The present invention relates to an improved frangible seal pouch, more particularly the present invention relates to a pouch wherein chambers are separated by frangible seals for integrated reconstitution and administration of medicament.
BACKGROUND OF THE INVENTION:
Packaging plays a significant role in maintaining product quality and promoting safe and effective use. Every day hospitals and other medical facilities rely on pharmaceutical devices for proper administration of medicines and hence maintaining good health. All these devices should maintain product integrity which may include sterile packaging to ensure of viability and safety of medicines.
Several aseptic packages for storing injectable medications are commercially available. Perhaps the most common aseptic package for injection production is glass vials. Some medications are stored in separate containers and mixed just prior to use. Often this is done to improve the medication's stability or to extend medication's shelf life. This however exposes medication to potentially fatal errors such as mismatching of two constituents during mixing or reconstitution. Consequently, such mixing requires highly trained professionals to ensure proper mixing of the medicines without any contamination. However, during mass immunization or medicament administration during emergencies and disease outbreaks sufficiently trained professionals are not necessarily available. Also, the glass vials which are available are highly susceptible to breakage and requires efficient transportation facilities.

Thus, there arises a need for a packaging, storage and transportation system that addresses above concerns. This invention describes such a package that comprise two separate compartments for proper packaging, storage, transportation and integrated mixing of constituents as well as subsequent administration
QBTECT OF THE INVENTION:
The main object of the present invention is to provide a frangible seal pouch.
Another object of the present invention is to provide a frangible seal pouch with chambers which are separated by frangible seals that can be broken for mixing or integrated reconstitution and subsequent administration of medicament more particularly single and/or multi component vaccines as well as other medicaments.
Yet another object of the invention is to provide a frangible seal pouch which provides a clog free pathway for the administration of medicine.
Yet another object of the invention is to provide a frangible seal pouch appropriate for administration of medication to pediatrics as well as adults.
Yet another object of the invention is to provide low cost frangible seal pouch for one dose administration.
Another object of the invention is to provide a frangible seal pouch for packaging vaccine in a sterile environment.

Yet another object of the invention is to provide a frangible seal pouch capable of keeping multiple constituents of a dose in a single pouch without interaction until so required.
Yet another object of the invention is to provide a frangible seal pouch with compatibility with multiple sterilization methods, safety in transit, tamper resistance, and excellent film clarity.
SUMMARY OF THE INVENTION:
Accordingly, the present invention relates to a frangible seal pouch for integrated reconstitution and administration of medicament. More particularly the present invention relates to a frangible seal pouch for the packaging of sterile vaccines and medicines.
The pouch is a flexible package made from the films or foil laminate or webs in which a product can be stored in an aseptic manner until the time of use. The pouch possesses at least two compartments that may contain two different medications or two components of same medication, either dry -liquid or liquid-liquid, and which can be mixed by rupturing the separating frangible seal at any specified time including just before the administration.
The pouch preferably has an oblong shape with flat back surface characterized by predetermined length and width to facilitate better ergonomics of dose preparation and administration as well as stacking during storage and transport.
Said pouch is sealed from all sides by a strong permanent seal and chambers within the body are separated by relatively weak frangible seal. The overall shape of the pouch is such that no sharp or pointed edges exists.

Said material of construction comprises foil laminate facilitating complete opacity as well as barrier for moisture and air.
Said material of construction comprises of transparent film or web facilitating clear visual observation of product through one side as well as provide barrier to gas and moisture.
Said material of construction comprises a hybrid construction using opaque foil laminate preferably aluminium laminates or similar that provides protection against moisture, light and gas internally and externally, and transparent film or web, facilitating visual observation of product.
In one aspect of the construction, the transparent side has peel off label affixed to protect the contents from light, moisture and air diffusion. Said material of construction comprises of contact layer of polymer that facilitates sealing at different and distinct temperature ranges that yields seals with different strengths conferring frangibility character to seals.
Said frangible seals strengths are modulated by adjusting the seal area.
Said frangible seal strengths are further modulated by adjusting the geometry of seal area.
Said compartments on the pouch are made by process including but not limited to cold forming or thermoforming.
Said compartments on the pouch have capacity to hold powders or liquids of predetermined volumes.

