The document focuses on key elements of design of multi-product facility for vaccine manufacturing. The guidance is also relevant for other products categories. This is just a brief introduction and further information on design of GMP facility can be obtained from the references provided at the end of the article.
BIO-PHARMACEUTICAL MULTI-PRODUCT FACILITY: A VACCINE EXAMPLE
INTRODUCTION:
Regulatory guidelines
have not given a clear guidance on design
and commissioning of a multiuse
facility for Biotechnology Products and little information is available on
the design consideration of a vaccine multiuse/multi-product facility. Since its
genesis, W.H.O. has been a standard body providing guidance on manufacturing
and quality control of vaccines. However, guidance on design of multiproduct
facility is scattered. This document attempts to provide conceptual guidance for vaccine manufacturers who want to establish
a multi-product facility and those who want to add a new product in their existing manufacturing unit.
PRESENT POSITION:
WHO through its different
guidance documents lays down the expectation for commissioning of a cGMP facility
but the design concept and guidance for use of facility as a multi-product
facility (for different vaccines) has not been emphasized. In fact, none of the
regulatory agencies, national or international has given a clear mandate on multiuse
facility.
Following are the guidance available on multi-product facility:
WHO_IVB_05.19_eng
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· Special areas for the handling of highly
toxic, hazardous and sensitizing materials.
· For products where a separate facility is
required (e.g. tetanus, BCG).
· Brief description of the Procedures for
cleaning manufacturing areas and equipment, and for multipurpose areas, the
system for cleaning and testing between campaigns.
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WHOQA, 2ed ( WHO Technical Report Series,
No. 902)
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· Products such as killed vaccines, including
those made by rDNA techniques, toxoids and bacterial extracts may after
inactivation be dispensed into containers on the same premises.
· Spore-forming organisms shall be handled in
facilities dedicated to this group of products until the inactivation process
is accomplished. Campaign manufacture of spore forming organisms occurs in a
facility or suite of facilities, only one product should be processed at any
one time.
· Dedicated facilities and equipment shall be
used for the manufacture of medicinal products derived from human blood or
plasma.
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U.S. Department of Health and Human Services Food and Drug
Administration Center for Biologics Evaluation and Research September 2007
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· Under the revised regulation, FDA no longer requires
the use of permanently dedicated buildings and equipment for spore-formers.
Prevention of spore contamination can be achieved by using a separate
dedicated building or by using process containment if manufacturing is
conducted in a multiproduct manufacturing building. AHUs should not be shared
with other buildings. FDA recommends that processing equipment be dedicated
for a specific product. Campaign changeovers involve the cleaning and
decontamination of a specific area that has been exposed to a spore-former in
preparation for the introduction of another product or process into that same
area
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EU Orange Guide
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·
Manufacturing
process, in which live organisms are used, may require additional precautions
with respect to facilities and equipment, such as the use of dedicated
facilities and equipment, production on a campaign basis and the use of
closed systems. The nature of the product as well as the equipment used will
determine the level of segregation needed to avoid cross-contamination.
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ICH Topic Q 7 Good Manufacturing Practice
for Active Pharmaceutical Ingredients
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· Dedicated production areas, which can
include facilities, air handling equipment and/or process equipment, should
be employed in the production of highly sensitizing materials, such as
penicillins or cephalosporins. Appropriate measures should be established and
implemented to prevent cross contamination from personnel, materials, etc.
moving from one dedicated area to another. Handling and storage of these
highly toxic non-pharmaceutical materials should be separate from APIs.
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PIC/S
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· The risk of cross-contamination between
biological medicinal products, especially during those stages of the
manufacturing process in which live organisms are used, may require
additional precautions with respect to facilities and equipment, such as the
use of dedicated facilities and equipment, production on a campaign basis and
the use of closed systems.
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DEDICATED AND MULTI-PRODUCT FACILITY:
Dedicated facility has all the advantages over
multiproduct facility as it is custom made for one product and optimized around
a single set of operations. All the quality and design functions are aligned to
one product only. But this is costly approach and new companies with limited
financial support cannot afford a dedicated facility especially when they have
products in R&D and Clinical Trial Stage. Also the company will not be able
to fulfill the ever changing requirement of the market (healthcare industry
market) and its R&D function will lag behind.
If
the regulatory agencies emphasize on the requirement of a dedicated facility,
it will be end of road to new and upcoming companies and in turn will promote monopoly
of the established companies. However to meet the
quality of the product there has to be a clear mandate on the requirements of the
multiproduct facility so that no compromises with product quality are made at
any stage.
