WO1993022073A1 - Removal of foreign particles from alum-adsorbed products - Google Patents

Removal of foreign particles from alum-adsorbed products Download PDF

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Publication number
WO1993022073A1
WO1993022073A1 PCT/US1993/003945 US9303945W WO9322073A1 WO 1993022073 A1 WO1993022073 A1 WO 1993022073A1 US 9303945 W US9303945 W US 9303945W WO 9322073 A1 WO9322073 A1 WO 9322073A1
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WO
WIPO (PCT)
Prior art keywords
alum
microns
sieve
product
particles
Prior art date
Application number
PCT/US1993/003945
Other languages
French (fr)
Inventor
Inc. Merck & Co.
Mark S. Rienstra
Original Assignee
Merck & Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co Inc filed Critical Merck & Co Inc
Publication of WO1993022073A1 publication Critical patent/WO1993022073A1/en

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B07—SEPARATING SOLIDS FROM SOLIDS; SORTING
    • B07B—SEPARATING SOLIDS FROM SOLIDS BY SIEVING, SCREENING, SIFTING OR BY USING GAS CURRENTS; SEPARATING BY OTHER DRY METHODS APPLICABLE TO BULK MATERIAL, e.g. LOOSE ARTICLES FIT TO BE HANDLED LIKE BULK MATERIAL
    • B07B1/00—Sieving, screening, sifting, or sorting solid materials using networks, gratings, grids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D29/00—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor
    • B01D29/01—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor with flat filtering elements
    • B01D29/03—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor with flat filtering elements self-supporting
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D43/00—Separating particles from liquids, or liquids from solids, otherwise than by sedimentation or filtration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants

Definitions

  • the current method for removing foreign particulate matter of a size equal to or greater than about 50 microns from alum-adsorbed vaccine particle preparations comprises visual inspection of
  • the foreign particles equal to or greater than about 50 microns in size may form due to the inherrent properties of the alum-adsorbed product or can arise due to the contact of the product with equipment and machinery used for preparation, storage and dispensing of the product.
  • an object of the present invention to provide a process for the selective removal of foreign particulate matter equal to or greater than about 50 microns from alum-adsorbed particle vaccine products without negatively
  • Alum-adsorbed vaccine product or other liquid not amenable to traditional filtration, is passed through a small pore size sieve which
  • the small pore size sieve is placed into a housing and the housing is placed in-line between the product or liquid reservoir and the appropriate dispensing vials or liquid receiving containers.
  • Figure 1 - a schematic diagram of the small pore size sieve placed in the filter housing showing the passage of product through the sieve removing particles equal to or greater than about 50 mircons in size.
  • Figure 2 - a schematic diagram of a complete
  • Figure 3 particle size distribution of alum- adsorbed Recombivax HB at equilibrium.
  • the present invention is useful for the selective removal of particles equal to or greater than about 50 microns in size from any alum-adsorbed particle vaccine or liquid suspension product including but not limited to any antigen or antigen-carrier
  • antigen-carrier conjugates can be any antigen or antigen-carrier conjugate which may be adsorbed onto alum (potassium aluminum sulfate) or other aluminum containing adjuvants.
  • Adjuvants containing aluminum include, but are not limted to, alum, aluminum hydroxide, and aluminum hydroxy phosphate.
  • the process of the present invention may be used with any alum-adsorbed vaccine, including but not limited to Recombivax HB, Pedvax HIB and hepatitis A vaccine.
  • the process of the present invention may also be used to selectively remove particles of 50 microns or greater from other liquids including alum suspensions, fine particulate liquid suspensions, and rehydrated lyophilyzed products, without product loss.
  • Any liquid suspension which cannot be filtered by traditional standard filtration techniques for example liquid suspensions desired to contain
  • particles smaller than about 50 microns may utilize the process of the present invention to selectively remove particles of 50 microns or greater.
  • a reservoir containing the liquid to be dispensed to individual vials or into a suitable liquid receiving container is attached to a filling line which delivers the suspension to the individual vials or receiving container (Figure 2).
  • the small pore size sieve is placed into a suitable housing ( Figure 1) and the housing is placed in-line between the liquid suspension reservoir and the vials or receiving container into which the liquid is dispensed ( Figure 2).
  • the liquid in the reservoir is forced through the small pore size sieve which
  • the small pore size sieve may be constructed of any suitable material, with 316 stainless steel being the most preferred.
  • the sieve may be used as a multi-layered unit by stacking the sieves one on top of the other in a single sieve housing.
  • one sieve may be utilized per sieve housing, with one or more sieve housings placed in-line at one time.
  • the small pore sieves contain pores with a size between approximately 20 to 40 microns, with pores of about 36 microns preferred.
  • a pilot scale testing demonstrated the success of a stainless steel wire mesh sieve in selectively separating 50 micron or greated sized particles from Recombivax HB alum-adsorbed product particles during the sterile vial filling operation.
  • the sieve configuration ( Figure 1) consists of a 47 mm, 400 mesh (36 micron pore size) 316 stainless steel disk used with a standard 47 mm Millipore or other appropriate sieve housing. The housing is placed in line between the filling syringe and the filling needle as illustrated in Figure 2.
  • the alum-adsorbed product (Recombivax HB) particle size distribution at equilibrium contains particles within the size range of approximately 1 micron to
  • particles of about 50 microns or greater from various human vaccine are particles of about 50 microns or greater from various human vaccine
  • Recombivax HB Three different losts of alum-adsorbed particle products (Recombivax HB) were processed to remove foreign particles, of about 50 microns and greater size by passage through an in-line sieve during the sterile vial filling procedure.
  • concentration of product filled on this line was also constant, 10 mcg/ml. Approximately 42,000 vials were filled.