Said compartments on the delivery pouch may be of various shapes more particularly they are dome shaped. In another aspect, the chambers have flat top to facilitate stacking of pouch during storage and transportation. The present invention provides a low cost, handy and easy to use aseptic pouch for the integrated mixing and delivery of sterile medications more particularly vaccines.
The pouch has an optimised spout for the delivery of medicament to prescribed anatomy in the most effective manner.
Said spout is made of materials or their combinations as well as sealing-area geometries enabling its compatibility to industrially common sealing mechanisms such as ultrasonic or thermal sealing.
In one aspect of the invention the sealing area at the base of spout (spout seal boat) is fashioned in shape promoting patient compliance.
Said spout is made of materials or their combinations as well as sealing-area geometries enabling its compatibility to pouch forming materials such as foil laminates, webs and films.
Said molded spout is engineered to contain channel with a predetermined internal diameter allowing modulation of flow rate of medication to suit intended recipient, viscosity of medication, volume of medication. Said molded spout is engineered to contain channel with predetermined length allowing delivery of medication suitable for intended recipient and application of medication in and on desired site.

Said molded spout is engineered to contain orifice with predetermined internal diameter allowing delivery and application of medication at a controlled rate.
Said molded spout is engineered to allow it to interface with various secondary delivery pouches such as but not limited to Luer-Lok allowing a needle to be twisted onto the tip and then locked in place for withdrawing medication or an oral syringe adaptor negating errors resulting in injection of oral medications.
Said molded spout is engineered to bear tamper-evident twist-off cap. In one aspect of invention the said twist-off cap has wings that facilitate uncapping. In another aspect of invention, the spout orifice is capped with a screw cap. In yet another aspect of invention the screw cap covers entire exterior surface of spout offering protection from cross-contamination.
In one aspect of invention, the frangible seal pouch has a needle for the delivery of medicament by injectable route in the most effective manner. In yet another aspect of invention the cap covers entire exterior surface of needle offering protection from cross-contamination.
In yet another aspect of invention, a syringe can be used for withdrawing the reconstituted vaccine from the pouch by inserting the syringe spout within the pouch spout and the dose can be administered by oral route or injectable route.
Therefore, the present invention provides a frangible seal pouch with at least two compartments which provides a uniform flow of the medicine or vaccine to the recipient. Said frangible seal pouch is compatible with many

sterilization methods, provides safety in transit, tamper resistance, and excellent film clarity.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 depicts top view of dual chambered frangible seal pouch (400) with
twist-cap (7).
Fig. 2 depicts the base foil (100) with length wise holding holes (17, 18),
width wise holding hole (16), cavities (13,14) for Chamber formation and a
chevron shaped cavity (15) for formation of spout base (9).
Fig. 3 depicts the lid foil (200) with length wise holding holes (20, 21) and
width wise holding hole (22).
Fig. 4 depicts the spout with spout mouth (6a), spout neck (6b), seal boat
(6c) and twist- cap (7).
Fig. 5A depicts the formation of frangible seals (3.4) before actual sealing of
the foils as observed from the lid foil (200) side.
Fig. 5B depicts the formation of permanent seal (5) as observed from the lid
foil (200) side.
Fig. 6A depicts the vertical cross- section of the spout (6) with screw cap
(10).
Fig. 6B depicts the front view of the spout (6) with screw cap (10).
Fig. 7 depicts the of top view (base foil side) of dual chambered frangible
seal pouch with spout (6) covered with a screw- cap (10).
Fig. 8 depicts the process flow chart for manufacturing frangible seal pouch
(400).
DETAILED DESCRIPTION OF THE INVENTION
In order to obviate the aforementioned drawbacks of existing packaging systems, the present invention relates to a frangible seal pouch and the process of preparing the same.

The invention is now described in detail with reference to the accompanying drawings which depicts some of the preferred embodiments of the invention. Description of the preferred embodiments should not be construed to be limiting the scope of the invention in any way and shall be referenced for the purpose of disclosure only.
The present invention discloses frangible seal pouch with twist-cap design comprising of at least one pouch (P) with at least one spout (6) annexed to the pouch (P), at least one spout base (9) and the pouch (P) comprising of at least two chambers (1, 2) having diluent and powder vaccine respectively and where the chambers (1, 2), the spout base (9) and the spout (6) all arranged on a linear axis and separated by means of a pair of frangible seals (3, 4). The first frangible seal (3) is placed between distal chamber (1) and proximal chamber (2), while the second frangible seal (4) is place between the proximal chamber (2) and spout base (9). A permanent seal (5) is placed on the periphery of the pouch (P) capable of preventing exposure to the moisture or air and spillage of the contents of the chambers (1, 2). The spout (6) comprising of a spout neck (6b) with spout mouth (6a) on its anterior end tipped with spout cap (7/10) and a seal boat (6c) on its posterior side and the chambers (1, 2), spout base (9), spout (6) and spout cap (7/10) are all employed in a manner that on applying appropriate pressure on the chambers shall break the frangible seal (3) and thereby mixing the contents of the chambers (1, 2) to prepare the medicament ready for administration to the subject. This is followed by pressing the chambers gently to break the second frangible seal (4) and making the medicament available to be administered to the subjects through the spout (6) after removing the spout cap (7/10).

