Sealing property of

containers
Objective
• Regulatory requirements for Drug product containers and closures
• Overview of closures
• Blister pack
• Bottle pack
• Blow fill seal (BFS)
• Glass ampoule
• Vials - Rubber stopper / crimping of seals
ICH Q7
9. Packaging and Identification labelling of APIs and intermediates
9.2 Packaging Materials

• 9.20 Containers should provide adequate protection against deterioration or contamination of

the intermediate or API that may occur during transportation and recommended storage.
• 9.21 Containers should be clean and, where indicated by the nature of the intermediate or API,
sanitized to ensure that they are suitable for their intended use. These containers should not be
reactive, additive, or absorptive so as to alter the quality of the intermediate or API beyond the
specified limits.

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https://database.ich.org/sites/default/files/Q7%20Guideline.pdf
21 CFR Part 211
PART 211 -- CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS
Subpart E--Control of Components and Drug Product Containers and Closure

• Sec. 211.94 Drug product containers and closures.

a) Drug product containers and closures shall not be reactive, additive or absorptive so as to alter the safety,
identity, strength, quality, or purity of the drug beyond the official or established requirements
b) Container closure systems shall provide adequate protection against foreseeable external factors in storage
and use that can cause deterioration or contamination of the drug product.
c) Drug product containers and closures shall be clean and, where indicated by the nature of the drug,
sterilized and processed to remove pyrogenic properties to ensure that they are suitable for their intended
use.
d) Standards or specifications, methods of testing, and, where indicated, methods of cleaning,
sterilizing, and processing to remove pyrogenic properties shall be written and followed for drug product
containers and closures.

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16 CFR 1700
• U.S. Consumer Product Safety Commission (CPSC) is responsible for enforcing the Poison Prevention
Packaging Act of 1970 (PPPA)
• Poison Prevention Packaging Act (16 CFR 1700) of 1970 requires a number of household substances to be
packaged in child-resistant packaging
• Drug products containing controlled substances, most human oral prescription drug products (including oral
investigational drugs used in outpatient trials), and OTC drug preparations containing aspirin,
acetaminophen, diphenhydramine, liquid methyl salicylate, ibuprofen, loperamide, lidocaine, dibucaine,
naproxen, iron, or ketoprofen, require special packaging (16 CFR 1700.14)
• Regulations issued under the PPPA establish performance standards and test methods that determine if a
packaging system is child-resistant and adult-use-effective (16 CFR 1700.15 and 16 CFR 1700.20, respectively)
• The standards apply to both reclosable and nonreclosable packaging systems (unit-dose packaging)
• Do not have to use special packaging if the drug is intended to be repackaged by the pharmacist.

1
www.cpsc.gov
Evolution of Tamper-Resistant Packaging
• Chicago Tylenol Murders were a series of poisoning deaths resulting from drug tampering in
the Chicago metropolitan area in 1982.
• The victims had all taken Tylenol-branded acetaminophen capsules that had been
laced with potassium cyanide.
• Ensuing deaths and shock at such a malicious and evil act swiftly brought an industry and FDA
forces to action and together started enforcing strict guidelines for tamper-evident packaging
• FDA guidelines for tamper-resistant packaging (TRP) are pretty clear that only over-the-counter
(OTC) human drug products (HDP) are in need of TRP.
• Tamper-evident packaging (TEP) has no FDA guidelines but is used widely in the packaging industry
as an added measure of tampering proof.

https://www.pbs.org/newshour/health/tylenol-murders-1982 6
Tamper-Resistant Packaging
Each of the following TRP options needs to be paired with another TRP measure such as a statement
on the label or package itself. Something like: “Do not use if seal is broken or missing.”

• Shrink wrap
• Blister packs
• Bubble packs
• Shrink bands
• Individual pouches (paper, foil, or plastic)
• HIS liners
• Caps with breakable ring
• Sealed metal tube
• Aerosol containers
• Sealed metal cans

7
2014 Packaging & Labelling Recall Events

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https://www.fda.gov/media/92847/download
• Drug recalls are on the rise (surges to 836 in 2014) - leached impurities have
been a key factor responsible for many of these recalls
• Regulations and standards governing analysis have proliferated in recent years,
in particular related to pharmaceutical packaging and biomedical devices

9
Container Closure System

• Refers to the sum of packaging components that together contain and

protect the dosage form.
• Includes primary packaging components and secondary packaging
components, if the latter are intended to provide additional protection
to the drug product.
• A packaging system is equivalent to a container closure system.

10
Closures

A device which protects the drug (or) drug product by preventing

the entry of air, moisture, particulate matter, and microorganisms
etc., thereby keeping the product in a safe condition and also
assists in proper use & of the drug.

11
Closures

The closure is normally the most vulnerable and critical component of a

container in so far as stability and compatibility with the product are
concerned.
An effective closure must prevent the contents from escaping and allow no
substance to enter the container.

12
Function of closures

• Provide a totally hermetic seal

• Provide an effective seal which is acceptable to the products

• Provide an effective microbiological seal

13
Characteristics of closure

• It should be resistant and compatible with the product and the product
/air space
• If closure is of re closable type, it should be readily operable and should
be re-sealed effectively
• It should be capable of high speed application where necessary for
automatic production without loss of seal efficiency
• It should be decorative and of a shape that blends in with the main
containers
14
Desirable Features of
closures

The closures must prevent -

• Loss of moisture. eg:-to moisture sensitive tablets and, because their shells are
hygroscopic to capsules.
• Loss of moisture from creams and from water-containing ointments and creams.
• Unintentional escape of the content, and
• Entry of direct (or) other contaminants such as odorous vapours
• Closures must be easily removed and replaced

15
Types of
closures

Closures are available in five basic designs

• Screw-on, threaded, or lug
• Crimp-on (crowns)
• Press-on (snap)
• Roll-on
• Friction.

16
Types of
closures
Different types of closures that perform a variety of functions. Some common types of
closures include –
• continuous thread closures (CT) - basic closure that can be easily sealed
and resealed
• disc top caps - allow the user to dispense product without having to remove the cap
• child resistant (CRC) closures - designed to keep children from opening the content
• pumps, and sprayers - allow the user to dispense an equal amount of high viscosity
product with each use

17
Types of closures available for glass
packaging

Corks, droppers, sprayers, metal caps, and pumps are the most common types
of closures used with glass packaging

18
Examples of Packaging Concerns for Common Classes of Drug
Products
Degree of Concern Likelihood of Packaging Component-Dosage Form Interaction
Associated with the Route High Medium Low
of Administration

Highest Inhalation Aerosols and Sterile Powders and

Solutions; Injections and Powders for Injections;
Injectable Suspensions Inhalation Powders
High Ophthalmic Solutions and
Suspensions; Transdermal
Ointments and Patches;
Nasal Aerosols and Sprays
Low Topical Solutions and Topical Powders; Oral Tablets and Oral(Hard
Suspensions Oral powders and Soft and Gelatin)
Topical and Lingual Capsules
Aerosols; Oral Solutions and
Suspensions
Term suspension is used to mean a mixture of two a immiscible phases (e.g., solid in liquid or liquid in liquid). As
such, it encompasses a wide variety of dosage forms such as creams, ointments, gels, and emulsions, as well as
suspensions in the pharmaceutical sense 19
General Considerations

Suitability for the Intended Use

Suitability refers to the tests and studies used and accepted for the initial qualification
of a Component or a container closure system for its intended use.