Manufacturing in the multiproduct facility can be of two types:
Concurrent Manufacturing:
In this case two different
products are handled in a same facility at a given time.
This scenario is rarely encountered in vaccine industry due to complex nature
of manufacturing activity. If this is followed at any stage substantial
scientific evidence need to be provided justifying the methodologies to avoid
any mix-ups as well as the facility should have a state of art design, perfect
engineering control and religiously followed operating procedures.
Campaign Manufacturing:
Processing of more than one product in the same facility, equipment or both in a sequential manner. Only one product is present in the facility at a time. Also product changeover form one to another need to be performed following validated change over (campaign change) procedures showing freedom of any residues of previous products from facility and equipment.
Processing of more than one product in the same facility, equipment or both in a sequential manner. Only one product is present in the facility at a time. Also product changeover form one to another need to be performed following validated change over (campaign change) procedures showing freedom of any residues of previous products from facility and equipment.
Following level of facility complexity is seen in a
typical vaccine manufacturing unit based on the segregation approach,
containment strategies and products handled. The demarcation is on the basis of
the suits which will help in controlling cross contamination and
containment.
Support/Preparation Area:
Level I
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Support Area/Preparation Area
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Level II
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Buffer Preparation
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Sterile Operations
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Level III
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Solution Preparation
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Buffer Preparation
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Sterile Operations
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Upstream Processing
Level I
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Fermentation/Multiplication Area
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Level II
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Inoculum Preparation
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Fermentation/Harvesting/
Disruption/Recovery
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Level III
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Inoculum Preparation
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Fermentation
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Harvesting
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Disruption
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Recovery
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Downstream Processing
Level I
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Purification Area
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Level II
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Crude/Final purification
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Bulk Processing
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Level II
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Crude Purification
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Final Purification
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Bulk Processing
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Filling Line shall be a separate from other production area and in case of multi-product facility shall be operated on campaign basis.
RISKS IN MULTI-PRODUCT FACILITY:
Possible risk in a multiproduct facility can be:
Mix up at any stage, carry over from previous
campaign (equipment and environmental).
DESIGN CONSIDERATIONS FOR MULTI-PRODUCT FACILITY:
The following shall be the basis of multiproduct
facility to overcome above risks:
- GOOD FACILITY DESIGN AND ENGINEERING CONTROL
- EQUIPMENT SELECTION (OPEN, CLOSED, DEDICATED)
- RISK ASSESSMENT (PROCESS AND CARRY OVER)
- VALIDATED CHANGE OVER PROCEDURES.
Good
Facility Design and Engineering Control
The design of the facility shall be on the basis of
current Good Manufacturing Practices (GMP),
Good Engineering Practices (GEP) and Local and International Regulatory
and Statutory Requirements, keeping
in mind the containment and contamination
control requirements of the product and process. The design of the facility
shall be such that it allows segregation of flows. For a multiproduct facility
the flow of Process, Personnel and Starting and Waste material shall be
designed to avoid any potential mix-up or cross contamination at any stage of
production starting from staging area to final finished product.
HVAC
System shall be designed not only for contamination
control but also containment to avoid any carryover.
Wherever, required by the process separate suits
shall be designed to avoid contamination. Area where live organisms or highly toxic
material is handled the design of the suit shall be once through (blow
through). Pressure cascading shall be designed keep in mind the requirement of
the processing stage (i.e., containment or contamination control).
It is of special emphasis that in multi product
facility the operation of filling line shall be dedicated and filling shall be
done on campaign basis only. The filling area shall be isolated from other
production areas. Areas for containment
and the aseptic filling operations cannot have a common hallway or shared
routes of access by personnel and equipment. A separate air handling system
shall be used. Dedicated equipment, components, and glassware should be
required for each function.
Equipment Selection (Open, Closed, Dedicated)
It is advisable to use closed system and equipments in a multiproduct facility to
protect the immediate environment from contamination and possible environmental
carryover to next campaign. Closed systems provide greater assurance of product
protection and allow for more thorough cleaning through the use of CIP System
that can be validated. The integrity of the closed system shall be maintained
throughout the operation. A specific processing area of suite can be used for a
number of products on a campaign basis, but only a single product should be in
a suit at a given time during the process.
A proper provision for cleaning and sterilization
of the equipment and supplies that enter the containment and processing area of
the facility shall be provided.
Risk Assessment (Process and Carry Over)
Risk assessment shall be done during the design of
facility of inclusion of new product to already functional facility. The risk
assessment shall be performed to know the risk
associated with contamination, cross contamination and carry over from the
previous campaign.
