Gmp Annex 1 Guidelines – The Rules Governing Medicinal Products In The European Union Volume 4 Eu Guidelines For Good Manufacturing Practice For Medicinal Products For Human And Veterinary Use
What is Annex 1?
A legally binding part of EU GMP, Annex 1 provides guidelines and information relating to the manufacture of sterile medicinal products.
When was the new version issued?
The new version of Annex 1 was published on 25th August 2022
When is the date of implementation?
25th August 2023 (one year from the date of publication)
What is the scope of Annex 1?
Annex 1 applies to all sterile medicinal products manufactured in the European Union and the UK, as well as those manufactured elsewhere and exported into the European Union and the UK and applies to:
• Finished products • Active substances • Packaging materials • Products provided in any size and combination • Any manufacturing process • Any manufacturing technologies • Any manufacturing scale, where the objective is to provide a sterile product • The design and control of facilities, equipment, systems and procedures
What is the biggest contamination risk during aseptic processing?
Sources of contamination within a cleanroom include raw materials, packaging, equipment, fluids, tools, processes and the most significant source of contamination, people. Microorganisms are shed from hair, skin, eyes and mucus membranes (1).
When people move around they shed 10 times more particles than when they are sitting or at rest, hence the reason for clear guidelines on the correct controlled behaviour of personnel.
(1). Brandes, R. Aseptic Processing: Qualification of Personnel, Mass & Peither AG-GMP Publishing, April 12, 2012
CLEANROOM GARMENT MATERIAL & CONSTRUCTION
Part 7 of Annex 1 outlines the requirements needed regarding personnel numbers, behaviours, skills and clothing. A precise contamination control strategy needs to ensure that the PPE they’re wearing is suitably assessed and monitored.
Outlined in the IEST-RP-CC003.4 standard - Garment system consideration for cleanrooms and other controlled environments, lists six types of non-woven fabrics for use in cleanrooms and other controlled environments, and describes each fabric as follows:
1. Spunbonded or thermal bond A nonwoven fabric typically made from polypropylene in a relatively open structure. More commonly used in bouffant caps, shoe covers etc. This type of non-woven fabric does not demonstrate high barrier performance.
4. Spunbonded/melt blown/spunbonded (SMS) A laminate structure made from polypropylene continuous fibres, SMS offer barrier protection and comfort.
2. Flash spun A nonwoven fabric made of high-density polyethylene continuous fibres. Flash spun non-wovens have some barrier properties and are splash-resistant to water.
5. Film laminate A spunbonded layer laminated to nonporous films. Demonstrates particle, blood and chemical barrier properties but lacks air and moisture permeability.
3. Melt blown Made from continuous polypropylene micro fibres and used in composite structures of many types off face masks because of its high filtration efficiency and repellence. Melt blown fabric does not have adequate strength to be used alone for garments.
6. Microporous film laminate A laminate made from a spunbonded layer and a microporous film for improved barrier properties. This laminate is a splash-resistant and a blood barrier. Microporous film laminate is optimal for use in surgical areas and critical environments.
When selecting garments for cleanroom use, depending on the specific application, the IEST standard recommends evaluating the fabric properties including testing for (selecting those relevant to the fabric type);
Construction of cleanroom garments is another important consideration, and the IEST standard outlines recommendations for thread and seam structure. Seams for cleanroom garments should be joining seams to avoid free-air/particulate passage from the inside of the garment to the outside environment. The IEST standard recommends for the construction of cleanroom garments that they are constructed using a bound joining seam, as shown in Figure 1.
CLEANROOM GARMENT SELECTION & DONNING
As well as consideration for how the cleanroom garments are constructed and the type of material used, Annex 1 Parts 7.11 & 7.12 indicates what garments to wear in each cleanliness grade and how they should be worn and donned has been outlined in Part 7.13 & 7.14.
ANNEX 1 PART 7 - PERSONNEL
Part 7.11 The clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way as to protect the product from contamination. When the type of clothing chosen needs to provide the operator protection from the product, it should not compromise the protection of the product from contamination. Garments should be visually checked for cleanliness and integrity immediately prior to and after gowning. Gown integrity should also be checked upon exit. For sterilised garments and eye coverings, particular attention should be taken to ensure they have been subject to the sterilisation process, are within their specified hold time and that the packaging is visually inspected to ensure it is integral before use. Reusable garments (including eye coverings) should be replaced if damage is identified, or at a set frequency that is determined during qualification studies. The qualification of garments should consider any necessary garment testing requirements, including damage to garments that may not be identified by visual inspection alone.
Part 7.12
Clothing should be chosen to limit shedding due to operators’ movement.
