• Guy Sambursky

FDA’s new guidelines for Inhalers – a game changer for micronization

Updated: Mar 21, 2019

On April 2018, FDA has released the draft guideline for the inhalation therapy industry. It contains many updated quality considerations that capture the vast advancement in research and industry, made over the last 20 years.

A significant part of the guideline is dedicated to micronization of API’s and excipients. This emphasizes the FDA’s recognition of two important factors:

  • Physical quality of the API is the most important factor for the performance of MDI’s and DPI’s.

  • Micronization is a key process in determining the physical and chemical quality of the API.

Whether the micronization is performed by the API vendor, by the Inhalation drug product maker or by an external contractor, the FDA would expect intensive study and controls over the micronization process, as if it was actual part of the formulation process.

Some examples are listed in the guideline:

  • “The crystallinity of the drug substance in MDIs and DPIs can be affected by mechanical processing, including micronization. This can lead to the generation of amorphous particles that are thermodynamically unstable, with a tendency to convert to a more stable crystalline state with time.” (p. 10)

  • “Increased drug substance particle cohesiveness resulting from the presence of very small particles can adversely affect flowability, fillability, and dispersibility” (p .11)

  • “If micronization is used to adjust the PSD, the in-process controls can include: total duration of micronization, PSD of the incoming materials, feed rate, inlet air flow rate, air pressure, physical and mechanical properties of input materials, number of times a lot is micronized, and re-introduction of carry-overs from previous micronized lots” (p. 13)

These references highlight Micronization parameters that are often overlooked. While feed rate and air pressure are known to critically affect particle size, the following interactions and effects are less known:

  • Mechanical impact (particle-particle collisions and particle-metal collisions) creates amorphous zones, especially on crystal surface. These amorphous zones lead to stickiness, poor flow and aggregation. Followed uncontrolled re-crystallization will make the product change its characteristics between time of QC release and time of formulation

  • Number of passes through the micronizer: In many cases, API’s for inhalation are passed multiple times in an air-jet mill to reach the desired PSD range of 2-3 microns. During the second pass and beyond, the starting material is poor flowing and sticky, hence these multiple micronizations are less efficient and increase the damage to crystal structure. It is always advised to micronize the material only once.

  • Overall time of micronization: micronized particles have active surface that is susceptible to aggregation, absorbance of moisture and oxidation. If micronization process is long, and especially if the material is fed again and again, more time passes until the material is safely stored in the right conditions (i.e. inert atmosphere, low humidity and low temperature). Hence, batch will have non-uniform characteristics. The key here is to have a short micronization process followed by quick packaging of the material.

  • Re-introduction of carry-overs from previous micronized lots: It is obvious by now, that residues of powder recirculating within the micronization process will have bad impact on quality. Source for this carry-over could result from Layer buildup that periodically disintegrates into the product stream. In standard jet mills such buildup is expected in the venturi tube, the micronization chamber and the cyclone. If the product is sticky and multiple micronizations are utilized, the carry over will be larger and less controlled with regards to its PSD and age distribution.

Another interesting topic mentioned in the guideline is the conditioning step:

“This recrystallization of micronized material could lead to uncontrolled particle growth, thereby affecting the MDI or DPI product CQAs (e.g., APSD, DDU). Therefore, a conditioning step should be considered following micronization to allow conversion of amorphous to crystalline form under controlled conditions of temperature and humidity.” (p. 10)

Conditioning is a step where after micronization, the material is left for a period of time to relax and re-crystallize. This time could be even 1 month. Only then the material is released and used in formulation. Conditioning is a time-consuming step that has implications on the supply chain.

To summarize, how would the guidelines affect API vendors and inhalation therapy makers?

API vendors Should be prepared for more scrutiny from customers of respiratory drugs, compared to manufacturers of other dose forms. The API vendors should get used to look at micronization step in “pharmaceutical” eyes: implementing pharma-level standards for process development and controls. Such standards could include:

  • Investment in micronization technologies that eliminate the need for multiple micronization and conditioning.

  • Perform a thorough development process for micronization step including Quality-By-Design (QBD) approach: identification of Critical Quality Attributes (CQA) and the derived Critical Process Parameters; perform Design Of Experiment (DOE) to explore the optimal range of parameters.

  • Upgrade manufacturing controls to include proper monitoring and recording of critical process parameters. Such advanced controls could include:

- Loss-in-weight feeders that compensate for variations in density of feed material

- In-line or at-line PSD measurement that can improve in-batch and between-batch consistency

Manufacturers of inhalation dose-forms should look carefully at the micronization step:

  • Work with the API vendor/contract micronizer company to carefully characterize all Critical quality attributes, including morphology, crystallinity, PSD, flow properties and cohesiveness. These should be measured in a reproducible and recordable manner that the vendor could incorporate into their QC producers. Yet, one should avoid specifications that are too restrictive or difficult to measure on a routine basis.

  • Allocate material and time to perform Proper process development, including DOE. The meaning is, to allocate material from few API batches to perform micronization at chosen process parameters according to a DOE plan.

  • Look “under the hood” of the micronization process: pay attention to material build-up, cleaning procedures and carry-over between micronization cycles and between batches.

  • Consider performing the micronization inhouse. This has various benefits:

- Full control over process development and product quality

- Larger selection of API vendors, as some vendors do not micronize their products

- Better control over supply chain and shelf life, especially if a conditioning step is required.

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