Validated Change Over Procedures.
A well written change over policy shall be
established. The policy shall justify the change
over operations, cleaning activity,
disinfection procedures and segregation strategies and time allocated for each changeover
procedure and line clearance activity. There should be well defined
acceptance criteria for accepting the facility for next campaign and decision
making responsibilities assigned.
Cleaning
procedures used for product changeover shall be validated. A
proper justification shall be give for any bracketing approach used for
cleaning validation. The analytical methods used for detecting residues, specific
and non specific (thus defining what is clean) shall be validated to ensure
proper sensitivity, accuracy and reproducibility.
The
above basis can be integrated together at in a systematic approach during
product realization steps. The flow chart gives one of the possible approaches:
Identify the Product
(Host System used,
Infectious/Bio-containment Level/Potential Risk by Cross
contamination/Toxic/biological effect, Cleaning Requirements)
↓
Development of Process
Description
(Targeted Annual
Production, Detailed description of the Process Steps, Equipment Requirements,
Support Processing Requirements, Time Realization form Multi-Product
manufacturing scenario)
↓
Development of
Drawings
(Process
Flow Diagrams, Engineering Controls and Layouts, Equipment Positioning and
Movement, Process Flow, Raw Material/Waster Material flow, Process Flow,
Containment Strategies, HVAC Layouts and Classification, Separate Suits to
minimize cross contamination)
(Design
shall be as per cGMP and GEP)
↓
Identification of
Dedicated Equipments and Components
(Design of the
equipments, Open/Closed)
↓
Sterilization,
Decontamination and Cleaning Procedures
[Risk
Assessment on the basis of product toxicity, carryover
(environmental/equipment), Allowable Daily Exposure (ADE) Limit]
↓
Operational Controls
(Gowning Procedures,
Access Control)
↓
Scheduling of
Production and Changeover Time
(Justified time
required for changeover from one product to another, with adequate time
required for cleaning cycles and line clearance activity)
↓
Changeover Cleaning
and Cleaning Validation
(Containment
Study, Sampling Procedure, Risk Based Sampling locations, Recovery Studies,
Limit of detection and Analytical Method validation)
RECOMMENDATIONS:
From the above discussion following recommendations
can be given for manufacturing and filling of vaccines:
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Inoculum Preparation area shall be
separate from fermentation area.
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Area where live organism and toxic
products are handled shall be as a separate suite with HVAC designed form
containment (Flow of air shall be once through/blow out type).
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Dedicated equipments shall be identified.
Preferably closed systems and equipments shall be used. Validation of closed
system/equipments shall be done to justify the claim.
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For use of facility on campaign basis,
a systematic risk approach shall be followed and proper justification given for
each product handled in a given facility, its containment and contamination
risk and carry over to next campaign.
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Campaign change procedures shall be
validated, proper acceptance criteria based on toxicity and Allowable Daily Exposure
Limit shall be defined.
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Filling line shall be separate from
other production areas.
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Filling shall be done only in campaign
basis with dedicated equipment, components, and glassware.
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Products shall be filled in one filling
only on risk evaluation is done for containment and carry over from previous
campaign.
ADE limit shall be used for selecting
products for filling in one facility. ADE of active pharmaceutical ingredient
is the estimated dose that is unlikely to cause an adverse effect if an
individual is exposed to the API by any route, at or below this dose every day
for a lifetime.
It is advisable to manufacture and fill
high risk products in a dedicated facility and shall only be handled in
multiproduct facility only after exhaustive risk assessment and mitigation strategies.
In such cases risk assessment shall be a continuous activity and records
maintained.
