be conducted near the end of the life of the product (when about 5% of doses remain) to allow for an assessment of the impact of any drug that has accumulated on the mouthpiece of the device or any other part of the device. Any changes to safety and/or efficacy identified in these studies should convert to product handling information, to be included in the product labelling.

Next up: A variety of other new or modified considerations for inhaled products

• A section on the manufacture of inhaled products has been expanded, with additional consideration for DPIs and MDIs. Any inhaled products “are considered specialized dosage forms manufactured by non-standard manufacturing processes.” Therefore, critical and non-critical process parameters should be justified with reference to the manufacturing process and sufficient detail should be included in the application. CQAs and Critical Process Parameters determined during development studies should guide the establishment of appropriate in-process controls. Additionally, batch validation data should be provided to support the manufacturing scale of the finished product.
• Excipients, which can have a substantial effect on the safety, quality and performance of these products, receive extra attention in this draft revision. Here, the EMA explains that additional functionality-related tests of excipients may be required, and that all excipient specifications should be developed while considering their impact on the product’s CQAs. In a sub-section on pharmacopeial excipients, the EMA notes that for those which do not have a well-established use in inhalation products or are used in concentrations higher than that previously established, safety must be demonstrated. The agency also provides guidance for novel excipients – or those which have not been previously used in an inhaled product – in a new sub-section. In addition to details on manufacturing, characterization and controls, developers must also provide information on the chemical structure, morphological information and provider/source of these novel excipients. The identity, purity, and physical and chemical characteristics of the excipient must be tested using validated analytical methods.
• The section on control of the finished medical product has undergone a small number of changes. A table that clarifies which specification tests are needed for each product type has been modified only minimally and covers the same delivery types included in the product development study table. Minor changes have been made to the discussions on each of these specification tests; only the discussion of the fine particle dose test (previously referred to as the fine particle mass test) has been expanded upon to a significant extent.
• All medical devices provided in container closure systems – including inhalers – must now fulfill the requirements of the Medical Device Regulation (MDR). The guideline now refers to the relevant sections of the MDR, clarifying that all products are expected to meet the relevant safety and performance standards. Developers are also encouraged to refer to a separate EMA guideline on the quality requirements for drug-device combination products.
• A new section now addresses considerations for abridged applications for generic inhaled products, which must ultimately meet the same quality requirements. These applications must provide comparative quality data that is supportive of therapeutic equivalence to the reference product. Specification limits for in vitro evaluations should be set based on batches used for establishment of in vitro equivalence if no in vivo studies are performed.
• Another new section directly addresses some of the specific expectations for the labelling of inhaled products. Although the guideline refers to these requirements throughout, this section offers a single point of reference for all quality-related labelling requirements. Here the EMA provides a list of expectations related to the name of the product itself, its qualitative and quantitative composition, relevant administration and handling instructions, excipients, the nature and contents of the container, and any special storage precautions.
• Finally, the guideline wraps up its discussion on inhaled products with a new section on lifecycle management. This new section notes that any proposed changes occurring during the lifecycle of the product require a risk assessment. To assist developers in understanding which changes would be expected to have a significant impact on the quality, safety or efficacy of a product, the EMA provides a non-exhaustive list of examples. For all situations, the EMA expects developers to support changes with “appropriate and representative batch data for all critical quality attributes before and after the proposed change.”