Every proposed packaging system should be shown to be suitable for its intended use:
it should adequately protect the dosage form; it should be compatible with the dosage
form; and it should be composed of materials that are considered safe for use with the
dosage form and the route of administration.

20
General Considerations
Protection
A container closure system should provide the dosage form with adequate protection
from factors (e.g., temperature, light) that can cause a degradation in the quality of
that dosage form over its shelf life.

Compatibility

Packaging components that are compatible with a dosage form will not interact
sufficiently to cause unacceptable changes in the quality of either the dosage form or
the packaging component.

21
General Considerations
Examples of interactions include -
• loss of potency due to absorption or adsorption of the active drug substance, or
degradation of the active drug substance induced by a chemical entity leached from
a packaging component;
• reduction in the concentration of an excipient due to absorption, adsorption or
leachable-induced degradation;
• precipitation;
• changes in drug product pH;
• discoloration of either the dosage form or the packaging component;
• increase in brittleness of the packaging component.

22
General Considerations
Safety

Packaging components should be constructed of materials that will not leach harmful
or undesirable amounts of substances to which a patient will be exposed when being
treated with the drug product.

This consideration is especially important for those packaging components which may
be in direct contact with the dosage form, but it is also applicable to any component
from which substances may migrate into the dosage form (e.g., an ink or adhesive).

23
General Considerations
Performance

Performance of the container closure system refers to its ability to function in the
manner for which it was designed. When evaluating performance, two major
considerations are container closure system functionality and drug delivery.

24
Typical packaging suitability considerations for common
classes of drug products
Route of Administration/ SUITABILITY
Dosage Form Protection Compatibility Safety Performance/ Drug
Delivery
Inhalation Aerosols and Solutions, Nasal L, S, M, W, G Case 1c Case 1s Case 1d
Sprays
Inhalation Powders L, W, M Case 3c Case 5s Case 1d
Injections, Injectable Suspensionsb L, S, M, G Case 1c Case 2s Case 2d

Sterile Powders and Powders for Injection L, M, W Case 2c Case 2s Case 2d

Ophthalmic Solutions and Suspensions L, S, M, G Case 1c Case 2s Case 2d

Topical Delivery Systems L, S Case 1c Case 3s Case 1d

Topical Solutions and Suspensions, and L, S, M Case 1c Case 1c Case 3s Case 2d

Topical and Lingual Aerosols

Topical Powders L, M, W Case 3c Case 4s Case 3d

Oral Solutions and Suspensions L, S, M Case 3s Case 2d

Oral Powders L, W Case 2c Case 3s Case 3d

Oral Tablets and Oral (Hard and Soft Gelatin) L, W Case 3c Case 4s Case 3d
Capsules

Explanation of Codes
Protection:
L (protects from light, if appropriate) Performance:
S (protects from solvent loss/leakage) Case 1d: Frequently a consideration.
M (protects sterile products or those with microbial limits from microbial contamination) Case 2d: May be a consideration.
W (protects from water vapour, if appropriate) Case 3d: Rarely a consideration.
G (protects from reactive gases, if appropriate)
Compatibility:
Case 1c: Liquid-based dosage form that conceivably could interact with its container
closure
Case 2c:system components
Solid dosage form until reconstituted; greatest chance for interacting with its container closure system components occurs after it is reconstituted.
Case 3c: Solid dosage form with low likelihood of interacting with its container closure system components.
Safety:
Case 1s: Typically provided are USP Biological Reactivity Test data, extraction/toxicological evaluation, limits on extractables, and batch-to-batch monitoring of extractables.
Case 2s: Typically provided are USP Biological Reactivity Test data and possibly extraction/toxicological evaluation.
Case 3s: Typically, an appropriate reference to the indirect food additive regulations is sufficient for drug products with aqueousbased solvents. Drug products with non-
aqueous based
suitability solvent systems or aqueous based systems containing co-solvents generally require additional
information 25
Case 4s: Typically, an appropriate reference to the indirect food additive regulations is sufficient.
Case 5s: Typically, an appropriate reference to the indirect food additive regulations for all components except the mouthpiece for which USP Biological Reactivity Test data is provided.
Blister pack - Sealing agent on
lidding foil (LDPE) / sealing
temperature / Thickness of foils
Blister Packing
Packaging options you can use to enhance your product & customer experience! Packaging exists to
serve all three elements

Three P's” – Protection, Preservation and Promotion

Blister packaging is a form of plastic packaging that is used for small consumer goods and
pharmaceuticals. It is mostly made from thermoformed plastics. Blister packs have a backing of
paperboard, aluminium foil, or even other plastic sheets. Blister packs that are sold without a card
should be virtually waterproof. Blister packs are especially popular in the pharmaceutical business. ...
With a blister pack, each pill or dose is hermetically sealed so that you can be sure no one has
tampered with its contents.

Blister packaging is a type of pre-formed plastic packaging used for small consumer goods

Two primary components of a blister pack are - cavity made from either plastic or aluminum and
lidding, made from paper, plastic or aluminum

The cavity contains the product and the lidding seals the product in the package
27
Blister Packing

Characteristics

• Protection from Environmental Conditions

• Non-reactive with the product

• No Impart Taste or Odor to the Product

• Non-toxic

• Adoptable to commonly employed high speed packaging equipment

• Meet applicable Tamper Resistance Requirements

28
Blister Packing

Advantages

• Product Integrity

• Product Protection

• Tamper Evidence

• Reduced Possibility of Accidental Misuse

• Patient Compliance.

29
Blister Packing Component

The four basic components of pharmaceutical blister packages are:

 The forming film (forming films account for approximately 80-
85% of the blister package)
 The lidding material (lidding materials make up 15-20% of the
total weight of the package)
 Heat seal coating
 The basic configuration of Blister packing

30
Blister Packing Component

Thermoformable
material Forming film:
The forming film is the
packaging component
that receives the product
in deep drawn pockets.

A key to package success

is selecting the right
plastic film for the blisters
in terms of its -
 Property / type
 Grade
 Thickness
31
Blister Packing Component

Thermoformable material
Monolayer PVC film : POLY(VINYL CHLORIDE) PVC

• Rigid PVC
• Very clear, stiff material with a low WVTR
• Excellent thermoformability
• Low permeability
• Low cost
• Good chemical resistance
• PVC films that are thermoformed have a thickness of about 10–15 mm.

32
Blister Packing Component

Thermoformable material
Polyvinylidene Chloride (PVDC)–Coated PVC:

• PVDC is the most common coating in blister packaging because it can reduce the gas and moisture permeability of
PVC blister packages by a factor of 5–10
• Coated PVC films have a thickness of 8–10 mil; the thickness of the PVDC coat amounts to 1–2 mil
• Coating is applied on one side and usually faces the product and the lidding material
• Excellent oxygen and moisture barrier properties as compared to normal PVC film
• Good thermoformability; PVDC is very cost- effective, as coating weight can be customized depending on the
requirements of the barrier properties
• Medical grade and non-toxic
• High levels of transparency which improves the aesthetics of the product

33
Blister Packing Component

Thermoformable material
PVC/Chlorotrifluoroethylene (CTFE):
• Films made from PVC and CTFE have the lowest water-vapour permeability of all films used for blister
packaging
• When compared with the water-vapor permeability of 10-mil PVC, the permeability of 8-mil PVC/0.76- mil
CTFE is lower by a factor of 15
• However, the environmental concerns regarding PVC also apply to PVC/CTFE films.