Recommendations for Filling Line
BCG Live
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Dedicated
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Rotavirus Vaccine, Live, Oral
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Dedicated
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OPV
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Dedicated
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LIVE VIRAL VACCINES
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Filling line shall have Once through HVAC Design/ Dedicated
Desirable
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Adenovirus Type 4 and Type 7 Vaccine, Live, Oral
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Influenza Vaccine, Live, Intranasal
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Measles and Mumps Virus Vaccine, Live
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Measles Virus Vaccine, Live
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Measles, Mumps, and Rubella Virus Vaccine, Live
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Measles, Mumps, Rubella and Varicella Virus Vaccine Live
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Mumps Virus Vaccine Live
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Rubella Virus Vaccine Live
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Smallpox (Vaccinia) Vaccine, Live
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Zoster Vaccine, Live
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Yellow Fever Vaccine
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Varicella Virus Vaccine Live
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Prerequisite
for filling live (attenuated) vaccines on campaign basis:
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BACTERIA, RECOMBINANT, COMPONENT AND POLYSACCHARIDE, VIRAL
(Inactivated Polio) (COMBINATION)
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Can be
filled on Campaign Basis
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Diphtheria & Tetanus Toxoids Adsorbed
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Diphtheria & Tetanus Toxoids & Acellular Pertussis
Vaccine Adsorbed
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Diphtheria & Tetanus Toxoids & Acellular Pertussis
Vaccine Adsorbed, Hepatitis B (recombinant) and Inactivated Poliovirus
Vaccine Combined
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Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed
and Inactivated Poliovirus Vaccine
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Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed,
Inactivated Poliovirus and Haemophilus b Conjugate (Tetanus Toxoid Conjugate)
Vaccine
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Tetanus & Diphtheria Toxoids Adsorbed for Adult Use
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Tetanus Toxoid
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Tetanus Toxoid Adsorbed
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Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular
Pertussis Vaccine, Adsorbed
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Hepatitis B Vaccine (Recombinant)
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Haemophilus b Conjugate Vaccine (Meningococcal Protein
Conjugate)
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Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)
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Haemophilus b Conjugate Vaccine (Meningococcal Protein
Conjugate) & Hepatitis B Vaccine (Recombinant)
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Hepatitis A Vaccine, Inactivated
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Hepatitis A Inactivated and Hepatitis B (Recombinant) Vaccine
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Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine,
Recombinant
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Human Papillomavirus Bivalent (Types 16, 18) Vaccine,
Recombinant
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Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide
Diphtheria CRM197 Conjugate Vaccine
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Pneumococcal Vaccine, Polyvalent
Typhoid Vi Polysaccharide Vaccine
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Anthrax Vaccine Adsorbed (Component Vaccine)
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Viral/Component
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Rabies Vaccine
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Japanese Encephalitis Virus Vaccine, Inactivated, Adsorbed
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Japanese Encephalitis Virus Vaccine Inactivated
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Poliovirus Vaccine Inactivated (Human Diploid Cell)
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Poliovirus Vaccine Inactivated (Monkey Kidney Cell)
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Influenza A (H1N1) 2009 Monovalent Vaccine
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Influenza Virus Vaccine
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Influenza Virus Vaccine, H5N1 (for National Stockpile)
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Influenza Virus Vaccine, Trivalent, Types A and B
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Prerequisite
for filling inactivated products on campaign basis:
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References:
Drugs and the
Pharmaceutical Sciences, Volume 146, Good Design Practices for GMP
Pharmaceutical Facilities, edited by Andrew A. Signore and Terry Jacobs.
Sterile Product
Facility Design and Project Management, Second Edition Jeffery N. Odum CRC Press,
(most of the text in this article is derived from Chapter 13)
EudraLex, Volume 4,
Annex 2, Manufacture of Biological active substances and Medicinal Products for
Human Use
EMEA: White Paper, In
Response to the EMEA’s Concept Paper. Dealing with the Need for Updated GMP
Guidance Concerning Dedicated Manufacturing Facilities in the Manufacture of
Certain Medicinal Products
Presentations on :Contamination
Control in MultiProduct Facilities, Cleaning Validation- The Toxicological
Approach, Dr Lorcan Allen, Pre-clinical assessor, Irish Medicines Board, Member
of Safety Working Party at EMA, 14thOctober 2010
Risk-MaPP: Manging the risk of cross contamination. Stephanie Wilkins at PharmaConsult US, Innovations in Pharmaceutical Techonology, EMA Statement on status of revision of Chapter 5 of the GMP guide concerning "dedicated facilities", London, 9 January 2008, Doc. Ref. EMEA/INS/GMP/14529/2008
Concept Paper on the
development of toxicological guidance for use in risk identification in the
manufacture of different medicinal products in shared facilities. 20 October
2011, EMA/CHMP/SWP/598303/2011, Committee for Medicinal Products for Human Use
(CHMP)
Concept Paper on the
Revision of the Guideline on Process Validation25 February 2010
EMA/CHMP/CVMP/QWP/809114/2009,
Committee for Medicinal Products for Human Use (CHMP) & Committee for
Medicinal Products for Veterinary Use (CVMP)
As the world switches to IPV, the demand of OPV is expected to fall. In the face of this situation, is there some specific reason why OPV (Fill finish only) cannot be run on campaign with other vaccines?
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