CRITICAL SELECTION OF PRIMARY PACKAGING. Shams Rustom Labopharm Sr. Director, Product Development & Manufacturing

Transcription

1 CRITICAL SELECTION OF PRIMARY PACKAGING Shams Rustom Labopharm Sr. Director, Product Development & Manufacturing

2 Outlines What is primary packaging? Types of Primary Packaging Selection criteria of primary pack mat for oral solid dosage form Packaging materials variables Packaging process variables & troubleshooting Packaging process validation strategy Anti-counterfeit packaging Global strategy & Regulatory requirements

3 Primary Packaging Definition Refers to packaging that immediately envelopes a product. It provides most of the strength and barrier needed to safeguard a product s s purity, potency and integrity from the time it leaves the assembly line until it s used by the consumer. Examples of primary packaging include Bottles, blister packs, etc.

4 Healthcare Packaging & Products Pharmaceutical Packaging Bottles Blister Films and Foils Closure Liners Aerosol/Pump System Components Pharma Rubber Components

5 Types of Primary Packaging Glass Bottles (colored / transparent) Polymer Bottles & Closures e.g. PET, HDPE etc Tubes & Pump System components Blisters PVC film with Aluminum foil PVC/PVDC film with Aluminum foil Aclar/ PVC or Aclar/PVC/PE with Al. Foil Cold Form Foil (CFF) COC (PVC free barrier film) Aluminum / Aluminum blisters

6 Selection Criteria Company Strategy & Goal (global or National?) Trouble free global submissions (USA, EU, Japan) Global acceptance of supplier (DMF) & materials Product stability & Required Barrier ICH conditions for zone-i I to II or Zone I-IVI IV Regulatory & Patient Compliance Child resistant, Senior friendly etc. Cost & Benefit Price, Advantages & Compliances of the specific packaging system.

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8 Properties & Advantages of Bottles Glass Bottles Convenience: Glass is a perfect barrier to atmospheric oxygen, avoiding rancidness, changes of colour & taste. Glass is inert. No migration of components Inconvenience: Fragile & heavy weight PET bottles Convenience: Light weight & not fragile Inconvenience: Not a good barrier & migration of components may happen. HDPE Bottles Convenience: Light weight & Unbreakable Comparatively better barrier Inconvenience: Migration of components may happen & may affect on product stability,

9 Types of Polymer Bottles *Type 1 - PETE Polyethylene Terephthalate (PET) *Type 2 - HDPE High-Density Polyethylene *Type 3 - Polyvinyl Chloride (PVC) e.g. blisters *Type 4 - LDPE Low-Density Polyethylene, *Type 5 - PP Polypropylene e.g. Most bottles caps. *Type 6 - PS Polystyrene e.g. Throwaway utensils,. *Type 7 - OTHER Usually layered or mixed plastic. The number indicates the class of resin. Types 1 and 2 are commonly recycled. Type 4 is less commonly recycled. The ``Other`` types are generally not recycled because of harmful chemicals, except perhaps in small test programs. Common plastics polycarbonate (PC) and acrylonitrile- butadiene-styrene (ABS) do not have recycling numbers.

10 Identification Symbols SYM BOL PET HDPE PVC LDPE PP PS NAME OTHER PROPERTIES Clarity, strength, toughness, barrier to gas and moisture. e.g. Soft drink, water, peanut butter etc. Stiffness, strength, toughness, resistance to moisture, permeability to gas. e.g. widely used for pharmaceuticals Versatility, ease of blending, strength, toughness. e.g. widely used for blister film Ease of processing, strength, toughness, flexibility, ease of sealing, barrier to moisture. e.g. squeezable bottles & etc. Strength, toughness, resistance to heat, chemicals, grease and oil, versatile, barrier to moisture e.g. bottle caps, Versatility, clarity, easily formed e.g. Egg cartons, disposable cup & plates etc. Dependent on polymers or combination of polymers e.g. Beverage bottle, baby milk bottles etc Non packaging uses: Compact disc.

