# Presentation: 114763

## DIFFICULTIES ASSOCIATED WITH COMPOUNDING METERED-DOSE INHALERS AND DRY POWDER INHALERS 

***DIFFICULTIES ASSOCIATED WITH COMPOUNDING METERED-DOSE INHALERS AND DRY POWDER INHALERS***** **

- Brian Rogers, Ph.D.
- Office of New Drug Chemistry
- Center for Drug Evaluation and Research
- Food and Drug Administration
- Rockville, Maryland

- Pharmacy Compounding Advisory Committee
- July 13-14, 2000

**Notes:**
Brian Rogers, Ph.D.
Office of New Drug Chemistry
Center for Drug Evaluation and Research
Food and Drug Administration

DIFFICULTIES ASSOCIATED WITH COMPOUNDING METERED-DOSE INHALERS AND DRY POWDER INHALERS

## Background

**Metered Dose Inhalers (MDIs)**
- Pressurized system
- Contains liquefied gas (propellant)
- Propellant suspends drug substance
- Provides energy
- Surfactant - stabilize suspension formulation
- Co-solvents - formulation aid
- Dispense micrograms to milligrams API per actuation
- Small precise volume delivered (25 - 100 L)

**Notes:**
Metered Dose Inhalers (MDIs)
Pressurized system containing a liquefied gas, the propellant
The propellant suspends the micronized drug substance and provides energy to both propel and disperse the drug substance in metered doses
Generally, surfactants are used to stabilize a suspension formulation
Co-solvents may be present to aid in formulating
MDIs may dispense from a few micrograms to milligrams of the drug substance per actuation
The volume of formulation delivered by the valve is typically 
25 - 100 L per actuation

## Background

**Metered Dose Inhalers (MDIs)**
- Sequence of events:
- Formulation expelled from valve
- Liquefied gas vaporizes
- Propelling and dispersing drug substance
- Dispersed drug substance characterization
- Particle size distribution (PSD)
- Dose content distribution (dose content uniformity)

**Notes:**
Metered Dose Inhalers (MDIs)
Once the specified quantity of formulation is expelled from the valve, the liquefied gas vaporizes, both propelling and dispersing the suspended or dissolved drug substance, along with any non-volatile excipients 
The dispersed drug substance in a discrete actuation contains a range of particle sizes characterized by a size distribution (PSD) 
Also, the distribution of the drug substance mass per minimum dose is characterized by dose content uniformity.

## Background

**Dry Powder Inhalers (DPIs)**
- Contains micronized drug substance with or without carrier
- Lactose - most common carrier
- Energy supplied by:
- Patient inspiration
- Compressed gas
- Motor-driven impeller
- Current designs
- Pre-metered
- Device-metered

**Notes:**
Dry Powder Inhalers (DPIs)
Dry powder inhalers contain a micronized drug substance with or without carrier with lactose being the most common carrier 
Energy for dispersion of particles is supplied by patient inspiration, compressed gas, or from a motor-driven impeller 
Current designs include pre-metered and device-metered DPIs

## BackgroundDPI Current Designs

**INHALATION POWDERS (DPIs)**
**Patient-Driven or Power-Assisted**

**PRE-METERED**
**DOSE**

**DEVICE-METERED**
**DOSE**

**DIRECT**

**TRANSFER**

**SINGLE DOSE**

**MULTIPLE DOSE**

**Notes:**
This slide shows the various designs of DPIs currently available

The device may have its formulation dispersed by the patient’s energy of inhalation, or by some form of internal power source such as a motor-powered fan or compressed air 
These two types may be further subdivided by whether or not the device has an internal metering process or is the dose pre-metered as in a blister or a capsule 
The pre-metered type of DPI can either have the dose removed directly from its container, or the dose can be transferred to a holding cavity for later inhalation.  The device-metered DPI generally has the dose transferred to a holding chamber. 
The pre-metered type of device may contain either single or multiple doses.  The device-metered DPI is exclusively multiple-dose in character.

## Background

**Dry Powder Inhalers (DPIs)**
- Further interactions - drug substance, carriers, and components of the container/closure system.
- Gravitational
- Fluid dynamic
- Electrostatic
- Van der Waals
- Capillary forces
- Responsible for differences in fluidization behaviors

**Notes:**
Dry Powder Inhalers (DPIs)
In addition to dose measurement and particle size issues, further complex and subtle interactions may occur between the drug substance, carriers, and components of the container/closure system. 
These may include gravitational, fluid dynamic, and other interactive forces, such as electrostatic, van der Waals, and capillary forces 
Together, these forces are responsible for the differences in fluidization behaviors exhibited by different powders in an inhaler.  It is critical to have a precisely reproducible formulation to obtain device-to-device and batch-to-batch reproducibility.

