# Presentation: 330436

## Inhalation Drug Products in LDPE Containers:A Quality (CMC) Perspective

**Vibhakar Shah, Ph.D.**
**Pulmonary and Allergy Drug Products**
**Division of New Drug Chemistry II**
**Office of New Drug Chemistry, OPS, CDER, FDA**

## Outline

**Inhalation Drug Products**
**Container-Closure System Overview**
**FDA Analytical Survey and Other Data**
**Quality Concerns **
**Potential Approaches**
**Recommendations for Packaging**
**Summary**

## Inhalation Drug Products

**Inhalation Solution**
**Inhalation Suspension**
- Inhalation Spray
- Solution
- Suspension
- Inhalation Aerosol (Metered Dose Inhaler)
- Solution
- Suspension
- Inhalation Powder (Drug Powder Inhaler)

## Drug Product Examples

- Albuterol SO4 Inhalation Solution
- Levalbuterol HCl Inhalation Solution
- Ipratropium Br Inhalation Solution
- Albuterol SO4 and Ipratropium Br Inhalation Solution
- Metaproterenol SO4 Inhalation Solution
- Cromolyn Na Inhalation Solution
- Budesonide Inhalation Suspension
- Tobramycin Inhalation Solution

## Current Container-Closure System

**Inhalation Solution and Suspensions**:
- Unit-Dose containers/Vials (UDV)
- LDPE vials
- Blow-Fill-Seal/Form-Fill-Seal Process
- Vial label
- Emboss, Deboss
- Self-adhesive Paper label
- Foil overwrap pouch (1, 4, 5, 12 vials/pouch)
- Pre-printed
- Self-adhesive Paper label

## Container-Closure Components LDPE vialPaper labelFoil-laminate

## LDPE Characteristics

- Low density polyethylene (LDPE) is a polyethylene homo-polymer resin:
- 			   **– ****[– CH****2**** – CH****2**** –]****n**** –**
- Resin Components:
- Reactant monomer, Chain transfer agent, Chain initiator, Antioxidant, Stabilizers, Slip Additive, Superfloss Antiblock additive
- Different grades for different applications
- Many sources: Manufacturers, suppliers

## LDPE Vial Properties 

- Flexible and malleable
- Stress crack, impact and tear resistant
- Considered chemically inert at room temperature
- May be usable up to 80°C for extended periods
- Sterilizable
- Amenable to high speed production lines
- Aesthetically, clear to translucent to opaque
**Permeable** to volatile chemicals and gases

## Container-Closure Components LDPE vialPaper labelFoil-laminate

## Typical Paper label Components

- Calcium Carbonate
- Kaolin Clay
- Ethylated Corn Starch
- Cationic Potato Starch
- Sodium Bicarbonate
- AKD
- Colloidal Silica
- Liquid Alum
- Latex Calcium
- Stearate

- Viscosity Modifier
- Polyvinyl Alcohol
- Ammonium Zirconium Carbonate
- Carboxymethylcellulose
- Dispersant
- Microbiocide
- Fluorescent Dye
- Pigment Dye

## Typical Adhesive Components

- Aromatic C5 hydrocarbon resin
- Polymeric hindered phenol (Anti-oxidant)
- Diastearyl pentaerythrotol diphosphate (Anti-oxidant)
- Styrene-isoprene-styrene block polymer,
- Naphthenic Oil
- Liquid C5 hydrocarbon resin

## Typical Over-lacquer Components

- Joncryl 60, 89, 624
- Wax dispersions (e.g., Liquitron 345)
- Defomers (e.g., Tego Foamex 1488)
- Non silicone Defomers (e.g., Nopco NDW)
- Grease resistant coating Agents (e.g., Scotchban FC-807)
- PTFE Dispersions (e.g., Fluotron 300)

- Slip Additives (e.g., Dow 51 Additive
- Lucidene 614
- Morcryl 360
- Surfactants (e.g., Aerosol OT-75)
- Syloid silicas
- Methyl-n-2-pyrrolidone
- Aqua Ammonia
- Normal propanol
- Water

## Typical Ink Components

- Acrylic resin
- Styrene acrylic polymers
- Surfactant
- Cellulosic defoamer
- Maleic resin chip
- Pigment Dyes:
- Carbazole violet 23
- Phthalocyanine blue
- Phthalocyanine green 7

- Pigment Dyes:
- Red 238
- Violet 23
- Black 7
- Yellow 74
- Green 7
- Blue 15
- Red 57
- Violet 3

## Container-Closure Components LDPE vialPaper labelFoil-laminate

## Typical Foil-laminate Components

**A = Exterior layer Polyester/PP/PE**
**	****(0.00048 inch)**
**B = Inks**
**C = Adhesive1**

**E = ****	****Adhesive2**
**F = ****	****Nylon/Polyester/ PP/PE(0.001 inch) **
**G = ****	****Adhesive3**
**H = ****	****Interior layer Polyester/PP/PE (0.003 inch)**

**D = Aluminum Foil**** **
**(0.00035 inch)**

## LDPE Vial Permeability: Implications

- Contamination of drug product with ingress of volatile chemicals from the environment that may be irritants or toxic to the respiratory tract, and may sensitize individuals.
- Degradation of the drug products in LDPE vials by reactive gases and light.
- Water evaporation through LDPE vials, altering the concentration of drug product in LDPE vials.
- Potential acceleration of drug product degradation (impurities) due to change in drug concentration.