11 Comparison of Polymer Bottle properties Resin Density (g/ml) MVTR 1 Oxygen 2 Stiffness 3 Impact Resist Hot Fill Max (F) PET-G Fair 160 O-PET Excellent 160 PET (hot fill) PP (polypropylene) O-PP (oriented) PVC polyvinylchloride HDPE (high density polyethylene) Excellent , Fair , Good Fair , Excellent g/mil/100 sq in - 24 hrs, 2 cc/mil/sq m - 24 hrs, 3 Flexural modulus (jpsi x 1000) Source : Westbridge

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13 Blister Films and Foils Mono PP Mono PVC PVdC-coated PVC PCTFE lamination COC co-extrusions PETG/PCTFE lamination CFF Cold Form Foil (Alu / Alu) PTA film for aggressive liquids (Tekniflex) Lidding foil

14 Film Layers Vs Product Contact Same product contact layer: Mono PVC PVdC-coated PVC PCTFE laminations (Aclar or Vaposhield) Cold-Form Foil PVC Puretherm 1001 LHD PVDC PCTFE Alu opa

15 Properties & Advantages of PVC Pharmaceutical and Food grade only Homopolymer type (more inert). Gauge range 125µ - 500µ (5mil to 20mil). Common gauges: 200µ - 250µ (7.5mil & 10mil). Colors: Clear, UV-blocker, White, Amber.. Better adhesion with lidding foil Cheapest packaging option Limited barrier

16 Properties & Advantage of PVDC PVDC Coated Film: PVC Gauges 200µ & 250µ (7.5mil & 10mil). PVDC coatings: 40gsm, 60gsm, 90gsm & 120gsm. Duplex or Triplex (25µ PE) Colors: Clear and White Medium barrier for moisture and oxygen

17 Duplex & Triplex PVDC coatings Triplex (example: VDC ) PVDC 60gsm Adhesive PE 25 micron PVC 250 micron Duplex (example: VDC ) PVDC 40gsm PVC 250micron

18 Properties of PCTFE Film PCTFE is a flexible thermoplastic film made from (polychlorotrifluoroethylene) fluoropolymer resin F C F C Homopolymer PCTFE film - 100% PCTFE (additive free) - Less shrinkage - More cost effective F Cl n Copolymer PCTFE film - Historically first - ~ % less barrier (vs. Homopolymer) - ~95% PCTFE content

19 PCTFE Laminations Triplex Lamination PCTFE Adhesive PE PVC or alternative Duplex Lamination Adhesive PCTFE PVC, PETG, BAREX, PP Or even LDPE

20 Advantage of PCTFE Lamination Triplex lamination (PVC/PE/PCTFE ) More forgiving in thermoforming Historically material of choice Duplex lamination (PVC/PCTFE ) Higher yield (more area per unit weight) Lower cost (source reduction) Better clarity Used widely outside North America Gaining greater acceptance

21 PVDC or PCTFE barrier? 40gsm and 60gsm PVDC are best in class 15µ PCTFE is better than 90gsm PVDC PCTFE: long shelf life, does not yellow PVDC: provides Oxygen barrier Flat Sheet Formed Blister PVC/PE/PVDC 90gsm PVC/PCTFE 15µ

22 Properties & Advantages of CFF Adhesive opa 25 micron ALU 45 micron PVC 60 micron 60µ PVC / 45µ Aluminum / 25µ opa. 100µ PVC / 45µ Aluminum / 25µ opa. Near absolute barrier for moisture and oxygen. Larger blisterpacks, Not transparent, Slower processing compared to thermoforming.

23 Properties of COC COC (Cyclic Olefin Copolymer) Film Standard range starts at 190 µm COC up to 300 µm COC COC core starts at 120 µm COC up to 350 µm of COC The skin layers can be 20, 30 or 40 µm thick, depending on the customers requirements. Polyolefine skin layer: PP, PE, COC Polyolefine skin layer: PP, PE, MVTR barrier: depends on the thickness of the COC core Production Process: Coextrusion (most cost effective)

24 Advantages of COC Films Properties & Advantages COC: Cyclic Olefin Copolymer A halogen free & PVC free copolymer Totally amorphous offering excellent clarity Highest Moisture Barrier Polyolefine Excellent Thermoformability Compatible with standard olefin lidding foil Conclusions: Remarks: Not the best oxygen barrier Sensitive to non polar solvents (haze) Need a skin of a PP or PE COC films are a viable alternative to PVdC (90 g up) or PCTFE high moisture barrier films (0.35 to 0.23 g/m2/day at 38ºC/90%RH) COC films are suitable for containing polar liquids

25 MVTR before & after Forming-COC New & Improved COC Film Structures Performance evaluation (before & after) forming PVC/PE/PVDC 90gsm Flat Sheet WVTR Formed Blister WVTR