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Mycology (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)

Abstract

A process for the selective removal of foreign particles, generally equal to or greater than about 50 microns in size, from an alum-adsorbed product is disclosed. The alum-adsorbed product is passed through a small pore size mesh sieve during the filling of vials, which selectively removes particles equal to or greater than about 50 microns and allows product particles smaller than about 50 microns to traverse the screen. The process of the present invention results in an alum-adsorbed product which is substantially free from foreign particles equal to or greater than about 50 microns in size.

Description

TITLE OF THE INVENTION
REMOVAL OF FOREIGN PARTICLES FROM ALUM-ADSORBED
PRODUCTS
BACKGROUND OF THE INVENTION
The current method for removing foreign particulate matter of a size equal to or greater than about 50 microns from alum-adsorbed vaccine particle preparations comprises visual inspection of
individual containers of the vaccine particle
preparation and removing any visible foreign
particle-bearing containers from the remaining lot. This process is time consuming, inefficient and expensive. In addition, due to the nature of the product (alum-adsorbed particle vaccines) this procedure of visual inspection is subject to interference by artifacts which can cause containers to be falsely rejected, and can allow 50 microns or greater foreign particle-bearing containers to be kept. It is also possible that entire lots of a product can be rejected by the presence of foreign particulate matter equal to or greater than about 50 microns in the containers.
The foreign particles equal to or greater than about 50 microns in size may form due to the inherrent properties of the alum-adsorbed product or can arise due to the contact of the product with equipment and machinery used for preparation, storage and dispensing of the product.
OBJECTS OF THE INVENTION
It is, accordingly, an object of the present invention to provide a process for the selective removal of foreign particulate matter equal to or greater than about 50 microns from alum-adsorbed particle vaccine products without negatively
affecting the product itself. It is also an object of the present invention to provide a process for the selective removal of particulate matter equal to or greater than about 50 microns from liquids, such as suspensions which cannot be filtered by traditional means.
SUMMARY OF THE INVENTION
Alum-adsorbed vaccine product, or other liquid not amenable to traditional filtration, is passed through a small pore size sieve which
selectively removes particles equal to or greater than about 50 microns, and the 50 microns or greater particle-free product is dispensed directly into the appropriate containers. The small pore size sieve is placed into a housing and the housing is placed in-line between the product or liquid reservoir and the appropriate dispensing vials or liquid receiving containers.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 - a schematic diagram of the small pore size sieve placed in the filter housing showing the passage of product through the sieve removing particles equal to or greater than about 50 mircons in size.
Figure 2 - a schematic diagram of a complete
system of removing particles equal to or greater than about 50 microns from a product in a reservoir, by an in-line small pore size sieve in a housing between the reservoir and a dispensing vial or liquid receiving vessel.
Figure 3 - particle size distribution of alum- adsorbed Recombivax HB at equilibrium.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is useful for the selective removal of particles equal to or greater than about 50 microns in size from any alum-adsorbed particle vaccine or liquid suspension product including but not limited to any antigen or antigen-carrier
conjugate adsorbed onto alum or other
aluminum-containing adjuvants. Antigens or