## Background

**General Concepts for MDIs and DPIs**
- Aerodynamic particle size - Affects deposition
- Smaller particles - greater airway penetration
- Patients need fine particles (< 5 m)
- Effective particle sizes - narrow range
- Larger particles
- Systemic exposure only
- No clinical benefit
- Classical BE and BA are usually not applicable
- Dose too small for blood analysis
- BE studies hindered
- 85 - 90% of dose absorbed through GI tract

**Notes:**
General Concepts for MDIs and DPIs
The aerodynamic particle size of the inhaled particles containing the drug substance affects the point of deposition in the airways.  
Normally, the smaller the particles, the greater the penetration into the lungs
Patients need to inhale drug substance particles generally less than 5 m in diameter to be effective in treating diseases of the airways (for example asthma)
The range of effective particle sizes is narrow with larger particles only contributing to systemic exposure and contribute no clinical benefit. 
Unlike other conventional drug products, they are highly dependent on their particle size distribution for their effectiveness and safety
Concepts of classical BE and BA are usually not applicable
Bioavailability is difficult to determine since the dose is too small for blood analysis
Bioequivalence studies are hindered by having 85 - 90% of dose absorbed through the GI tract instead of the biological target

## Difficulties in Compounding

**Drug Delivery System**
- Dosing and performance
- Design
- Reproducibility
- Performance characteristics
- Affects safety and efficacy
- Formulation compatibility
- Metering valve
- Canister lining - corrosion of underlying metal
- Drug absorption into plastic components
- Swelling
- Leaching

**Notes:**
Drug Delivery System
Dosing and performance and thus safety and efficacy are directly dependent on design, reproducibility, and performance characteristics of the container and closure system 
The most important dosing and performance characteristics are particle size distribution and dose content uniformity. 
Both the metering valve and any canister lining must be compatible with the formulation 
A canister lining should be proven to not have pin holes.  Pin holes or porosity in the lining will allow corrosion of the canister metal by reaction of the underlying metal with components of the formulation 
There is also a definite potential for absorption of drug into plastic components.  Absorption may also cause swelling of elastomers. Extraction of plastic and elastomeric components by the formulation may result in leaching of carcinogens or compounds that patients are sensitive to.

## MDI COMPONENTS - Canister and Actuators

**Notes:**
Here is a couple of versions of actuators. 
This is an actuator designed to be used with an integral spacer which is not shown 
The other on the right is a standard acutator which is not specifically designed to be used with a spacer. 
Above the actuator is a canister with the valve stem and ferrule showing here.  The canister fits in the actuator with the valve stem seating here. Inside the canister is the valve and the formulation. 
When the canister is depressed the pressurized formulation is released and jets out of the orifice here, more or less perpendicular to the valve stem.

## MDI COMPONENTS - Metering Valve

**Notes:**
This is a diagram of a typical MDI valve in a relaxed or pre-actuation configuration.
As you can see, a valve is very complex with many of the components interacting with and depending on one another.  Any changes to a valve will likely cause changes in the performance characteristics.
The parts of the valve are housing body, the seals, the ferrule, the stem, and the metering chamber etc.
In the rest position, as shown here, the metering chamber is full and in contact with the bulk formulation.
Once the canister is depressed to actuate the device, the stem is moved inward and the metering chamber is removed from contact with the formulation.  After this happens, this hole in the stem intrudes on the metering chamber and the compressed formulation in the metering chamber is allowed to expand into the stem and thus through the orifice in the actuator.

## Difficulties in Compounding

**Drug Delivery System**
- Actuator function
- Generates aerosol particles
- Directs plume
- Influences velocity
- Controls medication delivered
- Controls particle size distribution
- Valve function
- Measure formulation
- Provide leak-proof seal

**Notes:**
Drug Delivery System

The function of the actuator is to generates aerosol particles, direct the dose, influence the velocity of aerosol, control amount of medication delivered, and the particle size distribution available to patient 
The valve precisely measures the formulation volume and provides a leak-proof seal to prevent changes in the formulation concentration.