## FDA Analytical Survey andOther Supportive Data

## FDA Analytical Survey

- Initiated by OGD & DPADP/OND in coordination with OC/ORA Field Offices and Pacific Regional Laboratory.
- 7 ANDAs and 1 NDA for Inhalation solutions covering five different _[drug substances](slide4.xml)__._
- 38 samples representing 37 Lots of various drug products in LDPE vials without a protective overwrap foil-pouch.
- Samples screened for potential volatile chemicals such as *vanillin, 2-phenoxyethanol, and 1-phenoxy-2-propanol *by GC-MS (sensitivity ~ 0.5 ppm) and HPLC methods.

## FDA Analytical Survey: Results

**29** out of **38** samples tested positive for chemical contamination originating from packaging.
- Detected **5** known chemical contaminants originating from packaging.
*Benzophenone (2 lots)*
*Polyethylene glycols (n = 4 -8), (3 lots)*
*2-(2-Butoxyethoxy)ethanol (DEGBE), (24 lots)*
*2-(2-Ethoxyethoxy)ethanol acetate (DEGEEA), (3 lots)*
*2-Hydroxy-2-methylpropiophenone (2-HMPP), (5 lots)*

## FDA Analytical Survey: Conclusion

- Potential for these chemicals to cause bronchospasm at levels detected is unknown, especially, in patients with respiratory diseases.
- Concentration of these chemicals might be greater at the end of expiry than what was detected.
- Ingress/Leaching of chemical contaminants into drug product formulations from packaging components demonstrates that **permeation** through LDPE is a real phenomenon.
- Additional chemicals may be present, but may not get detected by the analytical procedures used.
- Future changes in the materials used in labeling and packaging may result in contamination with different chemicals.

## Typical Sources of Product Contamination

**Formulation components (Degradation)**
- Drug substance, excipients, formulation vehicle
**Resin components (Leaching)**
- Monomer, dimer, antioxidants, plasticizers, catalysts etc.,
**Paper label components (Leaching)**
- Paper, adhesive, varnish/over lacquer, inks, residual volatile solvents
**Foil overwrap components (Leaching)**
- Adhesive, residual volatile solvents
**Cartons (Leaching)**
- Adhesive, residual volatile solvents
**Environment (Leaching)**
- Reactive gases, volatile pollutants

## Extractable/Leachable: Examples

**Resin components**
- Irganox 129, 2, 2, 6-trimethyloctane
**Paper label components**
- Benzoic acid, ethyl phthalate, benzophenone, Danocur 1173, cyclic phthalates
**Foil overwrap components (Leaching)**
- Methacrylic acid, 2-phenoxyethanol
- Acetone, 2-butanone, ethylacetate, propylacetate, heptane, toluene
**Cartons (Leaching)**
- Methacrylic acid, 1-phenoxy-2-propanol

## Quality Concerns

- Proprietary components and composition of packaging materials.
- Change in the components and composition of these materials without the knowledge of applicant and the Agency.
- No one analytical procedure to detect known/unknown chemical contaminants.
- Incomplete toxicological data for many of the identified chemical contaminants.
- Variable environmental conditions may introduce new contaminants.

## PotentialApproaches

## Agency’s Quality Control Approach

- Characterize/Identify all possible _[extractables](slide26.xml)_ and establish a profile for each packaging component (e.g., resin, vial, paper label, foil-laminate overwrap).
- Establish a correlation between *extractable* and its _[leachable](slide27.xml)_ potential.
- Set meaningful acceptance criterion for a given *extractable* in corresponding incoming packaging components, based on its _qualification_ level and actual observed data.
- Set meaningful acceptance criterion for a given *leachable* based on actual observed data in the drug product.

## Extractable & Extractable Profile

**Extractable** is a chemical compound (volatile, non-volatile) that gets extracted from a packaging component in a suitable solvent by utilizing optimum extraction conditions (time and temperature).
- Extractable profile for a given packaging component, typically can be a chromatogram (GC, HPLC, GC-MS, LC-MS) representing all possible extractables.
- Extractable profile is established for all packaging components (resin, vial, foil-laminate) for their consistent quality assurance.