antigen-carrier conjugates can be any antigen or antigen-carrier conjugate which may be adsorbed onto alum (potassium aluminum sulfate) or other aluminum containing adjuvants. Adjuvants containing aluminum include, but are not limted to, alum, aluminum hydroxide, and aluminum hydroxy phosphate. The process of the present invention may be used with any alum-adsorbed vaccine, including but not limited to Recombivax HB, Pedvax HIB and hepatitis A vaccine.
The process of the present invention may also be used to selectively remove particles of 50 microns or greater from other liquids including alum suspensions, fine particulate liquid suspensions, and rehydrated lyophilyzed products, without product loss. Any liquid suspension which cannot be filtered by traditional standard filtration techniques (for example liquid suspensions desired to contain
particles smaller than about 50 microns) may utilize the process of the present invention to selectively remove particles of 50 microns or greater.
A reservoir containing the liquid to be dispensed to individual vials or into a suitable liquid receiving container is attached to a filling line which delivers the suspension to the individual vials or receiving container (Figure 2). The small pore size sieve is placed into a suitable housing (Figure 1) and the housing is placed in-line between the liquid suspension reservoir and the vials or receiving container into which the liquid is dispensed (Figure 2). The liquid in the reservoir is forced through the small pore size sieve which
selectively retains any particles of about 50 microns or greater in size, while the liquid which traverses the sieve is particle free or contains particles of a size less than about 50 microns. The liquid is then dispensed as desired into vials or other suitable liquid receiving vessel or container.
The small pore size sieve may be constructed of any suitable material, with 316 stainless steel being the most preferred. The sieve may be used as a multi-layered unit by stacking the sieves one on top of the other in a single sieve housing.
Alternatively, one sieve may be utilized per sieve housing, with one or more sieve housings placed in-line at one time. The preferred method to use a single sieve per housing and further utilizing only , one sieve housing in-line at a time.
The small pore sieves contain pores with a size between approximately 20 to 40 microns, with pores of about 36 microns preferred.
The following examples are provided as an illustration of the process of the present invention without, however, limiting the same thereto.
Example 1
Use of an in-line sieve to selectively remove
particles of about 50 microns or greater from
Recombivax HB
A pilot scale testing demonstrated the success of a stainless steel wire mesh sieve in selectively separating 50 micron or greated sized particles from Recombivax HB alum-adsorbed product particles during the sterile vial filling operation. The sieve configuration (Figure 1) consists of a 47 mm, 400 mesh (36 micron pore size) 316 stainless steel disk used with a standard 47 mm Millipore or other appropriate sieve housing. The housing is placed in line between the filling syringe and the filling needle as illustrated in Figure 2. The alum-adsorbed product (Recombivax HB) particle size distribution at equilibrium contains particles within the size range of approximately 1 micron to
approximately 12 micions (Figure 3).
In addition to demonstrating the selective removal of foreign particles about 50 microns or greater, the pilot scale run (using 28L of Recombivax HB previously rejected for high 50 micron and greater particle content) demonstrated that the sieve will completely pass the product without product loss or holdup (Table 1). No pressure increase was observed throughout the run at a flow rate of 90 ml/min.
Additional experimentation has indicated that flow rates of up to 600 ml/min can be achieved before experiencing a slight (0.5 psig) increase in back pressure. The pump was stopped for 30-60 minutes at three points during the run to simulate filling stoppages. No adverse effect of the stoppage was observed. A 142 mm sieve has been used to accomodate flow rates of 3-4L/min. TABLE 1
Summary of Analytical Results from Pilot Scale
Recombivax HB Sieve Run