Last but not least: Nasal medicinal products

• Right up front, the guideline clarifies that most quality considerations for inhaled products also apply to nasal products. As a result, the EMA’s recommendations for nasal products are very similar to those for inhaled products. However, there are some important differences between the expectations for these products, which are specifically noted in this separate section of the document.
• One key difference between inhaled and nasal products: Desired particle size. Inhaled products must reach the lungs, requiring a particle size of less than 5 microns. However, if particles of this small size are used in nasal products, then a drug intended for nasal delivery could reach the lungs, causing undesired effects. Therefore, particle size is considered to be a CQA for nasal drugs as well. Pharmaceutical quality testing must confirm that the drug is localized to the nasal cavity and that the “vast majority of the particles/droplets” are larger than 10 microns.
• To assist in determining which pharmaceutical development studies are needed for each nasal product type, the guideline includes a table similar to that in the section on inhaled products. This table includes six different types of delivery technologies: pressurized metered-dose nasal spray, nasal powders (device-metered), single-dose drops, multi-dose drops, single-dose sprays, and non-pressurized multi-dose metered-dose spray. A total of 16 different studies are listed in the table, clarifying whether a given study is relevant to a specific product type. However, unlike the section on inhaled drugs, only certain individual study types are discussed in further detail; the guideline refers readers back to the section on inhaled drugs for more information on studies that have already been discussed.
• This section also provides a separate table regarding the relevance of various finished product specification tests. This table includes the same six delivery technologies as the prior table, along with 12 specification tests. The only test discussed in further detail in this section relates to particle/droplet size distribution; developers should refer back to the inhaled product section for all other tests. Similarly, developers should refer to the section on inhaled products for discussions on excipients, stability and container closure systems.
• Demonstration of therapeutic equivalence for generic nasal products may depend on the site of action for the active substance, which may be local or systemic. An in vitro evaluation of therapeutic equivalence should consider a variety of factors, which are listed in this section. Since changes in these factors have the potential to affect the deposition within the nasal cavity, as well as absorption, developers should provide a rationale justifying why any identified changes are not expected to impact product performance.
• The recommendations for product information and lifecycle management are similar to those for inhaled products. Again, the guideline lists all relevant expectations for product labelling, including the name of the product itself, its qualitative and quantitative composition, relevant administration and handling instructions, excipients, the nature and contents of the container, and any special storage precautions. The EMA also reiterates its expectation that any proposed changes occurring during the lifecycle of the product require a risk assessment and provides a sample list of changes which would be expected to significantly impact a product’s quality, efficacy or safety.

Analysis

• This significant revision to the EMA’s original guideline pays special attention to the differences between nasal and inhaled products. Nasal products now receive targeted attention in a separate section, which has been structured to note only the considerations which are unique to nasal products, or which differ significantly from the considerations for inhaled products. Additionally, while the 2006 version of the guideline mentioned a minimum particle size for nasal products, this draft revision provides a dedicated explanation regarding the importance of particle size for both nasal and inhaled products.
• Many of the issues identified in the concept paper have been addressed as anticipated. This includes a full sub-section on evaluation of an inhaled spray in conjunction with a spacer or holding chamber, methods that can be used to evaluate APSD, the importance of intra- and inter-device variability on dose uniformity, and reference to various ICH guidelines.
• However, there are also a significant number of additions and changes which were not anticipated in the concept paper. Considering that the concept paper was released seven years prior to the draft revision, this is not necessarily surprising. Some of these additional changes may have been spurred by comments received on the concept paper; however, these have not been released for review.
• Although the draft features quite a few changes, they may not come as a surprise to experienced developers. The EMA indicates in both the concept paper and the draft revision that many of the changes made to the document stem not only from scientific advances in the field, but also from the actual review of applications and issues that have arisen during scientific advice sessions with developers.

What’s next?

• The draft revised guideline is open for public consultation until October 31. EMA will take any comments received under consideration while finalizing the guideline, although there is no anticipated timeline for finalization. Comments should be provided the EUSurvey form.
• In conjunction with this revised draft, the EMA also released a new draft guideline focused on the demonstration of therapeutic equivalence for orally inhaled products. The Executive Summaries of both guidelines indicate that these draft documents are intended to be complementary to each other and used in conjunction. Stay tuned for an upcoming, in-depth analysis of this separate draft guideline.

To contact the author of this item, please email Kirsten Messmer ( [email protected]).
To contact the editor of this item, please email Chelsey McIntyre ( [email protected]).

Key Documents and Dates

• EMA/CHMP/20607/2024 – Revised draft guideline on the pharmaceutical quality on inhalation and nasal medicinal products, April 12, 2024