34
Blister Packing Component

Thermoformable material

Polystyrene (PS)
Polystyrene (PS) is perfectly compatible with thermoforming, but its high water vapor permeability makes it
unsuitable as a blister material for pharmaceutical purposes.

35
Blister Packing Component

Aluminum blister foil

• Used in cold foaming technique

• Alu alu packaging
• Good barrier to moisture, vapour and gases
• 20-25 micron thick

36
Blister Packing Component

VIDEOS

• Lovell Industries - Blister Packaging South Africa Animation.mp4

• DPP-250F blister machine for tablet- Carlos.mp4

• Fig 2: Blister machine

37
Blister Packing Component

Lidding material

Lidding material provides the base or main structural component upon which the final blister package is built

• After the tablets have been properly fed to the preformed support materials, the lidding material is sealed
onto the support material
• Temperatures range: 140-300 deg C
• Lidding materials can also use soft (annealed) foil (0.025 mm) or laminations of soft foil and other substances
(tissue paper)
• Soft and embossed soft foil extends in the push-through stage, hence may give added child safety provided it
does not damage the item concerned

38
Blister Packing Component

Lidding material

• Must be selected according to:

• Size
• Shape
• Weight of the product
• Style of the package to be produced

39
Blister Packing Component

Lidding material

• An essential component of lidding material is the sealing coating

• The side of the lidding material that faces the product and the forming film must be provided with a coating
material suitable for heat sealing
• This is usually accomplished by means of a heat sealing lacquer
• An additional requirement is that the sealing strength must fall within a predetermined tolerance

40
Blister Packing

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

41
Blister Packing

Tamper evident features

Individual doses (for example, capsules or tablets) are sealed in pockets between a pre-formed
tray and a lidding material, or between two layers of material bonded together to form a
continuous strip, so that the dosage units are separated and individually protected.
• The blister or strip pack seals around individual compartments and the strip as a whole, must
be intact and complete
• The individual compartment of the pack must be ripped or broken to gain access to the product
• The layers forming the blister or strip pack cannot be separated or replaced without leaving
visible evidence of entry

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https://www.tga.gov.au/publication/code-practice-tamper-evident-packaging-therapeutic-goods
Blister Packing

Design and validation

The sponsor or manufacturer must have documented evidence to support the suitability of the tamper-
evident packaging (TEP) that includes the:
• design qualification of the TEP and its suitability/compatibility of components with the product and
compliance with required TEP statements
• specifications for the TEP including details of the approved supplier, functional /performance criteria
and critical attributes
• validation of the effectiveness (function) of the TEP as wells as the manufacturing process used to
apply the TEP to the goods
• requirements for routine sampling and testing of incoming TEP packaging componentry and applied
(assembled) TEP devices

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https://www.tga.gov.au/publication/code-practice-tamper-evident-packaging-therapeutic-goods
Blister Packing

Tamper evident features

Tamper-evident statement must be placed:
• on the package so that it will be unaffected if the tamper-evident feature is breached or
missing

Examples of acceptable wording are listed in the table below:

Tamper-evident feature Examples of acceptable wording
Blister or strip packs Do not use if blister seal is broken
Do not use if blister backing is damaged

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https://www.tga.gov.au/publication/code-practice-tamper-evident-packaging-therapeutic-goods
Blister Packing
Technical data of PTP blister foils:
PTP blister foil that is also known as blister foil or push-through lidding foil is offered for heat sealing with PVC,
PVDC-coated PVC, PP for pharmaceutical purpose
Sealing temperature :170 to 180 deg. C
Recommended operating Sealing pressure : 2.8 to 5.6 kg/Sq. cm, 40 to 80 lbs/Sq. inch
conditions: Dwell time : 0.25 to 0.5 sec.

Table showing thickness

tolerances of foil:

(a) 4-6 GSM with a tolerance of +/- 0.5 GSM

Coating Thickness Options: (b)6-8 GSM with a tolerance of +/- 0.5 GSM Standard, if not specified,
heat sealing coating GSM is 4 with a tolerance of +/- 0.5.
Seal Strength with 8 N/25 mm min.
PVC/PVDC:
Printing and Lacquer Printing inks and lacquer coatings are capable to withstand 180 deg. C
Coating: for 1 sec. dwell time.
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http://www.hlybky.com/PTP%20blister%20foil.html
Blister Packing

Heat Seat Coating

• Heat-seal coatings provide a bond between the plastic blister and the printed lidding material.
• For blister packages, heat-seal coatings are perhaps the most critical component in the entire
system.
• The appearance and physical integrity of the package depends upon the quality of the heat-seal
coating.
• These solvents or water based coatings can be applied to rolls or sheets of printed
paperboards using roll coater or flexographic methods, knives, silk screenings or sprays.

46
Blister Packing
Heat Seat Coating
• Whatever the system, it is essential that the proper coating weight be applied to the lidding
material for optimum heat sealing results.
• A successful heat-seal coating for blister packages must exhibit
- Good gloss,
- Clarity,
- Abrasion resistance,
- hot tack,
- must seal to various blister films

47
Blister Packing
Hot Tack
- Hot tack is particularly important because the product usually is loaded into the blister and the
lidding material heat sealed in place (face down) onto the blister
- When the package is ejected from the heat-seal jig, the still- warm bond line must support its
entire weight
- The heat seal coating must precisely match the lidding material and the plastic material of the
forming film
- Precisely match means that with pre determined sealing parameters, a permanent sealing
effect between the lidding material and the forming film must be guaranteed under any
climatic condition.

48
Blister Packing
Printing inks
- Printing inks provide graphics and aesthetic appeal
- They can be applied to the lidding material by letterpress, gravure, offset, flexographic, or silk-
screen printing processes
- Printing inks must
- Resist heat sealing temperatures as high as 300 °C without showing any
discoloration or tackiness
- Sufficiently resist abrasion, bending, and fading
- Be safe for use with the intended product
- Comply with FDA recommendations.

49
Blister Packing
Printing inks
- Printing inks provide graphics and aesthetic appeal
- They can be applied to the lidding material by letterpress, gravure, offset, flexographic, or silk-
screen printing processes
- Printing inks must
- Resist heat sealing temperatures as high as 300 °C without showing any
discoloration or tackiness
- Sufficiently resist abrasion, bending, and fading
- Be safe for use with the intended product
- Comply with FDA recommendations.

50
Blister Packing
Production of blisters

51
Blister Packing
Thermoforming
- In the case of thermoforming, a plastic film or sheet is unwound from the reel and guided
though a pre-heating station on the blister line
- The temperature of the pre-heating plates (upper and lower plates) is such that the plastic will
soften and become pliable
- The warm plastic will then arrive in a forming station where a large pressure (4 to 8 bar) will
form the blister cavity into a negative mold
- The mold is cooled such that the plastic becomes rigid again and maintains its shape when
removed from the mold
- In case of difficult shapes, the warm film will be physically pushed down partially into the cavity
by a "plug-assist" feature. Plug-assist results in a blister cavity with more uniform wall
distribution and is typically used when the cavity size and shape is larger than a small tablet.
52
Blister Packing
Thermoforming
- Advantages of thermoforming blister pack: The most basic material for the forming web is PVC
or Polyvinyl Chloride, for ease of thermoforming and low cost. The product can be visually
examined through the transparent plastic. The faulty blister card can be rejected via the
inspecting camera or naked eyes. Because the cavity or pocket contain the item snugly, it can
adopt the universal feeder which consists of circular brushes and planetary agitators that
sweep the products into blister pockets. Parts are not required for different formats. This feeder
is noted for its low cost and ease of operation.

