The impact of packing material on the stability of pharmaceutical products
What is the packaging?
Packaging is described as the collection of various components surrounding a pharmaceutical product from the moment it is manufactured until it is used.
The significance of packaging
(1) Guards against all extraneous influences that could affect the product’s qualities.
(2) Prevent biological contamination.
(3) Guard against physical damage.
(4) Carry the relevant product information and identification.
(5) Tamper evident / Child resistance / Anti-counterfeit.
What are the purposes of pharmaceutical packaging?
Containment of pharmaceutical products;
- To prevent leaks, diffusion, and permeation.
- Sufficient to hold the contents while being handled.
Protection of pharmaceutical products against;
- Biological contamination
- Mechanical damage
Ideal characteristics of pharmaceutical packaging materials
Pharmaceutical packaging material should consist of the following qualities for its effective use and to protect the product
- It must maintain and retain the physical qualities of all dosage forms against damage or breaking.
- It must not change the product’s identity.
- It must preserve the characteristic of the product to comply with specifications.
- It must safeguard the product against potentially harmful or adulterating chemical, biological, or physical elements.
How to choose the appropriate primary packing material for pharmaceutical formulations
Selection criteria for appropriate primary packing material for pharmaceutical formulations
The choice of primary packaging materials is mostly determined by the product qualities that require protection from certain climatic or atmospheric conditions.
Following are the conditions against those pharmaceutical products that might require protection.
Pharmaceutical product characteristics and sensitivity that may affect the product stability
- Chemical degradation
- Physical degradation
- Drug release properties
- Gas liberation tendency
- Mechanical properties
- Dimensional aspects
Following are key barrier requirements that help in selecting the packaging material for pharmaceutical products
- Moisture barrier requirements
- Chemical properties
- Light barrier requirements
- Gas barrier requirements
Choosing suitable polymers for blister packs
The industry offers a wide variety of packing materials with varying degrees of protection from various conditions. In a perfect world, packaging materials that meet all the requirements would be utilized to package pharmaceutical products. However, such an option might not be economical, and the patient would ultimately be responsible for paying the price.
The following table provides information to select the appropriate packaging material for pharmaceutical products having different protection levels.
|Materials of Construction/ Type||Important Properties||Area of use|
|PVC 200/ 250/ 350||Low barrier/ Simple unit pack/ Aesthetic||Stable products like Metformin, Co-trimoxazole, Paracetamol, some soft gelatin capsules etc.,|
|PVC/PVdC (250/40)||Low barrier however, better than PVC||Products not very sensitive to moisture, gases and with moderate self life for example – Multivitamin capsules and tablets|
|PVC/PVdC (250/60)/ (250/90)/ (250/120)||Good barrier||Moderate to high sensitive range of products, certain FDC/ Enzyme products|
|PVC/PE/PVdC (200/25/60)/ (250/25/90)(300/30/90)||Good barrier||Quite high sensitive range of products – 4 FDC (RHZE)|
|Ultrasafe Duplex||High barrier/ economical||Quite high sensitive range of products|
|Ultrasafe Triplex||High barrier/ economical||Quite high sensitive range of products|
|PVC/Aclar (10u to 100u)PVC/COC, PE/COC||Excellent barrier||Extremely moisture sensitive range of products|
|OPA/AI foil/PVC, Alu/Alu||Excellent barrier||Extremely sensitive range of products – Cefuroxime Axetil tablets, Levocetirizine Tablets|
|OPA/AI foil/PVC, Alu/Alu with desiccant||Excellent barrier||Extremely moisture sensitive range of products|
|Aluminium foil with HSL (Hard tempered) 0.02 / 0.025||Excellent barrier||Lidding foil for blister packing|
|Aluminium foil (Hard tempered with special coating)||Excellent barrier||Lidding foil for COC|
|Aluminium foil / poly (30-40 microns (soft tempered)||Excellent barrier||For strip packing use of very sensitive range of products – Omeprazole Capsules, Ranitidine Tablets etc.|
|Aluminum foil / VMCH (30 -40 microns (soft tempered)||Excellent barrier||For strip packing use of dark-colored sugar-coated tablets.|
|Paper /Poly||Very low barrier / Simple unit pack / Aesthetic look||Very economical pack for very stable products.|
|Paper/Al/HSL||Excellent barrier||For Child resistance blisters pack|
To have better visibility on Water Vapor Transmission Rate, the following information will be very helpful.
Comparative Water Vapor Transmission Rate (WVTR) values of various blister films on flat sheet (38 ° C/ 90% RH – g/m2/day)
|Materials of Construction / Type||WVTR values (g/m2/day)|
|PVC / PVdC (250/40)||0.75|
|PVC / PVdC (250/60)||0.5|
|PVC/10μ PCTFE (Aclar)||0.45|
|COC 190 μ||0.35|
|PVC/15μ PCTFE (Aclar)||0.36|
|PVC / PE / PVdC (250/25/90)||0.31|
|PVC/20μ PCTFE (Aclar)||0.27|
|COC 240 μ||0.28|
|COC 300 μ||0.23|
|PVC/23μ PCTFE (Aclar)||0.23|
|COC 350 μ||0.2|
|PVC/38μ PCTFE (Aclar)||0.15|
|PVC/51μ PCTFE (Aclar)||0.11|
|PVC/75μ PCTFE (Aclar)||0.08|
|PVC/102μ PCTFE (Aclar)||0.05|
|CFF (Alu/Alu) PVC/Alu45/OPA25||0|
Choosing suitable polymers for containers and closures system
Unlike the polymer used for the blisters, various materials are used for the container and closure system. The selection of those materials depends on the required protection for the product.