Sample Aluminum EIA
* No. mg/ml mcg /ml
Start 0.54 12. 9
IL 0.53 12. 6
4L 0.56 12.3
8L 0.55 12.5
12L 0.53 12.0
16L 0.56 12.6
20L 0.54 12.4
24L 0.54 13.2
28L 0.54 12.1
*Note: The sample labeled "Start" was a control taken from the bulk before passing through the sieve. The volumes for the other samples indicate how much product had passed through the sieve. The samples were taken directly from the filling needle
EIA-Enzyme Immunoadsorbant assay. Example 2
Use of an in-line sieve to selectively remove
particles of about 50 microns or greater from various human vaccine
products
Three different losts of alum-adsorbed particle products (Recombivax HB) were processed to remove foreign particles, of about 50 microns and greater size by passage through an in-line sieve during the sterile vial filling procedure.
In addition to demonstrating the selective removal of particles the data shown below
demonstrates that the sieve will pass the product particle without product loss.
Lot A
This lot of 10 mcg/ml pediatric product exposed the sieve to the lowest concentration of product at the slowest flow rate through the seive, 50 ml/min. It was filled on the slow speed filling line, yielding approximately 35,000 vials.
Sample Particles Aluminum EIA In Vitro No. per Dose 0.35-0.62 mg/ml mcg/ml Pot. >0.52 pre-sieve avg. 2.0 0.50 14.3
1 0.4 0.54 13.4 1.10
2 1.0 0.57 13.4 1.06 3 0.8 0.54 13.1 1.16
4 0.2 0.53 13.6 1.10
5 0.6 0.54 13.3 1.13
6 0.4 0.53 13.5 1.04 7 0.8 0.55 13.5 1.00
8 0.2 0.54 13.5 1.07
9 1.2 0.54 13.5 1.09
10 0.8 0.57 12.9 1.12 average 0.6 0.55 13.4 1.09
Lot B
This lot of 10 mcg/ml single dose adult product was filled on the high speed filling line. The flow rate was constant (3L/min) and a larger sieve was used (142mm). The
concentration of product filled on this line was also constant, 10 mcg/ml. Approximately 42,000 vials were filled.
Sample Particles Aluminum EIA In Vitro No. per Dose 0.35-0.62 mg/ml mcg/ml Pot. >0.52 per sieve avg. 2.0 0.58 16.5
1 0.4 0.51 15.3 1.49
2 0.6 0.48 15.0 1.51
3 1.0 0.49 14.4 1.40
4 0.8 0.51 16.2 1.37
5 0.4 0.52 15.2 1.49
6 0.5 0.53 16.5 1.38
7 0.4 0.51 16.0 1.41
8 0.5 0.51 16.7 1.41
9 0.4 0.51 15.6 1.38
10 0.6 0.50 16.0 1.65 average 0.6 0.51 15.7 1.45 Lot C
This lot of 10 mcg/ml, 3 dose product exposed the sieve to the highest flow rate on the slow speed line (250 ml/min.), as well as the highest total volume through the 47 mm sieve (90 L). Approximately 24,000 vials were filled.
Sample Particles Aluminum EIA In Vitro
No. per Dose 0.35-0,62 mg/ml mcg/ml Pot. >0.52 pre sieve avg. 2.0 0.54 14.7
1 0.5 0.47 13.7 1.26
2 0.3 0.48 13.5 1.27
3 0.7 0.50 12.8 1.29
4 0.5 0.49 12.7 1.20
5 0.5 0.49 12.7 1.31
6 0.3 0.49 13.5 1.24
7 0.0 0.50 13.3 1.27 average 0.4 0.49 13.2 1.26

Claims

WHAT IS CLAIMED IS:
1. A process for the selective removal of particles equal to or greater than about 50 microns in size, from a liquid suspension, comprising:
(a) placing a 20-40 micron pore size mesh sieve in-line between a reservoir of the liquid suspension and a liquid receiving container;
(b) passing the liquid suspension through the sieve; and
(c) collecting the liquid suspension in the liquid receivng container.
2. The process of Claim 1, wherein the liquid suspension is an alum-adsorbed particulate vaccine product.
3. The process of Claim 2, wherein the
alum-adsorbed particulate vaccine product is
Recombivax HB.
4. The process of Claim 1, wherein the mesh sieve has a pore size of about 36 microns.
PCT/US1993/003945 1992-05-01 1993-04-22 Removal of foreign particles from alum-adsorbed products WO1993022073A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US87755192A 1992-05-01 1992-05-01
US877,551920501 1992-05-01

Publications (1)

Publication Number Publication Date
WO1993022073A1 true WO1993022073A1 (en) 1993-11-11

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WO (1) WO1993022073A1 (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3327866A (en) * 1964-06-15 1967-06-27 Pall Corp Woven wire mesh

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3327866A (en) * 1964-06-15 1967-06-27 Pall Corp Woven wire mesh

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