53
Blister Packing
Thermoforming
- Disadvantages of thermoforming blister pack: The protective properties are not strong
because of the PVC’s poor barrier against moisture and oxygen ingress. Not suitable for light-
sensitive drugs because of the transparency of PVC.

54
Blister Packing
Thermoforming
- Thermoforming process consists of four basic stations where following operations occur
- 1. Forming
- • Pre heating
- • Thermoforming
- • Cooling
- 1. Filling (Loading)
- 2. Sealing
- 3. Finishing

55
Blister Packing
Schematic Representation of Thermoforming

56
Blister Packing

Pre-heating
• Heating station is present only in thermoform & thermo- cold form blistering machines
• Prior to entering forming station, reel-fed base (tray) web (blister material) passes through the
heating unit
• Heating is achieved either by
• Infra-red heaters
• Contact heaters
• The temperature , based on the blister material used and on the speed at which that material
travels through the heating station , is a critical parameter for optimal performance

57
Blister Packing
Forming
• At the forming station the blister material is heated to the point where the plastic softens
sufficiently to allow the cavity to be formed by
• Mechanical forming between male and female moulds
• Vacuum or negative pressure-which draws the softened film over or into a mould

58
Blister Packing
Forming (Cont.)
• Pressure-in which compressed air forces the film over or into a mould
• Combination of the two
• For an identical blister shape, pressure plus plug assistance generally gives most uniform
blister.

59
Blister Packing

Cooling

• The moulds into which the plastics is formed can be cooled by air, water or chilled water

• The cooling station cools the films after the forming process

• Laminates containing aluminum do not need to be cooled

60
Blister Packing

Filling (Loading)
• Here product is loaded into blister cavity either manually or with the aid of feeding mechanism
• Uncoated tablets or capsules are normally fed from vibratory bowl via channels or tubes by
gravity
• Vacuum extraction is frequently applied to the bowl tubes etc to minimize powder and tablet
chips which may finish up in the seal or tray
• The critical parameter is the proper filling of formed blisters

61
Blister Packing

Sealing
• At this station, lid stock is sealed to filled blister cavity, using heat and pressure
• The critical parameters to be considered at this station are temperature, pressure
• The lid stock material is staged on a roll above the blister cavity and may be preprinted or
printed on line
• Lot no. and expiration dates may be applied at this point
• Preprinted lid stock materials will require a print registration system to control the position of
the printing relative to the blister cavity
• The critical parameters at this part of station includes legible and correct labeling

62
Blister Packing

Finishing
• Includes embossing, perforation and cutting
• Embossing involves application of lot no. and expiration date to package. This process is carried
out at printing station
• Steel type is used to emboss information on the edges of the blister package
• At Trimming station, the blisters are cut into individual unit
• Embossing, perforation, cutting process should not compromise blister lid or seal. Package
integrity and quality of embossing are critical parameter in the process.

63
Blister Packing

Cold forming

• In the case of cold forming, an aluminum-based laminate film is simply pressed into a mold by

means of a stamp

• The aluminum will be elongated and maintain the formed shape. In the industry these blisters

are called cold form foil (CFF) blisters.

64
Blister Packing

Advantage of cold form foil blisters

• Use of aluminum offers a near complete barrier for water and oxygen, allowing an extended
product expiry date
Disadvantages of cold form foil blisters
• The slower speed of production compared to thermoforming;
• The package is opaque, making the inspecting system, which rejects the faulty blister card,
complicated and costly
• The cost of cold forming aluminium film is higher than PVC
• The larger size of the blister card (aluminium cannot be formed with near 90 degree angles)
increases the material cost
• Because the cavity or pocket is larger than the drug, the feeder should be dedicated. this
increases the cost and difficulty of operation. 65
Blister Packing
Operation of Cold Forming

The sequence involves:

• Installing the Aluminium Foil,
• Cold forming it into blister cavities via punch pins,
• Loading the blister with the product,
• Placing lidding material over the blister,
• Heat-sealing the package
• Cutting into individual blisters

66
Blister Packing
Types of Cold forming processes
1. Clamping the material and carrying out a true punch action where the non-held area is
extended (stretch forming)
2. Taking a foil which has been embossed or finely creased; can be extended by air or mechanical
pressure without showing flex cracks
3. Taking a reel of material with regular cross-direction slits (as used on suppository machine)
4. A male/female mechanical forming operation is carried out between each slit. This mechanical
operation forms the foil and the slit area moves (opens), thereby preventing any high degree
of stress
5. Latest innovations include a double forming operation which reduces the tray size to 20%
(Advanced Forming Technology (AFT) process). These tend to use Teflon stretching dies.

67
Blister Packing
Larger size of the cold forming blister pack compared to thermoforming blister pack.

68
Blister Packing
Thermo-cold forming
Example: ALU-Tropical Machine
Operation: The sequence involves
• Heating the plastic
• Thermoforming it into blister cavities
• Loading the blister with the product
• Placing lidding material over the blister
• And heat-sealing the package
• Installing the aluminium foil
• Cold forming it into blister Pouch & seal it on thermoformed blister to give extra protection
• Cutting into individual blisters

69
Bottle pack - Heat sealing of
HDPE bottles / induction sealing
temperature and wad thickness
Heat
Sealing
• Heat sealing is the process of sealing one thermoplastic to another similar thermoplastic using heat
and pressure.
• Heat sealing is used for joining thermoplastic films, typically less than 0.5 mm thick.
• Two main types of heat sealing: hot-bar welding and impulse welding - are most widely used in the
packaging industry for sealing bags, films, and containers made from thermoplastics.
• Many medical devices are also heat-sealed in packages of thermoplastic and plastic coated paper.
• Heated region is textured to reduce and control the joint strength. This offers the opportunity to
supply a sterile component in an easy-to-open package. Outer packets for intravenous bags,
laminated packs for powders, colostomy bags, and some tablet blister packs are also heat-sealed.
• Unlike some welding and sealing techniques, such as radio frequency welding, heat sealing is not
material dependent, and is used for joining many different types of thermoplastic materials.
71
Heat-sealing method

• A plastic container is provided with a plastic bead seal at the junction of the interlocking fastener and
the side edges of the container.
• The plastic bead seal acts as a barrier to the passage of fluids or contaminating bacteria through the
fastener at this junction.
• A method and apparatus are provided for flowing plastic under heat and pressure into and across the
junction to form the bead seal barrier.

72
Induction
sealing
• Induction sealing is the process of bonding thermoplastic materials by induction heating. This
involves controlled heating an electrically conducting object (usually aluminum foil)
by electromagnetic induction, through heat generated in the object by eddy currents.
• Induction sealing is used in many types of manufacturing. In packaging it is used for package
fabrication such as forming tubes from flexible materials, attaching plastic closures to package forms,
etc.
• Probably the most common use of induction sealing is cap sealing, a non-contact method of heating
an inner seal to hermetically seal the top of plastic and glass containers.
• This sealing process takes place after the container has been filled and capped.