## Leachable

**Leachable** is any chemical compound (volatile, non-volatile) that leaches into the drug product formulation either from a packaging component or local environment on storage (time and temperature) through expiry of the drug product.  An extractable can be a leachable.
- To ensure batch-to-batch consistency of the drug product, appropriate specification (test method, acceptance criteria) for a leachable is established based on its qualification (toxicity) and observed levels in the drug product on storage.

## Recommendations

## Recommendations

- Adequate knowledge of composition and physico-chemical properties of packaging components for appropriate selection.
- Resin components, foil-laminate, paper label, inks (aqueous vs. non-aqueous base), etc.
- Discourage paper label directly on the LDPE vial.
- Encourage alternative approaches, including embossing/debossing in lieu of the paper label on the LDPE Vial.
- Extended bottom flanges to UDV to carry essential vial labeling information and product identity.

## Recommendations

- Use of protective overwrap foil-pouch for the LDPE unit-dose vial (UDV)
- Can minimize ingress and leaching of chemical contaminants from the local environment.
- Self-adhesive paper label on a foil-pouch or pre-printed foil-pouch and different color schemes to differentiate multiple strengths of the drug product.
- Prevent ingress/leaching of chemical contaminants from paper labels and also improve the legibility issues.

## Recommendations

- Limit the number of unit-dose-vials per pouch, ideally to one LDPE vial per foil-pouch.
- Minimize the risk of medication error by patients and health care professionals
- Prevent unnecessary exposure to local environment (When compared to packaging of multi UDVs/Foil-pouch)

## Summary

- Volatile chemicals present in the packaging components and local environment have great potential to permeate through LDPE vials into drug product formulation on storage (time and temperature).
- Agency’s Analytical Survey and other supportive data have confirmed ingress/leaching of such volatile chemicals into the drug product formulations.

## Summary

- Ingress/leaching of such chemicals into drug product formulation poses a safety concern for patients with respiratory illness (Asthma, COPD).
- Embossing/debossing of LDPE vial in lieu of paper label is recognized to have legibility issue.
- Paper labels, although perceived to address legibility issue, overall may not be the **optimum** solution because of the safety concerns associated with potential leaching/ingress of paper label components in the drug product through LDPE vial.

## Summary

- Agency’s current recommendations as stated in the draft guidance may serve as a _first step_ in right direction to address the issues that are being discussed today.
- Agency is seeking other** **_viable_** **approaches to address these issues to promote safe product use without compromising the integrity of the drug product.

## Inhalation Drug Products in LDPE Containers:A Quality Perspective

**Thanks.**

## Blow-Fill-Seal (BFS) a.k.a Form-Fill-Seal (FFS) Process

## Blow-Fill-Seal / Form-Fill-Seal Processes

**Thermoplastic resin beads are pneumatically fed into the B/F/S machine. The beads enter an extruder where they are melted by heat generated by electric band heaters and physical compression. **
**The molten thermoplastic is then continuously extruded through an orifice in a tubular shape [parison, (A)].  **
**The machine simultaneously extrudes six parisons per machine cycle and forms/fills four vials per parison. Filtered ballooning air continuously passes through the formed parison to maintain its shape.  **

_**Extrusion**_

## Blow-Fill-Seal / Form-Fill-Seal Processes

**When the tube (parison) reaches the proper length, the main mold (B) closes and the parison is cut off at (C). **
**The bottom of the parison is pinched closed and the top is held open by a set of holding jaws (D). **
**Vacuum ports in the mold cavity walls activate to form the container. The mold then moves to a position under the filling nozzle.  **
**The filling nozzle (E) lowers Into the parison unit it forms a seal with the neck of the mold. **
**A metered amount of product is then transferred Into the container. **

_**Blow & Fill**_

## Blow-Fill-Seal / Form-Fill-Seal Processes

**When the container is filled, the filling nozzle retracts to its original position. **
**At this point in the cycle, the length of parison between the top of the mold and the holding jaws is still semi-molten. **
**A sealing mold (F) doses to form the top and hermetically seal the container. **
**Once the container is sealed, the sealing mold, main mold, and holding jaws open. A trim die removes residual plastic (G) and a formed, filled, and sealed container is conveyed out of the machine.**

_**Seal**_

## Drug Product Examples

- Albuterol SO4 Inhalation Solution (AccuNeb®, Proventil®, Ventolin®)
- Levalbuterol HCl Inhalation Solution (Xopenex®)
- Ipratropium Br Inhalation Solution (Atrovent®)
- Albuterol SO4/Ipratropium Br Inhalation Solution (DuoNeb®)
- Metaproterenol SO4 Inhalation Solution (Alupent®)
- Cromolyn Na Inhalation Solution (Intal®)
- Budesonide Inhalation Suspension (Pulmicort®)
- Tobramycin Inhalation Solution (Tobi®)