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27 Process Variables & Validation Strategy Bottling Critical Process Variables Torque Pressure / Induction seal Tablet counter & Line speed Blistering Critical Process Variables Machine Speed (Dwell time) Forming Temperature Sealing Temperature Blistering Minor Process Variables: Cooling Temperature Perforation Temperature Packaging Trial Strategy: Identify critical SKUs: based on unique size, shape & impact by the critical parameters Establish critical parameters range: Low speed Vs High temperatures res and Vice versa. Packaging Process Validation Strategy: In case of multiple packaged SKUs, take a matrix approach to select ect the number of batches or run of each SKU. Validate the range of each critical process parameter during the run

28 Film Vs Blistering Process Variables PVC PVDC PCTFE Film heating Upper & Lower same Lower than PVC face Lower than PVC face Cavity Formations At any cooling temp. Require Teflon coated. Cold tools may cause PVDC cracking Teflon avoided. RT & Plug assist recommended Sealing Properties Lidstocks seals very well Lidstocks seals adequately Lidstocks seals poorly except Novel lidstock Sealing Temperature ( C) Generally Higher temp may cause curling

29 Lamination, Winding & Product Contact

30 Troubleshooting of Aclar Blistering Easily thermoformed on all conventional thermoforming lines e.g. Uhlmann, Noack, Klockner, IMA, Romanco etc. Slightly more heat required to form cavities than with mono PVC film Machine speed comparable with mono PVC film Appropriate gap between cavity & edge to avoid any partial leakage Appropriate blister sealing by maintaining uniform sealing & cooling temp Use plug assist for deep draw ratio if depth >6 mm to avoid malformation. Proper mold design- draft angle of 5 5 to avoid non-uniform forming Shrinkage 3-5% TD shrinkage for copolymer PCTFE 1-3% TD shrinkage for homopolymer PCTFE Curl Towards PCTFE side of blister Causes Higher TD shrinkage of raw PCTFE compared to PVC film (Up to 15% Vs~0) Recommendations Decrease heat applied to PCTFE side of lamination

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33 Film Cost Vs Performance Analysis Product Yield (sq. in./lb.) Avg. $/lb. at 5M lbs. Avg. $/msi (1,000 sq in) MVTR - g/m²/24 hrs. MVTR - g/100 in.²/24 hrs. A 1,866 $11.90 $ B 2,028 $9.50 $ C 1,860 $9.75 $ D 1,730 $10.75 $ E 1,528 $14.00 $ F 1,355 $15.50 $ PRODUCT MVTR (g/100in²/24 /24 hrs) PRICE IN US$ X: 7.5mil PVC/2.0 mil PE/ 1.5 mil PCTFE ~ $ 40 / Kg Y: 7.5mil PVC/2.0 mil PE/ 0.9 mil PCTFE ~ $ 27 / Kg M: 10.0 mil PVC/ 2.0 mil PE/ 1.5 mil PCTFE ~ $ 33 / Kg N: 10.0 mil PVC/ 2.0 mil PE/ 0.9 mil PCTFE ~ $ 23 / Kg

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35 Pharmaceutical Lidding Foils 20µ hard or soft temper & 25µ hard or soft temper push-through foils Paper/Foil push-through structure. Paper/PET/Foil CR peel-push structure. Paper/PET/Foil CR peelable structure. Other lidding foils available with a variety of heat sealable layers & CR technology.

36 Anti-Counterfeit Anti-Counterfeiting Technology in Blister Films: ACF films and foils incorporate UV Markers to protect against counterfeiting. Company logo or product brand logo can be combined in the film and foil such that when exposed under a standard UV light, the logo and blister film illuminate to verify authenticity. Covert Marker Technology for Product: Available form of Indicia containing logos or unique mark, batch no, text etc can be embedded on the product which are not easily visible

37 Anti-Counterfeit Digital Imaging: e.g. Cryptoglyph on-packaging protection on folding cartons, blisters, labels and leaflets A unique pattern made by printed dots, invisible to naked eye Using existing holes on the varnish layer and Camouflaged within the natural imperfections of the varnish layer Unique characters camouflaged within the structures of the aluminium foil Fingerprints: on-dosage or on-product protection Use of existing anti-counterfeit feature on molded caps, Vial flip-off tops, bottle closures etc. Several companies from USA & Europe have their patented technology

38 Global Strategy Strategy for packaging materials based on Compliance to different parts of the world Stability study at the early development stage Assurance of protection against different climatic zones Target markets requirement & their most popular SKU Cost-effectiveness: Barrier (MVTR), Availability, Price, Yield and Ease of thermoforming.