73
Induction
sealing
Sealing process
• closure is supplied to the bottler with an aluminum foil layer liner already inserted
• a typical induction liner is multi-layered
• top layer is a paper pulp that is generally spot-glued to the cap
• next layer is wax that is used to bond a layer of aluminum foil to the pulp
• bottom layer is a polymer film laminated to the foil
• After the cap or closure is applied, the container passes under an induction coil, which emits an
oscillating electromagnetic field
• As the container passes under the induction coil (sealing head) the conductive aluminum foil liner
begins to heat due to eddy currents.
• The heat melts the wax, which is absorbed into the pulp backing and releases the foil from the
cap
• The polymer film also heats and flows onto the lip of the container
• When cooled, the polymer creates a bond with the container resulting in a hermetically sealed
product
• Neither the container nor its contents are negatively affected, and the heat generated does not
harm
the contents 74
Induction
sealing
Advantages of induction sealing:

• Tamper evidence
• Leak prevention
• Freshness Retention
• Protection against package pilferage
• Sustainability
• Production Speed

75
Induction
sealing
Induction liners or wads
• Induction liners (wad) are cap sealers which prevents from leaks, tampering and extension of shelf
life.
• It is also known as heat seal liners.
• It is made of three layers- a heat seal, a foil middle and a backing piece.
• Users have to break through or remove the seal to use the product.
• Liner attachment process is either done manually or by automated sealing unit.
• The cap is torque firmly depending on the size and capacity of the container. The torque helps secure
the cap therefore making sure the cap sealed properly.
• Once the sealing cools down, the bottle should be set to be shipped.

76
Induction
sealing
Two types of Induction Sealing Wads :
Cap sealing wads: cap or closure for the container is separate from the induction sealing wad which is inserted into it. There are
various kinds of wads and all are normally multi-layered. Broadly they can be categorized as :
• Single Piece Sealing Wads are fitted into cap of the containers and screwed around the container mouth. These capped-
containers are made to pass the induction heat sealer. With the threaded cap upon bottle providing required pressure, as
sealing layer cools, it adheres to bottle and provides for a perfect sealed surface
• Two piece sealing wads normally consists of a uppermost layer of paperboard (that maybe glued to the cap). The next layer is
wax that is used to bond a layer of aluminum foil to the paperboard. The lowermost layer is a polymer film laminated to the
foil. After the cap or closure is screwed to the container , the container is passed under an induction coil, which emits an
oscillating electromagnetic field. The induction coil begins to heat-up the conductive aluminum foil. The heat melts the wax,
which gets absorbed into the paperboard layer and the foil is released from the cap. The polymer film also heats and flows
onto the lip of the container. After cooling, the polymer creates a bond with the container resulting in an airtight sealed
product. Two piece sealing wads are used for leaving some type of secondary seal in cap so as to prevent leakage when
induction seal is removed from the mouth of the container.

77
Induction
sealing
Two types of Induction Sealing Wads :
Capless Sealing Wads:
are used when the container is not meant for reuse and the screwable cap is made redundant. The function of the cap seal is
limited to providing an airtight and spill-proof seal to the contents of the container which are meant for single use only.
The aluminum foil laminate is supplied either pre-cut in container neck shape or in reel form.
Where it is supplied in a reel, it is die cut online and placed onto the container neck.
It is then pressed down by the seal head, the induction cycle is activated and the seal is bonded to the container.

78
Induction
sealing
SEALING TEMPERATURE
• Seal initiation temperature is defined as the heat sealing jaw temperature at which a specific level
of seal strength is obtained and may be determined by plotting the seal strength
versus seal jaw temperature.

79
Induction
sealing
SELECTING SEALANT RESINS
Sealing Performance includes -
• Seal initiation temperature
• Ultimate seal strength
• Hot tack
• Sealing temperature range
• Seal through contamination
• Sealant contributes to other features of the package such as clarity, puncture resistance, abrasion
resistance, tear strength, moisture barrier, and oil and grease resistance.
• Sealant may also need to contribute to the ease of making the structure into a film, such as melt
strength for bubble stability in blown film and drawability for extrusion coating

Polyethylene and ethylene copolymers are the most common sealant resins used in multilayer flexible
packaging. 80
Induction
sealing Resin LDPE LLDPE VLDPE mPE EVA ACR Ionomer
Name Low density polyethylene Linear Low density Very low density Metallocene polyethylene Ethylene vinyl acetate Acid copolymer resin Acid copolymer resin
polyethylene polyethylene (plastomers) partially neutralized with a
metal cation

General characteristics as Good processing in Better toughness than Lower melting point range, Lower melting point, better Lower melting point, better Lower melting point, better Low melt point; excellent
a sealant extrusion coating and LDPE in film applications. broader hot tack, lower clarity, and greater clarity, and greater clarity, and toughness than clarity; low seal initiation
blown film due to its high More difficult to process seal initiation temperature toughness than LLDPE. toughness than LDPE. Low LDPE. Excellent adhesion to temperature; very broad
melt strength (via long than LDPE. than LLDPE. More difficult to process. seal initiation temperature. metal in extrusion coating. hot tack temperature
chain branching). Excellent Low seal initiation Low heat seal initiation and window; excellent oil and
clarity in blown film. temperature and high hot broad hot tack window. grease resistance; excellent
Moderate adhesion to foil tack. Excellent optical properties; good
in extrusion coating. organoleptics. adhesion to metal;
excellent formability;
excellent abrasion
resistance; and depending
on the grade higher
stiffness than ACR, mPE,
and EVAs.

Polymerization process High pressure, free radical Low pressure (1000 psi), Low pressure (1000 psi), Low pressure (1000 psi), High pressure, free radical High pressure, free radical High pressure, free radical
initiated catalyst catalyst catalyst initiated initiated initiated
Comonomer None Butene, hexene, octene Butene, hexene, octene Butene, hexene, octene Vinyl acetate Acrylic acid (AA) or Acrylic acid (AA) or
methacrylic acid (MAA) methacrylic acid (MAA)
MWD Very broad Broad Broad Narrow Very broad Very broad Very broad
Comonomer distribution None Broad Broad Narrow Random Random Random
Long chain branching Yes No No No or limited Yes Yes Yes
Density (g/cc) 0.915–0.93 0.915–0.935 0.89–0.91 0.89–0.91 0.94–0.95 0.94–0.95 0.94–0.95
Typical melting point (°C) 108 123 115–123 95–99 87 (18% VA) 97–103 87–100
Modulus, kpsi (MPa) 30 (207) 30–40 (207–275) 10–20 (69–138) 9–13 (62–89) 7 (48) 20 (138) 7–70 (48–480)

Description of Some Common Ethylene-Based Sealant Resin Families 81

Induction sealing
Summary of Qualitative Assessment of Common Ethylene-Based Sealant Polymers
Attribute LDPE LLDPE VLDPE mPE EVA ACR Ionomer
Low seal initiation ♦♦♦ ♦ ♦♦ ♦♦♦♦♦ ♦♦♦♦♦ ♦♦♦♦ ♦♦♦♦
temperature

Ultimate seal strength ♦♦♦ ♦♦♦♦♦ ♦♦♦♦♦ ♦♦♦♦♦ ♦♦♦ ♦♦♦ ♦♦♦

Peak hot tack strength ♦ ♦♦ ♦♦ ♦♦♦♦♦ ♦ ♦♦♦ ♦♦♦♦

Hot tack temperature ♦ ♦♦ ♦♦♦ ♦ ♦ ♦♦♦♦ ♦♦♦♦♦

window

Seal through ♦♦ ♦♦ ♦♦ ♦♦♦♦ ♦♦ ♦♦♦♦ ♦♦♦♦♦

contamination

Grease and oil ♦♦♦ ♦♦♦ ♦ ♦ ♦ ♦♦♦♦ ♦♦♦♦♦

resistance
Adhesion to PE ♦♦♦♦♦ ♦♦♦♦♦ ♦♦♦♦♦ ♦♦♦♦♦ ♦♦♦♦♦ ♦♦♦♦ ♦♦♦
Adhesion to Al foil ♦♦ ♦♦♦♦♦ ♦♦♦♦
Low MVTR ♦♦♦ ♦♦♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦
Transparency ♦♦ ♦ ♦♦ ♦♦♦ ♦♦♦♦♦ ♦♦♦♦ ♦♦♦♦♦
Melt strength ♦♦♦ ♦♦ ♦ ♦ ♦♦♦ ♦♦♦♦ ♦♦♦♦♦
Tear strength ♦♦♦♦ ♦♦♦♦♦ ♦♦♦♦♦ ♦♦♦♦♦ ♦♦♦♦♦ ♦♦♦ ♦♦
Abrasion resistance ♦♦♦ ♦♦♦ ♦♦ ♦♦ ♦♦ ♦♦♦♦ ♦♦♦♦♦