The invention further discloses the pouch (P) essentially comprises of at
least one base foil (100) and at least one lid foil (200). Two cavities (13, 14)
and one chevron shaped cavity (15) are formed on to the base foil (100) by
means of cold forming process. The base foil (100) and the lid foils (200) are
5 selected from Aluminium laminates based on their capabilities to resist the
moisture and light ingress. The thickness of the base foil (100) is such that to be capable of being cold formed, while the lid foil (200) can be thinner than the base foil (100).
10 Two length wise holding holes (17, 18) and one width wise holding hole
(16) punched on the base foil (100) similarly two length wise holding holes (20, 21) and one width wise holding hole (22) punched on the lid foil (200). The length wise holding holes (17, 18) and (20, 21) are capable of holding the base foil (100) and lid foil (200) respectively while sealing, whereas the
15 width wise holes (16, 22) will facilitate accurate placement of seal boat (6c)
during sealing of the spout (6) on the base foil.
The invention further discloses the spout (6) comprises of at least one spout
mouth (6a), at least one spout neck (6b), at least one seal boat (6c) and at
20 least one spout cap (7/10). The length of the spout neck (6b) may range from
24 mm to 48 mm while the diameter of the spout mouth (6a) may range from 1.5 mm to 6 mm. The seal boat (6c) comprises of ribs to form strong heat seal at the spout base (9).
25 It is to be noted that the present invention discloses a frangible seal pouch
with container closure integrity, and which is capable of minimizing Water Vapor Transmission Rate of frangible seal pouch in the process protecting the medicament inside from being subjected to moisture and light.
10

Accordingly, the spout (6) material is selected from materials that are
approved for use in injectable or oral delivery of the vaccines and comprises
of but not limited to low-density polyethylene (LDPE), linear low-density
polyethylene (LLDPE), high-density polyethylene (HDPE),
5 polytetrafluoroethylene (PTFE), polyethylene terephthalate (PET) or their
combinations in various ratios to modulate transparency, stiffness, and thermoplastic behavior of spout molded from these materials.
In one of the other preferred embodiments the present invention discloses
10 a frangible seal pouch (400) comprises of at least one pouch (P), at least one
spout (31) with threads (11) formed on the spout to enable screw cap (10) to
move clockwise or anti clockwise for opening and closing. The spout (31)
comprising of a spout neck (31b) with spout mouth (31a) on its anterior end
tipped with screw-on spout cap (10) and a seal boat (31c) on its posterior
15 side capable of being affixed onto said spout base (9), said spout neck (31b)
being threaded to facilitate the affixing of said screw cap (10) on the spout (31), to protect the spout from contamination before administration of medicament to a subject (Fig. 6a, 6b, 7).
20 The present invention also discloses that the optimal dimensions of the
pouch to facilitate better ergonomics of dose preparation and administration as well as stacking during storage and transport. Thus, the pouch (P) of the present invention has an oblong shape with flat back surface. The length of the spout (6) is in the range of 97 mm to 109 mm more
25 preferably 103.5 mm (see table 5 below). This length includes the length of
the spout (6) which is in the range of 28 mm to 38 mm more preferably 33.7 mm. Thus, the optimum length of the pouch (P) excluding the spout (6) is optimized at 69.8 mm. To optimize the quantum of the medicament i.e. the diluent and powder vaccine in their respective chambers the optimal width
11