39 Packaging Vendor Interchangeability For FDA approval follow the 4 steps: Step-1: : Classification of Change ( Major / Moderate or Minor? ) Step-2: : Is the packaging Material CDER approved? Step-3: : Does the new package provide the same or better protective properties? Step-4: : If the answer of the step-3 3 yes, then make the Change Control and include in the Annual Report

40 Packaging Vendor Interchangeability Step-1: Classification of the Change in a reporting Category: Major / Moderate / Minor The changes of supplier/material can be classified as Minor Change since : A change in the container closure system of unit dose packaging (e.g., blister packs) for non-sterile solid dosage form products, as long as the new package provides the same or better protective properties and any new primary packaging component materials have been used in and been in contact with CDER-approved products of the same type (e.g., solid oral dosage form, rectal suppository).

41 Packaging Vendor Interchangeability Step 2: Is the Packaging CDER approved? If Yes for relevant product, then this certificate is to be included in the Annual Report.

42 Packaging Vendor Interchangeability Step 3: Does the new package provide the same or better protective properties? Light Transmission: applicable for opaque blisters only. Moisture Transmission: to be documented via the official compendial test: USP <671> Containers - Permeation. Use the test "Single Unit Containers and Unit-Dose Containers for Capsules and Tablets". Use Method II for blisters with multiple unit dose containers. The new blisters should have equal or better WVTR compared to the current blister. A tolerance of +/-10% is industry accepted as variation on the method. The WVTR data is to be included in the Annual Report.

43 Packaging Vendor Interchangeability Step 4: Change Control and Annual Report If the results from step 3 show the new blister offers equal (+/-10%) or better protection from moisture compared to the current blister the change can be made. Document the changes in the next Annual Report to the FDA for each Drug Product.

44 Example of Interchangeability FDA Change Protocol Example-1: Change from PVC/PVDC to Copolymer Aclar. Changing between the group based on MVTR & availability The MVTR of PVC/PVDC is 0.65 g/m²/day & MVTR of PVC/PE/Aclar is 0.11 g/m²/day. Eample-2: Change from Co-polymer to Homo-polymer Aclar Changing within the group based on MVTR & price. The MVTR for 7.5mil PVC/2.0 mil PE/ 1.5 mil PCTFE is and for 10.0 mil PVC/ 2.0 mil PE/ 0.9 mil PCTFE is g/m²/day Justification for minor change: The PVC/PE/Aclar offers 5 times more barrier protection than that of the PVC/PVDC, classified as a minor change. Same justification applies on other example. Product contact (PVC) is also remain same

45 Regulatory Compliance Verification Worldwide compliance For Film : USA food contact: 21CFR EU food contact: 2002/72/EC Japanese Food and Sanitation Law, Ministry of Health and Welfare Notification 20. USP: <661> Ph.Eur and Ph.Eur max VCM levels Heavy Metal Directives CDER approval for oral solid dosage forms

46 Regulatory Guidelines Web site of FDA guidelines for submitting documentation for human drugs & Biologics. FDA guideline Container Closure Systems for Packaging Human Drugs and Biologics. Child resistant packaging: US CPSC (US Consumer Product Safety Commission) EU guideline 3AQ10A Plastic Primary Packaging Materials.

47 Recapping Select cost-effective pack mat at early stage of development Appropriate barrier (MVTR) required for product in target market HDPE bottle can be the best & cheapest choice if target market allowsa Appropriate thickness & thermoforming yield for blister PVC/PCTFE blister can be cost effective than PVC/PVDC & CFF Availability from multiple vendors to keep purchasing flexibility y & control Compliance to global regulatory requirements & interchange ability Critical issues to consider for blister packaging development Designing the blister card, Forming mold design, Blister machine operation, Sealing, Die cutting, Lid stock, Seal failure may not be seen in leak test but through ICH accelerated condition. Anti-counterfeit Packaging Select cost-effective anti-counterfeit packaging based on the need Packaging Process validation strategy Perform packaging trials & establish parameters range prior to validationv Select cost-effective validation strategy by taking matrix approach

48 Comments & Questions??