Puncture resistance ♦♦♦ ♦♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦♦♦♦

Stiffness ♦♦♦ ♦♦♦♦ ♦ ♦ ♦ ♦♦ ♦♦♦♦♦

The greater the number of diamonds, the better the performance is for a given attribute. 82
Liquid bottle - Sealing of liquid
bottles / wad with liner thickness
inside cap
Induction
sealing
Choosing a one piece liner or a two piece liner:
• One piece liner would be used for a single-use product or dry product,
• Two piece liner would be used if there is liquid inside or if the package will be resealed
• Two piece liner makes it possible for a package to function as a resealable, multi-serving container

Liners can be cut a variety of ways:

Disc Cut Heat Seal Liners: Disc cut or round cut liners are the same size as the container (no tabs to
grab).
Tri-Tab Heat Seal Liners: Tri-tab liners have three tabs cut into them for the consumer to grab to
remove the liner.
Lift 'n Peel Heat Seal Liners: Lift 'n peel liners have a half moon on top to easily remove the liner (this is
a one-piece liner).
Top Tab Heat Seal Liners: Top tab liners look very similar to lift 'n peel liners, but it is a two piece liner.
Folded Back Tab Heat Seal Liners: Folded back tab liners utilize a single tab that folds back.
Folded Down Tab Heat Seal Liners: Folded down tab liners utilize a single tab that folds down. 84
Blow-fill- seal for injectables -
bead size, forming and sealing
temperature
Blow-Fill-Seal
(BFS)

Blow-Fill-Seal (BFS) technology was developed in the early 1960s and was initially used for filling many
liquid product categories, for example, nonsterile medical devices, foods, and cosmetics.
The technology has been developed to an extent that today BFS systems are used to aseptically produce
sterile pharmaceutical products such as respiratory solutions, ophthalmic, Biological and wound-care
products throughout the world.

86
Blow-Fill-Seal
(BFS)

Steps involved in BFS technology :

1. Extrusion and parison formation,
2. Blowing,
3. Filling,
4. Sealing

87
88
Blow-Fill-Seal
(BFS)
1. Extrusion molding
• Pharmaceutical BFS process combines the formation of plastic containers by blow/vacuum-molding
extruded pharmaceutical-grade polymers with an aseptic solution filling system.
• Polymer granules are continuously fed to a machine hopper through an adiabatic screw extruder.
• Within the extruder the polymer is subjected to high temperature (usually above 160°C) and pressure
(up to 350 bar or 105 Pa) and melts.
• It is then extruded through a die-and-pin set forming an open-ended tube of molten polymer known as
a parison.
• The parison is supported by sterile air (parison support air) which is fed into its center through a
sterilizing-grade air filter with oil free compressed air.

89
Blow-Fill-Seal
(BFS)
1. Extrusion molding (contd..)
• Parison is held in position by a clamp, which on some machines also serves to seal the parison bottom.
• Mold set consisting of two halves then moves over to the parison and closes around it.
• Molding is facilitated by vacuum slots in the mold.
• Molded plastic is severed from the continuously extruding parison by a hot knife, and is shuttled within
the mold set to the filling position.
• Variety of polymers may be used in the process, low and high-density polyethylene and polypropylene
being the most popular.

90
Blow-Fill-Seal
(BFS)

91
Blow-Fill-Seal
(BFS)
2. Blowing
• Nozzle assembly lowers into the parison until the nozzles form a seal with the neck of the mould.
• Container formation is completed by applying a vacuum on the mould-side of the container and
blowing sterile filtered air into the interior of the container.

92
Blow-Fill-Seal
(BFS)
3. Filling
• Patented electronic fill system delivers a precise dosage of product into the container.
• Nozzles then retract into their original position

93
Blow-Fill-Seal
(BFS)
4. Sealing
• Following completion of the filling process, the top of the container remains semi-molten. Separate
seal moulds close to form the top and hermetically seal the container.
• Moulds open and the container is then conveyed out of the machine.

94
Blow-Fill-Seal
(BFS)
Filling environment
• Aseptic BFS machines are housed within classified clean areas of a minimum specification of class M5.5
(Federal Standard 209E) for 0.5μ particles and greater (or equivalent) at rest.
• Localized filling environment or air shower is of a higher classification, meeting the specification of class
M3.5 (FS 209E) for 0.5μ particles and greater.
• Total particle levels should meet the required specifications and be measured, with the machine at
rest, at defined intervals by means of a laser particle counter (or other suitable instrument) to
demonstrate continued compliance.

95
Blow-Fill-Seal
(BFS)
Filling environment
• BFS technology has the advantage of being able to operate without the continuous presence of
personnel within the clean area.
• So an effective routine cleaning and disinfection program and the adoption of appropriate clean room
behaviour and practices by trained personnel is avoided.
• Within the European forum it is required that the clean room garments be worn to enter the class
M5.5
(FS 209E) clean room are of a standard appropriate for a higher (M3.5) classification clean room

96
Blow-Fill-Seal
(BFS)
Filling environment
• Routine microbiological environmental monitoring program should be established and documented
based on historical and operational data to demonstrate continued compliance with specifications and
to monitor trends i.e., quantitative air and surface monitoring, etc.
• Semiquantitative air monitoring by the use of settle plates can also be useful in producing data
associated with a longer period of time in operation (up to 4 hr exposure).
• Recommended limits for viable contaminants (not specific to BFS processes) in clean rooms are quoted
in various guidelines, including the current USP and EC directive 91/356 (MCA rules and Guidance for
Pharmaceutical Manufacturers and Distributors 1997, Annex 1, see Table 1).
• Alert and action levels should be clearly defined based upon both operational data and published
recommendations.

97
Blow-Fill-Seal
(BFS)
Filling environment

98
Blow-Fill-Seal
(BFS)

Contamination of BFS container from the environment-

• For aseptic BFS, the container is filled in a localized air shower provided with sterile filtered air.
• However, there is a short period of time between container formation and filling, when the open
container is transferred from the parison formation position to the filling position and exposed to the
clean room environment.
• During this shuttling period, there is a possibility for contaminants from the room environment to enter
the container.
• Air used to form the parison (parison support air) is typically sterile filtered air.

99
Blow-Fill-Seal
(BFS)

Contamination of BFS container from the environment-

• If this is not the case, it is also possible for nonsterile air to enter the parison during parison formation.
• It has been demonstrated during a simple practical experiment that broth-filled units (totaling over
44,000) manufactured over several days in a highly contaminated environment remained sterile.
• The environment was contaminated by means of high levels of personnel activity in order to generate
contaminants in keeping with those generated under normal conditions.