of the pouch is in the range of 28 mm to 38 mm more preferably 33 mm (see Table 5).
It is further disclosed that the length of the spout base (9) is 21.32 ± 0.20 mm,
5 the width of the seal boat (31c) is 7.00 ± 0.20 mm and the total length from
the seal boat (31c) to spout mouth (31a) with twist cap (7) is 40.70 ± 0.30 mm.
The present invention further discloses a method of manufacturing
frangible seal pouch (400) for integrated reconstitution and administration
10 of medicament. The method significantly prevents the medicament from
being subjected to excessive heat at the time of sealing.
The method of manufacturing the frangible seal pouch (400) comprises of multiples steps starting from selecting foils for lid foil (200) and base foil
15 (100), said base foil (100) being thicker than said lid foil (200) followed by
aligning one each of base foil (100) with the lid foil (200) and cutting it to size using a sterilized cutting tool and punching holding holes (17, 18, 20, 21), and widthwise holes (16) in base foil (100) and corresponding widthwise hole (22) in lid foil (200).
20
The method of manufacturing the pouch (P) comprises of forming the cavities (13, 14, 15) in the base foil by cold forming process followed by sealing the spout (6) by its seal boat (6c) in the cavity (15) of said base foil (100) by heat sealing process.
25
The method of manufacturing the frangible seal pouch further comprises of sterilization of the foils (100, 200) by subjecting them to the process of gamma irradiation. After sterilization the cavities (13, 14) are filled with liquid component and powder component of the medicament in an aseptic
12

environment followed by placing the lid foil (200) over base foil (100) by aligning the holding holes of lid foil (20, 21) over the holding holes of base foil (17,18) (Fig. 8).
5 The method further comprises of sealing the aligned foils (100, 200) around
the cavities at a temperature range of 145°C ± 5°C to form frangible seals (3,
4) thereby forming chambers (1, 2) and spout base (9) and sealing the pouch
permanently at the periphery at temperature range of 195°C ± 5°C to form
permanent seal (5). Once sealed the excess foil from the sides of the pouch
10 is cut to obtain the final frangible seal pouch (400) (Fig. 8).
Said foils (100, 200) preferably made of aluminum laminates and capable of to resisting the moisture and light ingress and the base foil (100) is thick enough to be capable of undergoing cold forming to form cavities (13, 14)
15
The method of punching the holes in the foils (100, 200) comprises the steps of cutting the said base foil (100) and lid foil (200) in desired dimensions with the help of a sterile cutting tool followed by aligning the foils respectively for punching followed by punching length wise holding holes
20 (17, 18) in the base foil (100) and length wise holding holes (20, 21) in the lid
foil (200) and also punching a widthwise hole (16) in the base foil (100) and punching a widthwise hole (22) in the lid foil (200) (Fig. 8).
The method formation of the cavities in the base foil (100) and the lid foil
25 (200) comprises the steps of placing said pre- cut base foil (100) in the
chamber forming machine and forming the cavities (13, 14) and the chevron shaped cavity (15) in the base foil (100) through cold forming process and placing said spout seal boat (6c) on the chevron shaped cavity (15) and sealing it with the base foil (100) by hot pressing.
13

Example:
The following example is provided for the purpose of illustrating the best mode of working the invention and should not be considered as limiting the invention in any way.
In the following example a dual chamber frangible seal pouch was prepared by way of the following steps:
Selection of foil material for pouch formation: The aluminium laminates were selected based on their capabilities to resist the moisture and light ingress. The composition of base foil (100) (for preparing chambers) and the lid foil (200) (for lidding the chambers) is given in Table 1.
Table 1: Composition of Base foil and Lid foil laminates used for manufacturing frangible seal pouch

Composition (Base foil) Thickness (Base foil) Composition (Lid foil) Thickness (Lid foil)
OPA (Oriented poly amide) 25.0 ± 2.5µm PET
(Polyethylene
terephthalate) 12.0 ± 1.2µm
Adhesive 3.5 ± 0 .9 g/m 2 Adhesive 3.0 ± 0 .9g/m 2
Primer 1.6 g/m 2 Aluminium foil 20.0 ± 1.6µm
Aluminium foil 45µm Adhesive 3.0 g/m 2
Adhesive 3.0 g/m 2 PE film 60.0 ± 6.0µm
Polyethylene film (PE film) 60.0 ± 6.0 µm
The PE film was used as the product contact surface.
Both base foil (100) and lid foil (200) laminates were evaluated for various
parameters as mentioned in Table 2.
14

Table 2: Evaluation parameters and their values for base foil and lid foil

Sr. Parameter Base foil Lid foil
No 1

Appearance Uniform in colour, Uniform in colour, texture and
2 texture and finish finish

Flex Crack 90 76
resistance
(no. of pinholes/
3 300 cm2)

Gloss (%age) 20o: 23.9 20o: 42.1
60o: 95.5 60o: 128.7
4 5 85o: 67.4 85o: 58.1

Grammage (GSM) 228 219

Heavy metal Cd: 5.1 Cd: 6.6
analysis (ppm) Pb: 2.0 Pb: 3.1
Hg: Not detected Hg: Not detected
Cr: 11.5 Cr: 32.2
6 Antimony: 10 Antimony: 0.002