##  DISKUS DPI CROSS-SECTION

**Notes:**
Here is a diagram of a typical dry powder inhaler.  The one shown here is of only average complexity relative to others we have seen.
This DPI is a pre-metered multi-dose unit.
It has the formulation inserted into individual blisters on a strip coiled around this wheel at the bottom.
When the dose is desired, the strip of blisters is advanced along this route here and just prior to the point of airflow, the backing of the strip is removed and coiled around this wheel, exposing the formulation to the passage the inhaled air will pass through. Once the dose is exposed, the patient places the device in his or her mouth and inhales, dispersing the powder in the airflow.  The used blister strip is coiled around this wheel here.
The complexity of this device and the strict requirements for formulating the blisters makes any modifications to the device or the formulation problematic for dose reproducibility.

## Difficulties in Compounding

**Drug Delivery System**
- Sophisticated and complex
- Crucial to drug dosing accuracy and reproducibility
- Direct effect on potency, purity, and quality
- Indirectly affects safety and effectiveness

**Notes:**
Drug Delivery System
In conclusion, the MDI and DPI drug delivery systems are sophisticated and complex. Precise formulating is crucial to drug dosing accuracy and reproducibility from the standpoint of both dose uniformity and particle size distribution

Container and closure components directly affect potency, purity, and quality of drug product, hence safety and effectiveness of the product 

## Difficulties in Compounding

**Drug Formulation and Consistency**
- Mixture of micronized or solubilized drug substance in matrix of oily excipient material, propellant, and possibly a co-solvent
- Composition and physical chemical properties of each component is crucial to performance.
- Composition has direct effect on extent of agglomeration and suspension stability

**Notes:**
In the interest of time, I have chosen to focus on the complexity of compounding MDIs.  However, the issues are equally applicable (with some obvious exceptions pertaining to liquid formulations) to DPIs

Drug Formulation and Consistency
The formulation in an MDI is a mixture of micronized or solubilized drug substance in matrix of oily excipient material, propellant, and possibly a co-solvent 
The composition and physical chemical properties of each component is crucial to performance. 
Also, the composition has direct effect on extent of agglomeration and suspension stability

## Difficulties in Compounding

**Drug Formulation and Consistency**
- Important drug substance properties:
- particle size distribution
- particle morphology
- solvates and hydrates
- clathrates
- morphic forms
- amorphous character
- solubility profile
- moisture and/or residual solvent content
- microbial quality
- pH profile (pKa)
- specific rotation
- All of the above properties must be controlled during production

**Notes:**
Drug Formulation and Consistency
Important drug substance properties which must be controlled during compounding include:
particle size distribution
particle morphology
solvates and hydrates
clathrates
morphic forms
amorphous character
solubility profile
moisture and/or residual solvent content
microbial quality
pH profile (pKa)
specific rotation

## Difficulties in Compounding

**Drug Formulation and Consistency**
- Important aspects of formulation liquid phase:
- Propellant, co-solvent, surfactant identity, concentration, and quality
- Relative proportions of volatile components influence pressure
- Polarity, surface tension, and density are critical properties

**Notes:**
Drug Formulation and Consistency
Important aspects of the formulation liquid phase include: 
Propellant identity, presence of a co-solvent, surfactant identity, concentration, and quality 
Relative proportions of the volatile components influence the internal canister pressure 
Important physical chemical properties of the formulation include: Polarity, surface tension, and density.  These all affect the suspension characteristics of a suspension formulation. 

## Difficulties in Compounding

**Drug Formulation and Consistency**
- Factors adversely affecting formulation physical stability:
- Preferential interaction of suspended drug substance with container components
- Settling and creaming resulting from differential densities
- Less homogeneous suspension - inconsistent dose delivery and particle size distribution
- Beginning- to end-of-canister variability
- Canister-to-canister variability
- Batch-to-batch variability
- Properties of liquid phase need to be optimized to minimize the above effects

**Notes:**
Drug Formulation and Consistency
Factors adversely affecting the formulation’s physical stability include:
Preferential interaction of suspended drug substance with container components
Settling and creaming resulting from differential densities 
Above factors result in a  less homogeneous suspension and thus inconsistent dose delivery and particle size distribution.  These inconsistencies are seen in 
Beginning- to end-of-canister variability
Canister-to-canister variability and
Batch-to-batch variability
Properties of liquid phase need to be carefully optimized and controlled to minimize the above effects