100
Blow-Fill-Seal
(BFS)
Contamination from product component -
• As with traditional aseptic filling, in order to comply with pharmaceutical GMP, it is important to minimize
contamination at all stages of manufacture.
• Raw materials should be of a high quality and tested for microbial contamination.
• Water used for product manufacture should be of low bioburden and high purity (preferably water for injection
quality, although this requirement is dependent upon the nature of the product being manufactured).
• A program of bioburden testing for each product batch at various stages of manufacture should be established and
documented. It is dependent upon the manufacturing process, but should as a minimum include bioburden
analysis of bulk solutions prior to any sterile filtration.
• The maximum life of the bulk solution in a nonsterile environment (generally within a mixing tank) should be
limited to prevent increase in bioburden beyond an acceptable level.
• Bioburden testing at this stage should be carried out on samples taken at the end of the holding period to
give
‘‘worst case’’ data. 101
Blow-Fill-Seal
(BFS)
BFS equipment and its handling -
• In order to produce sterile pharmaceutical products with a high degree of sterility confidence, it is of key
importance that the equipment is operated by experienced and trained personnel with a full understanding of
both the technology and aseptic processing.
• Operator intervention during machine operation is limited due to the nature of the technology. However, BFS
machines are complex and some operator activity is required from time to time during normal manufacture.
• There must be clearly documented rules to clarify which activities are prohibited during batch manufacture and
which are permitted.
• For example, if a fault occurs which requires immediate corrective actions involving the sterile product pathway, or
within the direct vicinity of the filling zone, these would typically be prohibited leading to termination of the
product batch.
• Activities such as parison and fill volume adjustments are part of the normal operation of the machinery and are
permitted. There should be a proceduralized means of documenting these activities, however routine they may be.
102
Blow-Fill-Seal
(BFS)

Validation -
• BFS machinery and associated equipment for aseptic manufacture should be constructed in such a way that the
product pathways are of hygienic design with hygienic valves and minimal joints to facilitate cleaning and sterilizing
in place.
• Validation processes :
• 1. Clean in place (CIP),
• 2. Steam in place (SIP)

103
Blow-Fill-Seal
(BFS)
Clean in place (CIP)
• As for all machinery involved in aseptic manufacture, CIP is necessary for all equipment in contact with the
product. This would typically include a bulk mixing tank, transfer lines, and the BFS machine itself, and also a
holding vessel with associated transfer lines.
• CIP validation should be carried out to establish routine CIP practices which clean the manufacturing equipment in
such a way that the products manufactured would be free of contamination and that safety, identity, quality, and
purity of the drug would be within requirements.
• CIP procedures should be established by cleaning validation following the manufacture of ‘‘worst case’’ products
(i.e., those which are most difficult to reduce to acceptable levels due to their solubility or activity).
• Means of measuring CIP efficacy include analysis of swabs taken directly from product contact machine parts and
analysis of rinse waters.
• When establishing areas for swabbing, account needs to be taken of the specific equipment design, and areas that
are potentially most problematic should be selected for analysis (e.g., filter housings or areas which may cause
104
product hold-up).
Blow-Fill-Seal
(BFS)
Steam in place (SIP)
• Aseptic BFS machines are subject to steam-in-place sterilization following standard CIP cycles.
• SIP cycles are routinely measured by thermocouples located in fixed positions along the product pathway.
• Validation of SIP cycles should be carried out to demonstrate that consistent sterilization temperatures are
achieved throughout the equipment to prove that the system can be effectively sterilized.
• Validation should also identify suitable positions for routine use, or justify the fixed probe positions already in
place. The SIP validation is generally carried out with the help of additional thermocouples and should include the
use of biological indicators (appropriate for moist heat sterilization).
• Test locations should include areas which may be prone to air or condensate entrapment.
• An accurate engineering line drawing of the system to aid identification of suitable test locations and document
test locations selected should be available.

105
Glass ampoule - heat sealing
Glass containers

• Glass has been widely used as a drug packaging material

• Glass containers are usually the first choice for pharmaceutical industry for oral and local

administration

• Borosilicate glass is a type of glass with silica and boron trioxide as the main glass-forming

constituents. Borosilicate glasses are known for having very low coefficients of thermal

expansion, making them more resistant to thermal shock than any other common glass.

107
Types of Glass

108
Types of Glass

109
Types of Glass

110
Types of Glass

111
112
Vials
• A glass or plastic container closed with a rubber stopper and sealed with an aluminum
crimp.

• Vials are available for single dosing or for multiple dosing

• Injection vials can be obtained in either neutral or soda glass and occasionally in treated
soda glass

Advantages:
• Glass vials has increased dose flexibility
• Has decrease cost per unit dose
• Cost of handling, transportation and storage is less

Disadvantages:
• Closures fragment may be released into the product when needle is inserted through
the
closure
• Risk of interaction between product and closure
• Repeated withdrawal of injection solution increase the risk of microbial contamination
113
Vials - Quality Control

114
Vial Types, Surface Treatments, Solution Chemistries, and Acceleration Conditions
Evaluated in the Extractables Study

Vial Types Surface Treatments Solutions Storage Acceleration

Temperature
s
• Aluminosilicate • Non-treated • pH 7.0, 25mM • 25°C • Nonautoclaved
• Borosilicate A, Vial A • 3% ammonium citrate buffer • 37°C • 1hr autoclave at
• Borosilicate B, Vial B sulfate • pH 8.0, 25mM • 50°C 121°C
• Borosilicate B, Vial E • Ion-exchange phosphate buffer
• Borosilicate B, Vial F • pH 6.0, 10mM
Hisdine buffer
• Water for
Injecon
(WFI)

115
116
Glass ampoules heat sealing

• The container should be sealed in the aseptic area immediately adjacent to the filling machine.

• In addition to retaining the content of the sterile product, sealing of containers assures sterility of its

contents.

• Temper-proof sealing is essential so as the sterility can be ensured until usage.

• Different approaches have been used for sealing of ampoules and the bottles.

117
Glass ampoules heat sealing

• Ampoules can be sealed either by tip or bead seal or pull seal. Both of the methods require heating with high-
temperature oxygen flame.
• During sealing, the heating must be even and carefully controlled to avoid distortion of the seal.
• It is sometimes necessary to displace the air in the space within the ampoule above the product to prevent
decomposition. This may be done by introducing a stream of inert gas, such as nitrogen or carbon dioxide, during or
after filling with the product. Immediately thereafter, the ampoule is sealed before the gas can diffuse out.
• The tip seals are made by melting sufficient glass at the tip of the ampoules neck to form a bead of glass and close
the opening. Thus, tip seal is also known as bead seals since a bead is formed during melting of the neck.
• Excessive heat of air and gases in the neck cause expansion against the soft glass with the formation of fragile
bubbles at the point of seal.

118
Glass ampoules heat sealing

• Open capillaries at the point of seal or cracks result in leakers.

• Fracture of the neck of ampoule often occurs during sealing if wetting had occurred at the time of filling, Also wet
glass at the neck increases the frequency of bubble formation and contaminating deposits of carbon or oxides as a
result of the effect of the heat of sealing on the droplet of the product.
• Pull seals are made by heating the neck of the rotating ampoule below the tip, then pulling the tip away to form a
small, twisted capillary just prior to being melted closed. Pull sealing is a slower process, but the seals are more
reliable than those from the tip sealing. Powder ampoules or other types having a wide opening must be sealed by
pull-sealing.
• With some sensitive products, it may be necessary to seal the ampoules with pull-seals to prevent combustion
produces of the flame from entering the ampoule at the time of sealing, as might occur with tip-sealing.