Overall migration (i) With distilled (i) With distilled water at 40oC for
(extraction value; water at 40oC for 10 days: 6.78 (no color migration)
mg/L) 10 days: 8.07 (no (ii) With
color migration) 3% acetic
(ii) With 3% acetic acid at
acid at 40oC for 10 40oC for
days: 8.97 (no 10 days:
color migration) 8.55 (no
(iii) With 10% color
ethanol at 40oC for migration)
10 days: 8.28 (no (iii) With 10% ethanol at 40oC for
color migration) 10 days: 8.57 (no color migration)
(iv) With n- (iv) With n-heptane at 38oC for 30
heptane at 38oC for 30 min.: 4.93 (no min.: 8.40 (no color migration)
7 color migration)

Peel strength 0.79/0.65 1.38/ delamination not possible
(Kgf/25 mm width; outer to
8 inner layer)

Seal strength 0.33 79.88
(Kgf/25mm
9 width)

Coefficient of Static: 0.22 Static: 0.40
friction (film to film) Dynamic: 0.17 Dynamic: 0.31
15

10
11 12 Coefficient of friction (film to metal) Static: 0.12 Dynamic: 0.09 Static: 0.16 Dynamic: 0.14

Weight (gm/m2) 216.3 ± 0.3 133.7 ± 1.0

Total thickness (µm) 119 8484 84
Sterilization validation of Aluminium laminates used for making frangible seal pouch:
Gamma irradiation method was adopted for the sterilization of aluminium
laminates. The verification dose for the gamma irradiation sterilization of
5 base foil (100) was calculated by evaluating the initial bioburden of ten
samples of aluminium foil laminate not less than 60 cm2 size. The average bioburden was calculated at 1.22 cfu/ item. The verification dose was evaluated as 1.7 KGy (a range of 1.53 KGy to 1.87 KGy). Based on the verification dose, the final sterilization dose to achieve a Sterilization
10 Assurance Level (SAL) of 10-6 was calculated as a minimum of 15.0 KGy.
The maximum acceptable dose was calculated by exposing the base foil (100) at doses of 25 and 50 KGy followed by the evaluation of various parameters such as tensile strength in longitudinal and transverse direction, elongation at break in longitudinal direction and transverse direction and
15 bursting strength. All the parameters were observed to be with in
acceptance criteria (Table 3).
Table 3: Evaluation parameters of the base foil before and after gamma irradiation at 25 KGy and 50 KGy dose levels.
20

Test Un irradiated Samples irradiated Samples
samples at 25 KGy irradiated at 50 KGy
Tensile strength- 178.9 186.3 190.6
Longitudinal
direction (MPa)
16

Tensile strength-Transverse direction (MPa) 179.3 186.6 190.9
Elongation at break-Longitudinal direction (%) 1.3 1.5 1.6
Elongation at break- Transverse direction (%) 1.4 1.6 1.6
Bursting strength (Kg/cm2) 13.2 12.7 12.5
The dose mapping was also conducted to establish the distribution of
radiation dose with in the irradiation carton and also to evaluate the
minimum and maximum doses exposed to the material. The minimum dose
5 recorded was 19.30 kGy and the maximum dose to which the material was
exposed was 27.29 KGy. The dose uniformity ratio (maximum dose/ minimum dose) was calculated as 1.41.
Once the sterilization validation data for base foil (100) was established, the
10 lid foil (200) was also irradiated at the gamma irradiation dose of 25 KGy
followed by its sterility testing. The irradiated lid foil (200) was found to be sterile.
Process for frangible seal pouch formation: This process consists of
following steps:
Cutting of base foil (100) and lid foil (200):
Both the base foil (100) and lid foil (200) were manually cut in the
dimensions of 280 mm x 160 mm and 220 mm x 160 mm respectively with
the help of sterile cutting tool. These pre-cut foils were used for further
processing.
Cold forming of pre-cut foils and spout sealing:
17