|Materials of Construction/ Type||Critical Properties||Area of use|
|HDPE container||Good barrier to moisture, gas, and light||All kinds of products from solid orals and dry syrup.|
|PET / PP (Amber)||Moderate barrier||Light sensitive products|
|Glass Bottles||High barrier||For highly sensitive products|
|Glass vials (USP I and II)||High barrier||For injectables product|
|Glass bottles and vials (USP type III)||High barrier||Dry syrup, suspensions and powder for injection.|
|Surface coated vials||High barrier||Sensitive products|
|Pre-filled syringe (PFS) made up of glass/ PE||Moderate to high||For unit dose injectables|
|Rubber stopper, natural rubber butyl, Halobutyl.||Chemical resistant, low permeability, low water/solvent||Injectable products|
|Rubber stopper, natural rubber butyl, Halobutyl (legged and slotted)||Chemical resistant, low permeability, low water/solvent||Lyo injectable products|
|Desiccant1. Silicagel bags (Tyvek packs and canisters)2. Activated Carbon3. Molecular sieves||Desiccant will effectively alleviate moisture and odor problems.||1. Moisture-sensitive products2. Product release odor/ gas3. Highly moisture-sensitive products|
Comparision of these materials are done based on the comparison of OxygenTransmission Rate (OTR) values. Oxygen Transmission Rate (OTR) is the steady-state rate at which oxygen gas permeates through a film at a given temperature and relative humidity.
Following are the OTR of the generally used material of construction (MoC) of the container closure system used in the packaging of pharmaceutical products.
|Materials of Construction / Type||OTR values (g.mm/(m2/day))|
Brief about the property and use of desiccants
- Desiccants have been utilized to control the exposure of products to the ingress of moisture.
- Desiccants vary in their capacity and the rate at which they adsorb/absorb ingressed moisture.
- Silica gel is very efficient at absorbing moisture at high relative humidity but comparatively poor at lower Relative Humidity.
- Molecular sieve desiccants – the opposite scenario prevails. Consequently, the more molecular sieve is required at higher relative humidity, the greater the handling precautions required during packaging operations.
- Based on the calculated WVTR of known container components and the rate of moisture adsorbed by desiccants, the amount of desiccant that would be required to maintain a specified relative humidity over the product’s shelf-life can be determined and used.
Testing of packaging materials and their stability
Similar to the incoming raw material, it is vital to test the primary packaging material that is going to be used for the packaging of pharmaceutical products. Primary packaging material quality has a direct impact on the product’s quality and shelf life. The following are critical parameters that are required to be verified or tested before selecting it as pharmaceutical packaging.
Critical parameters during screening and for selection as primary packaging material for the pharmaceutical products
- Degradation of packaging components in contact with pharmaceutical products.
- Release of visible and/or sub-visible particles.
- Chemical reaction between pharmaceutical product and packaging material.
- Adsorption or absorption of pharmaceutical components by packaging material.
- Influence of manufacturing process on the container.
- Release of chemicals from components of packaging material.
Quality Control (QC) test for primary packing material for routine analysis as part of incoming material testing
The Quality Control test for primary packing material for routine analysis varies according to the material used. Following are a few examples of QC tests carried out as part of incoming material testing.
- Visual inspection
- Identification test
- Dimensional test
- Physical tests
- Chemical tests
- Microbiological tests
Additional tests that can be performed as part of QC testing (frequency based/ skip lot testing)
- What needs to be looked at in WVTR (Water Vapour Transmission Rate)
- Flat film
- Formed blister
- OxygenTransmission Rate (OTR)
- Extractables and Leachables
- Periodic review and re-qualification in case of major change and source change
Impact of pack integrity failure on pharmaceutical product quality
If the seal integrity at the interface of an impervious container closing system fails, moisture, oxygen, or microbiological contamination may enter and influence the stability of the drug product.
Following are a few examples that have an impact on pharmaceutical product quality because of the pack integrity issues.
- Blsyter cavity forming can have impact on WVTR
- Blister sealing pressure, temperature, and dwell time have a direct impact on the permeability
- Bottle sealing temperature, toque, and dwell time have a direct impact on the filled product
Commonly performed pack integrity testing for the pharmaceutical products
Following are various types of integrity testing that are used to carryout for the pharmaceutical product pack integrity testing.
Bubble test: Applicable for Blister/ strip pack, liquid bottles/ cap, etc.
Pressure decay test: Applicable for Vials, Ampoules, Blisters, Pouches, IV bags, etc.
Vacuum decay test: Applicable for Vials, Ampoules, etc.
Regulatory References to help select packaging materials for pharmaceutical products
i. US – Guidance for Industry, Container Closure Systems for Packaging of Human Drugs and Biologics
Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics
ii. Europe – CPMP/QWP/4359/03 – Guideline on Plastic Immediate Packaging Materials – specific to plastics only