119
Vials - Rubber stopper / crimping
of seals
121
122
123
124
125
126
127
128
129
Rubber formulations to reduce moisture
transmission in lyophilisation stoppers
Moisture can reach a lyophilised drug product in a variety of ways. The simplest source of moisture ingress
is a lack of seal integrity in the stopper-vial combination. If there is not a tight seal, moisture can travel
easily into the vial and permeate into the freeze-dried drug product. Residual moisture driven into the
closure—mostly during steam sterilisation and not removed due to insufficient drying conditions—may
affect the drug product, as the captured excess water vapour could be released from the rubber stopper
into the vial headspace and permeate into the drug over time.
Water vapour also can migrate from the environment through the rubber stopper during long-term
storage. Every rubber formulation has a characteristic rate for water vapour to migrate through this
material over time, called Moisture Vapour Transmission Rate (MVTR). This can be measured during
development of a rubber formulation on a vulcanised rubber plate of specific thickness that is used as a
permeation barrier in a humid chamber. The MVTR is expressed in [g/m2 x day], based on a 0.035 inch
thick vulcanised test plate of a specific rubber formulation. 130
Rubber based components
• Rubber components may be made from either natural or synthetic sources. Natural rubber has got
good resealing (multi-dose injection), fragmentation and coring(description for the means by which
particles are created when a needle is passed through a rubber) when compared to synthetic rubber;
but is poor in respect to ageing and chances of moisture and gas permeation and the absorption of
preservative systems is more.
• Most rubber formulation are relatively complex and may contain one or more of the vulcanizing agents,
accelerators, fillers, activators, pigments, antioxidants, lubricants, softeners or waxes. The main types of
rubber used for pharmaceutical products include natural rubber, neoprene, nitrile, butyl, chlorobutyl,
bromobutyl and silicone. Of these silicone is the most expensive and although the most inert, is readily
permeable to moisture, gases and absorbent to certain preservatives.
• Rubber components are likely to contain more additives than plastics. Hence product-package
interactions should be properly tested before they are used for injectable or intravenous type products.
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Rubber closures

• Rubber stopper is used primarily for multiple dose vials and disposable syringes. The rubber polymers
most commonly used are natural, neoprene and butyl rubber. Butyl rubber, nitrile rubber are some
synthetic rubbers used for the manufacturing of closures.
• In the manufacture of rubber closures the types of ingredients commonly found are: Rubber,
Vulcanizing agents, Accelerator/ activator, Extended filer, Reinforced filler, Softener / plasticizer,
Antioxidant, Pigment , Special components waxes
• B.P requirements for rubber closures:
Rubber closures for containers used for aqueous parenteral preparations, powders and freeze dried
products are made of materials obtained by vulcanization(cross-linking) of macromolecular organic
substance (elastomers) with appropriate additives.

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Tests to control quality of rubber caps
This include tests for
1) Quality:
2) Finish
3) Penetrability
4)Fragmentation
5)Self sealability
6) Water
extractive Test
7) Acid or Alkali
Treatment
8) Compatibility
with contents
9) Permeability
to water vapor
10) Absorbance
13) Titration 133
11) Test to
Crimping of seals

• Rubber stopper is used primarily for multiple dose vials and disposable syringes. The
rubber polymers most commonly used are natural, neoprene and butyl rubber. Butyl
rubber, nitrile rubber are some synthetic rubbers used for the manufacturing of
closures.
• In the manufacture of rubber closures the types of ingredients commonly found
are: Rubber, Vulcanizing agents, Accelerator/ activator, Extended filer, Reinforced
filler, Softener / plasticizer, Antioxidant, Pigment , Special components waxes
• B.P requirements for rubber closures:
Rubber closures for containers used for aqueous parenteral preparations, powders
and freeze dried products are made of materials obtained by vulcanization(cross-
linking) of macromolecular organic substance (elastomers) with appropriate additives.

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Summary

• Selection and utilization of Container Closure Systems can greatly affect drug stability
and safety
• Blow-Fill-Seal (BFS) systems and technology are used to aseptically produce
sterile pharmaceuticals products
• USFDA’s QbD (Quality by Design) initiative attempts to provide guidance oh
pharmaceutical development to facilitate design of products and processes that
maximizes the product’s efficacy and safety profile while enhancing product
manfacturability

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References
• https://database.ich.org/sites/default/files/Q7%20Guideline.pdf
• Compatibility Of Pharmaceutical Products And Contact Materials - Dennis Jenke
• https://www.pharmatutor.org/articles/guideline-on-pharmaceutical-product-packing-compatibility
• https://www.slideshare.net/Protik007/pharmaceutical-packaging-incompatibility/4
• https://www.fda.gov/media/70788/download
• http://steriletechportal.pda.org/content/pdajpst/68/5/527.full.pdf
• Container–Content Compatibility Studies: A Pharmaceutical Team’s Integrated Approach - PDA J Pharm
Sci and Tech 2009, 63 285-293
• https://www.expresspharma.in/pharma-ally/selecting-stoppers-for-moisture-sensitive-drug-products/
• www.cpsc.gov
• https://www.containerandpackaging.com/resources/starting-a-business-selecting-the-right-closure/
• https://www.gen-techno.com/assets/docs/presentations/vial_integrity.pdf

187
Abbreviations
• AL - Aluminum • PCTFE - Polychlorotrifluoroethylene (PCTFE)
• BHT - Butylated hydroxytoluene • PQRI – Product Quality Research Institute
• BFS – Blow fill seal • PTP - Press through Packing
• CCI – Container Closure Integrity • PVC - Polyvinyl Chloride
• CZE - Capillary zone electrophoresis • PVC IV - polyvinyl chloride intravenous
• CFF - Cold Form Foil • PVDC -Polyvinylidene chloride (PVDC)
• CDA - Confidential Disclosure Agreement • QbD – Quality by Design
• COC - Cyclic olefin copolymers • QT - quantification threshold
• CFR – Code of Federal Regulations • Rh - Relative Humidity
• DMF – Drug Master File • SVP - Small-Volume Parenterals
• ELSIE - Extractables and Leachables Safety Information Exchange • TBA - 2,4,6-tribromoanisole
• GC/MS - Gas chromatography–mass spectrometry • USP – United States Pharmacopoeia
• HPLC/DAD-MS - High-performance liquid chromatography: photodiode- • VC – Vinyl coating
array-detection combined with mass spectrometry • WVTR - Water Vapour transmission rate
• HS-GC-MS - Head space gas chromatography: mass spectrometry
• ICH - International Conference On Harmonisation Of Technical Requirements
For Registration Of Pharmaceuticals For Human Use
• ICH Q7 - International Conference On Harmonisation Of Technical
Requirements For Registration Of Pharmaceuticals For Human Use; Good
Manufacturing Practice Guide For Active Pharmaceutical Ingredients - Q7
• ICP-MS -Inductively coupled plasma mass spectrometry
• ISO 10993-1:2018 - Biological evaluation of medical devices — Part
1: Evaluation and testing within a risk management process
• LVPs – Large Volume Parenterals
• LC/NMR - Liquid chromatography/nuclear magnetic resonance
• LOD - Limit Of Detection
• LOQ - Limit Of Quantitation
• MEKC - micellar electrokinetic chromatography
• MVTR - Moisture vapor transmission rate
• MW - Molecular Weight
• OP - Outer printing
• layer OTC - over-the-
• counter
188
OTR - Oxygen
Transmission Rate