The pre- cut base foil (100) was placed in the chamber forming machine, to make the chambers through cold forming process at 23oC ± 2oC. The force of 25 KN ± 10 KN was applied to the pre-cut base foil (100) through a set of plungers to form two chambers in the series; each with a volume of 2.25 mL ± 0.05mL. A chevron shaped cavity was also formed in series with one of the chambers in the pre-cut base foil (100). This cavity will serve to hold and seal the spout in further steps, by thermo-sealing. The drawing of twist- cap spout used is shown Fig. 4 .
For spout attachment, the spout was placed on the chevron shaped cavity and was sealed with the base foil (100) at a temperature of 195oC ± 5oC.
Punching of base foil (100) and lid foil (200): Two holes were punched lengthwise in both the foils with a specialized punching tool. These holes will help to prevent the movement of foils at the time of sealing. Both the foils were also punched/ cut width wise at the top to avoid accidental sealing of foil with spout neck. The base foil (100) with cold formed chambers with attached spout, two length wise holes and a width wise punch (Fig. 2) and the lid foil (200) with two length wise holes and a width wise punch (Fig. 3) were sterilized by gamma irradiation at an irradiation dose of 25 KGy.
Filling of powder vaccine and diluent: The irradiated base foil (100) was placed on the machine platform under aseptic conditions with a nitrogen atmosphere with percent relative humidity of <5.0%. One chamber of the pouch (P) which is closer to the spout i.e. proximal chamber (2) (Fig. 1) was filled with powder vaccine using Kinematics portable powder filler (Model no. 4400/ VC). In the distal chamber (1) (Fig. 1), the diluent, to be used for reconstitution of powder vaccine, was filled using Flexicon PF6 liquid filling machine.
18

Frangible sealing and permanent sealing of pouch: Once powder vaccine and diluent were filled in respective chambers, the lid foil (200) was placed over the base foil (100) followed by frangible sealing at a temperature of 145ºC ± 5ºC. Two frangible seals were made, one (3) in between the powder and liquid chamber and other (4) between the powder chamber and the spout. The width of first frangible seal (3) was optimized as 2.2 mm and the second frangible seal (4) as 2.8 mm (Fig. 5a). The frangible sealed pouches were sealed permanently at the periphery at a temperature of 195oC ± 5oC. These frangible seal pouches were trimmed from all the sides to obtain final frangible seal pouches. The schematic diagram of final frangible seal pouch thus obtained is shown in Fig. 5b.
Evaluation parameters of frangible seal pouch (with twist cap spout):
The frangible seal pouches were evaluated for the following parameters-
Container Closure Integrity Testing: This test was conducted to verify the
integrity of pouches in terms of any leaks, using LF- S11 benchtop leak
tester. Vacuum Decay Method which is a non-invasive, non-destructive
method of inspecting packs to ensure a leak-free quality product, was used.
5 An appropriate level of vacuum is established inside the testing chamber
followed by stabilization of system. The leaks were identified by measuring
the vacuum level change. It was observed that all the frangible seal pouch
samples were conforming with no significant variation in the vacuum with
time. All the frangible seal pouch samples were observed to be leak- free.
10 Water Vapor Transmission rate: This test was conducted to understand the
rate of diffusion of moisture through the frangible seals and if there is any moisture uptake in the chambers contents from the atmosphere under different temperature conditions and vice versa. For this, the frangible seal pouches were prepared as- (i) both the chambers empty (ii) one chamber
19

filled with HPLC grade water and another empty or (iii) both the chambers filled with HPLC grade water were prepared. These pouches were tested at (i) temperature of 25°C± 0.5°C and a relative humidity of 60% ±3% and (ii) temperature of 40°C± 0.5°C and a relative humidity of 75% ± 3%. The water vapor transmission from the chambers and through the frangible seals at 25°C± 0.5°C and a relative humidity of 60% ±3% was observed to be in the range of 0.0 to 0.00021 gram/pack/day and 0.00005 to 0.00012 gram/pack/ day respectively. Under the temperature condition of 40°C± 0.5°C and a relative humidity of 75% ± 3%, the values were 0.00006 to 0.00108 grams/ pack/ day and 0.0 to 0.00006 grams/ pack/ day respectively.
Evaluation of temperature inside the chamber at the time of sealing: The objective was to determine the maximum temperature that can be reached with in the chambers during sealing process. It was observed that a maximum temperature of 25.7°C was reached during the sealing process.
All the above-mentioned tests are summarized in the Table 4 given below. Table 4: Test parameters and their results for frangible seal pouch

Test Parameter

Method Details

Results

Container-Closure Integrity Testing
Water Vapor Transmission rate (WVTR)

LF- Sll benchtop leak tester. Vacuum Decay Method was used.
Rate of diffusion of moisture through the frangible seals, moisture uptake in the chambers contents at 25°C± 0.5°C/%RH 60% ± 3% and 40°C± 0.5°C/ %RH 75% ±3%.