## Difficulties in Compounding

**Drug Formulation and Consistency**
- Formulation components
- Require very careful control of impurities and degradation products
- Minor change in concentration or dose - large change in toxicological properties
- Montreal Protocol - CFC Propellants
- Formulation of MDIs and DPIs
- Complex composition and high overall complexity
- Require dedicated manufacturing environment
- Product-to-product uniformity
- Critical for dosing accuracy
- Difficult to achieve
- Necessary for maintaining safety and efficacy

**Notes:**
Drug Formulation and Consistency
The individual formulation components require very careful control of impurities and degradation products
Minor changes in concentration or dose of excipient can result in large changes in toxicological properties
Very careful control of impurities and degradation products in all formulation components is required to prevent possible bronchospasm in lungs of sensitive patients
As a result of the Montreal Protocol, CFC propellants are becoming very difficult to obtain in acceptable purity. Tight controls on purity need to be implemented to assure drug product quality.
As a result, the composition of the formulation and complexity of this dosage form makes it very difficult to formulate outside of a dedicated manufacturing  environment.
Minimizing product-to-product variability, that is obtaining the best possible dosing accuracy is necessary for maintaining safety and efficacy.

## Difficulties in Compounding

**Complexity of Compounding**
- Multiple, complicated and interrelated steps
- Significant potential for error
- Formulation
- Container and closure system design and performance characteristics
- Internal temperature control
- Monitor and control external environmental conditions
- Manufacturing parameters
- Assay of concentrate
- Pressure filling
- In-line heating
- Aging

**Notes:**
Complexity of Compounding
Compounding requires multiple, complicated and interrelated steps.  In each of these, there is a significant potential for error. 
The formulation must be carefully handled, mixed, dispensed and so on.
The container and closure system design and performance characteristics are critical and require careful assembly
Temperature control at well-controlled sub-freezing temperatures are necessary for certain stages of compounding
At all times during compounding, environmental conditions such as temperature, humidity, etc. must be carefully monitored and controlled.
Manufacturing parameters such as assay of concentrate, pressure fill, in-line heating, aging, etc. add considerable complexity to the compounding process
It is important to remember that even the simplest type of DPI requires complex formulation development to ensure accurate and reproducible dose delivery.  

## Difficulties in Compounding

**Complexity of Compounding**
- Errors - high potential to adversely affect safety and/or effectiveness
- Careful control critical for:
- Dosing reproducibility
- Performance
- Stability
- Bioavailability

**Notes:**
Complexity of Compounding
Errors in compounding have a high potential to adversely affect safety and/or effectiveness

All of the above need to be carefully controlled to ensure dosing reproducibility, performance, stability and bioavailability 
Where the concept of dosing reproducibility applies equally to the dose content uniformity and particle size distribution of the active

## Difficulties in Compounding

**Facilities and Equipment**
- Complex formulation and container and closure system
- Stringent environmental controls required
- Air cleanliness
- Humidity
- Temperature
- High temperatures or humidity
- Disruptive to particle size distribution
- Resulted in recalls of commercial products
- Sophisticated equipment required
- Crimper
- Pressure filler
- Propellant pump
- Precise product filler

**Notes:**
Facilities and Equipment
The complex formulation and container/closure system require extensive manufacturing controls
Stringent environmental controls are required for air cleanliness, humidity, and temperature
Temporary exposure to high temperatures or humidity can disrupt the particle size distribution - 
Exposure to high temperatures has resulted in recalls of commercial products
Some sophisticated equipment required include
Crimper
Pressure filler
Propellant pump
Precision product filler

## Difficulties in Compounding

**Training**
- Training required for production and quality assurance
- Special formulation requirements
- Critical attributes of container and closure system
- Lack of proper training in formulating requirements may affect all aspects of product performance
- Inadequate training in quality assurance will prevent timely detection of formulation errors.

**Notes:**
Training
Special formulation requirements and attributes of the container/closure system necessitate specialized technical training for both production and quality assurance
Lack of proper training in manufacturing requirements may affect all aspects of product performance
Inadequate training in quality assurance will prevent detection of production errors.