No significant variation in the vacuum with time. All the frangible seal pouch samples were observed to be leak- free.
At 25°C± 0.5°C/%RH 60% ± 3%: WVTR from the chambers - 0.0 to 0.00021 gram/pack/day WVTR from the frangible seals: 0.00005 to 0.00012 gram/pack/ day
At 40°C± 0.5°C/ %RH 75% ± 3%:
WVTR from the chambers:
0.00006 to 0.00108 grams/ pack/
day

WVTR from the frangible seals: 0.0 to 0.00006 grams/ pack/ day

Evaluation of
temperature
inside the
chamber at the time of sealing

Star-Oddi DST nano-T temperature recorder

A temperature of 25.7°C was reached during sealing of chambers

Based on the example all the critical processing parameters (CPP) for final frangible seal pouch design are as provided in Table 5:
Table 5: Critical Processing Parameters for frangible seal pouch

Sr. No. Critical Processing Parameter Measured Values
1 Chamber volume (mL) 2.67
2 Maximum fill volume (for liquid; ml); n=3 2.35
3 Chamber depth (mm) 7.50
4 Frangible sealing temperature (°C); n=3 145.0 ± 5.0
5 Permanent sealing temperature (°C); n=3 195.0 ± 5.0
6 Spout sealing temperature (°C); n=3 195.0 ± 5.0
7 Final Pouch length (including spout; mm) 103.5
8 Final Pouch width (mm) 33.0
9 Frangible seal strength (N/15mm) 10.0
10 Permanent seal strength (N/15mm) 25.0
11 Force required to break frangible seal (N); n=3 145.0 ± 5.0
tn=3 represents average of 03 independent values ± SD.

We claim:

A frangible seal pouch for integrated reconstitution and administration of medicament wherein said frangible seal pouch (400) comprises of
- at least one pouch (P)
- at least one spout (6) wherein

- said pouch (P) of predetermined dimensions comprises of at least two chambers (1, 2) having diluent and powder vaccine respectively, and at least one spout base (9), all arranged on a linear axis and separated by means of frangible seals (3,4),
- said spout (6) comprising of a spout neck (6b) with spout mouth (6a) on its anterior end tipped with spout cap (7/10) and a seal boat (6c) on its posterior side capable of being affixed onto said spout base (9),
wherein said frangible seal pouch is capable of providing a clog free pathway for administration of medicament to a subject.
A frangible seal pouch as claimed in claim 1 wherein said pouch (P) comprises of thicker base foil (100) having 3 cavities (13, 14, 15) arranged in linear axis and holding holes (16,17,18), and thinner lid foil (200) having holding holes (20,21,22), said base foil (100) and lid foil (200) being adhered in a manner to form
distal chamber (1) and proximal chamber (2 ) separated by first
frangible seal (3),
- proximal chamber and spout base (9) separated by second frangible seal (4), and
- permanent seal (5) around the periphery to form said pouch (P).

A frangible seal pouch as claimed in claim 2 wherein said base foil (100) is of a thickness in the range of 75 |am to 125 |am and lid foil (200) is of a thickness in the range of 75 |am to 100 jxm.
A frangible seal pouch as claimed in claim 1 wherein said predetermined dimensions of said pouch are in the range of 97 mm to 109 mm in length more preferably 103.5 mm, and 28 mm to 38 mm in width more preferably 33 mm.
A frangible seal pouch as claimed in claim 1 wherein said spout (6) comprises of a spout mouth (6a), spout neck (6b) and seal boat (6c) wherein the diameter and length of said spout neck (6b) is optimized to prevent clogging of medicament during administration.
A frangible seal pouch as claimed in claim 1 and claim 5, wherein said spout (6) is capped with spout cap.
A frangible seal pouch as claimed in claim 6 wherein said spout cap is selected from twist cap (7) or screw cap (10).
A frangible seal pouch as claimed in claim 5 wherein length of said spout neck (6b) ranges from 24 mm to 48 mm and diameter ranges from 1.5 mm to 6 mm.
A frangible seal pouch as claimed in claim 8 wherein said length of said spout neck (6b) preferably in the range of 34.0 mm ± 7.0 mm and diameter preferably in the range of 2.52 mm ± 0.75 mm.