## Difficulties in Compounding

**Testing**
**Examples of complex tests necessary to ensure product quality:**
- Particle size distribution
- Moisture content
- Leak rate
- Leachables
- Microbial limits

**Notes:**
Testing
Examples of complex tests which are necessary to ensure product quality include:
Particle size distribution
Moisture content
Leak rate
Leachables
Microbial limits

## Difficulties in Compounding

**Testing**
**Particle size distribution - Cascade impactor**
- More critical for MDIs and DPIs
- Not solely determined by initial drug substance particles
- Change in PSD
- Decrease in efficacy
- Increase in systemic exposure
- Critical independent variables - complex
- Formulation
- Valve
- Mouthpiece
- Inability to meet particle size distribution specifications has resulted in product recalls

**Notes:**
Particle size distribution,  
This is usually performed on a cascade impactor 
More critical for MDI and DPI than most other conventional dosage forms and not solely determined by the size of drug substance particles initially suspended in the formulation 
Change in the PSD may lead to a decrease in efficacy and an increase in systemic exposure 
It is critically dependent on formulation, valve, and mouthpiece 
The inability to meet particle size distribution specifications has resulted in product recalls

## Difficulties in Compounding

**Testing**
**Moisture Content**
- Most critical for MDI suspension formulations and for DPIs
- Strict limits needed to prevent changes
- Particle size distribution
- Morphic form
- Crystal growth and aggregation
**Leak Rate**
- Affects internal canister pressure
- Influences performance of actuator and valve
- Delivery of the proper dose to the patient
- Leakage may influence formulation composition
- Change particle size distribution and/or dose content uniformity
- Failure to meet specifications have resulted in product recalls

**Notes:**
Moisture Content
Most critical for MDI suspension formulations and for DPIs
Strict limits are needed to prevent changes in, for example, particle size distribution, morphic form, crystal growth and aggregation

Leak Rate
Canister pressure directly influences the performance of the actuator and valve - thus the delivery of the proper dose to the patient
Leakage of the propellant may be great enough to influence the composition of the formulation and change PSD and/or dose content uniformity
Failure to meet leak rate specifications have resulted in recalls of commercial drug products

## Difficulties in Compounding

**Testing**
**Leachables**
- Compounds extracted into formulation from
- Elastomers
- Plastic components
- Requires identification and quantitation
- Concentration profile established
- Make evident undisclosed changes

**Notes:**
Leachables 
The liquid formulation extracts compounds from elastomeric and plastic components  
Identification and quantitation of potential leachables are necessary 
A concentration profile of leachables in the formulation must be established for each drug product to prevent undisclosed changes to the container/closure components

## Difficulties in Compounding

**Testing**
- Microbial Limits
- Total aerobic count
- Total yeast and mold count
- Freedom from pathogens
- Additional testing is necessary for product development
- Ensure formulation does not support microbial growth
- Microbial quality is maintained throughout the expiration dating period

**Notes:**
Testing of Microbial content include testing for
Total aerobic count
Total yeast and mold count
and assuring freedom from pathogens
Additional testing is necessary to ensure the formulation does not support the growth of microorganisms and the microbial quality is maintained throughout the expiration dating period

## Conclusion

- Because of the above complex and necessary criteria for compounding, MDI and DPI drug products present demonstrable difficulties in this endeavor
- These difficulties would likely have an adverse effect on the safety and effectiveness of such drug products.

**Notes:**
Because of the above complex and necessary criteria for compounding, MDI and DPI drug products clearly present demonstrable difficulties in this endeavor 
These difficulties would likely have an adverse effect on the safety and effectiveness of such drug products.

## Conclusion

- Difficulties in compounding result from the following characteristics and requirements:
- Sophisticated drug delivery systems
- Require extensive development
- Dosing accuracy (dose uniformity and particle size distribution)
- Reproducibility of delivered dose
- Product-to-product uniformity critical - difficult to achieve
- Reproducible bioavailability - difficult to achieve
- Sophisticated formulation required
- Compounding of MDI and DPI products - complex
- Sophisticated facilities and equipment required
- Specialized technical training essential
- Difficult to perform testing required

**Notes:**
Difficulties in compounding result from the following characteristics and requirements:
MDIs and DPIs are sophisticated drug delivery systems that require extensive development to ensure dosing accuracy and reproducibility.
Precise dosing  must be achieved by accurate and reproducible delivery of both mass and particle size distribution of the active.
A sophisticated formulation of the drug product is required to ensure dosing accuracy and reproducibility.  Product-to-product uniformity is critical for dosing accuracy and is usually difficult to achieve
Reproducible bioavailability of the compounded drug product is difficult to achieve
Compounding of MDI and DPI products is complex
Sophisticated facilities and equipment are required to ensure proper compounding of the drug product 
Specialized technical training is essential to ensure proper compounding
Sophisticated and difficult to perform testing is required to ensure potency and purity