A frangible seal pouch as claimed in claim 8 and 9 wherein said length of said spout neck (6b) is 27.0 mm and diameter is 3.25 mm for optimal delivery of medicament.
A frangible seal pouch for integrated reconstitution and administration of medicament, said frangible seal pouch (400) comprises of
- at least one pouch (P),
- at least one spout with threads (31) wherein
said pouch (P) comprising of at least two chambers (1, 2) having diluent and powder vaccine respectively, and at least one spout base (9), all arranged on a linear axis and connected by means of a pair of frangible seals (3,4),
- said spout (31) comprising of a spout neck (31b) with spout
mouth (31a) on its anterior end tipped with screw-on spout cap
(10) and a seal boat (31c) on its posterior side capable of being
affixed onto said spout base (9), said spout neck (31b) being
threaded to facilitate the affixing of said screw-on spout cap for
opening and closing during administration of medicament to a
subject.
A method of manufacturing frangible seal pouch for integrated
reconstitution and administration of medicament said method
comprising the steps of:
- selecting foils for lid foil (200) and base foil (100), said base foil (100) being thicker than said lid foil (200), aligning one each of base foil (100) with the lid foil (200) and cutting it to size using a cutting tool and punching holding

holes (17,18, 20, 21), and widthwise holes in base foil (16) and corresponding widthwise hole in lid foil (22),
- forming the cavities (13,14,15) in the base foil by cold forming process,
- sealing the spout (6) by its seal boat (6c) in the cavity (15) of said base foil (100) by heat sealing process,
sterilization by irradiation,
- filling the cavities (13,14) with liquid component and powder component of the medicament,
- placing the lid foil (200) over base foil (100) by aligning the holding holes of lid foil (20, 21) over the holding holes of base foil (17,18),
sealing the said aligned foils around the cavities at a temperature range of 145°C ± 5°C to form frangible seals (3,4) thereby forming chambers (1, 2) and spout base (9), sealing said frangible sealed pouches permanently at the periphery at temperature range of 195°C ± 5°C to form permanent seal (5),
- cutting the excess foil from the sides of the permanent seal to
obtain the final frangible seal pouch (400).
A method of manufacturing frangible seal pouch as claimed in claim 12 wherein said foils (100, 200) comprise materials that are capable of resisting moisture and light ingress, preferably aluminium laminates.
A method of manufacturing frangible seal pouch as claimed in claim 12 wherein said base foil (100) is subjected to cold forming to form cavities (13,14,15).

A method of manufacturing frangible seal pouch as claimed in claim 12 wherein punching holding holes in said base foil (100) and said lid foil (200) comprises the steps of
- cutting the said base foil (100) and lid foil (200) in desired
dimensions with the help of a sterile cutting tool,
aligning the foils respectively for punching,
- punching length wise holding holes (17, 18) in the base foil (100),
- punching length wise holding holes (20, 21) in the lid foil (200),
- punching a widthwise hole (16) in the base foil (100),
- punching a widthwise hole (22) in the lid foil (200).
A method of manufacturing frangible seal pouch as claimed in claim 12 wherein formation of the cavities in the base foil (100) comprises the steps of
- placing said pre- cut base foil (100) in the chamber forming machine,
- forming said cavities (13, 14) and the chevron shaped cavity (15) in the base foil (100) through cold forming process,
- placing said spout seal boat (6c) on the chevron shaped cavity (15) and sealing it with the base foil (100) by hot pressing.
A method of manufacturing frangible seal pouch as claimed in claim 12 wherein said base foil (100) and said lid foil (200) are sterilized by exposing said base foil (100) and lid foil (200) to gamma irradiations of the range of minimum 15.0 KGy to achieve
Sterilization Assurance Level (SAL) of 106-

A method of manufacturing frangible seal pouch as claimed in
claim 12 wherein the filling of the medicament into said chamber
(1) and chamber (2) comprises the steps of
- filling of powder vaccine into chamber 2 by placing the base foil (100) on the machine platform under aseptic conditions with a nitrogen atmosphere with percent relative humidity of <5.0%, followed by
- filling said chamber 1 with the diluent.
A method of application of frangible seal pouch, said method comprising the steps of :
- pressing the distal chamber (1) gently till the frangible seal (3) gives way allowing the diluent to enter the proximal chamber (2) containing the powder vaccine,
- shaking the pouch (P) gently to mix the contents of the chambers (1, 2) to prepare the medicament,
- opening the spout cap,
- placing the spout near the orifice of a subject,
- pressing the chambers further to break the second frangible seal (4) to administer said medicament to said subject.