Part 7.13 A description of typical clothing required for each cleanliness grade is given below:
i. Grade B (including access / interventions into grade A):
appropriate garments that are dedicated for use under a sterilised suit should be worn before gowning (see paragraph 7.14). Appropriately sterilised, non-powdered, rubber or plastic gloves should be worn while donning the sterilised garments. Sterile headgear should enclose all hair (including facial hair) and where separate from the rest of the gown, it should be tucked into the neck of the sterile suit. A sterile facemask and sterile eye coverings (e.g. goggles) should be worn to cover and enclose all facial skin and prevent the shedding of droplets and particles. Appropriate sterilised footwear (e.g. over-boots) should be worn. Trouser legs should be tucked inside the footwear. Garment sleeves should be tucked into a second pair of sterile gloves worn over the pair worn while donning the gown. The protective clothing should minimize shedding of fibres or particles and retain particles shed by the body. The particle shedding and the particle retention efficiencies of the garments should be assessed during the garment qualification. Garments should be packed and folded in such a way as to allow operators to don the gown without contacting the outer surface of the garment and to prevent the garment from touching the floor.
ii. Grade C:
Hair, beards and moustaches should be covered. A single or two-piece trouser suit gathered at the wrists and with high neck and appropriately disinfected shoes or overshoes should be worn. They should minimize the shedding of fibres and particles.
iii. Grade D:
Hair, beards and moustaches should be covered. A general protective suit and appropriately disinfected shoes or overshoes should be worn. Appropriate measures should be taken to avoid any ingress of contaminants from outside the clean area.
iv. Additional gowning including gloves and facemask may be required in grade C and D areas when performing activities considered to be a contamination risk as defined by the CCS.
Part 7.14
Cleanroom gowning should be performed in change rooms of an appropriate cleanliness grade to ensure gown cleanliness is maintained. Outdoor clothing including socks (other than personal underwear) should not be brought into changing rooms leading directly to grade B and C areas. Single or two-piece facility trouser suits, covering the full length of the arms and the legs, and facility socks covering the feet, should be worn before entry to change rooms for grades B and C. Facility suits and socks should not present a risk of contamination to the gowning area or processes.
BARRIER TECHNOLOGIES
Annex 1 places considerable emphasis on barrier technology to separate the operator from the product to maintain Grade A conditions. This can be accomplished using RABS and Isolators:
Annex 1 Part 4.18
Isolators or RABS, which are different technologies, and the associated processes, should be designed to provide protection through separation of the grade A environment from the environment of the surrounding room. The hazards introduced from entry or removal of items during processing should be minimized and supported by high capability transfer technologies or validated systems that robustly prevent contamination and are appropriate for the respective technology.
Annex 1 Part 4.21
The materials used for glove systems (for both isolators and RABS), should be demonstrated to have appropriate mechanical and chemical resistance. The frequency of glove replacement should be defined within the CCS.
Solution
Our clean and sterile Nitrile RABS and Isolator glove range comprises of gloves, mittens and sleeve/glove systems. 100% water leak tested for glove integrity and resistant to VHP, IPA and disinfectants for in situ sanitizing.
Other RABS and Isolator glove materials available are CSM, NRL, Neoprene, EPDM & EPDM+ the most suitable material will be dependent on the applications and can be decontaminated by autoclaving, VHP or IPA**.
**Please check product validation pack for full test results.
CHOOSING THE RIGHT RABS/ISOLATOR GLOVE MATERIAL
Nitrile is a synthetic, non-solvent based, FDA approved polymer and is an ideal alternative to CSM, EPDM and latex, where the risk of latex allergies is a concern. With excellent anti-static properties, preventing the buildup of static electricity, nitrile is ideal for use with flammable liquids and powders. It can also be sanitised by Gamma Irradiation, Vapourised Hydrogen Peroxide (VHP) and Isopropyl Alcohol (IPA) and non-sterile options can also be washed, processed and packaged within a cleanroom environment, ensuring the gloves are an ultra-low contamination risk before being introduced into the isolator glove box.
CHEMICAL PERMEATION RESULTS TABLE - BIOCLEAN™ GGL & CGL
*ASTM F739 - Breakthrough of the test chemical is deemed to have occurred when the permeation rate has reached 0.1 μg/cm2 /min. **EN 16523-1: 2015 (formerly EN374-3) - Breakthrough of the test chemical is deemed to have occurred when the permeation rate has reached 1.0 μg/cm2 /min.
ANSELL STERILE PORTFOLIO
Our extensive portfolio of sterile garments, gloves, goggles and facemasks detailed below ensure you meet all the guidelines set out in Annex 1 Part 7.
**Please check product validation pack for full test results.
PACKAGING & STERILISATION PROCESS
How PPE is packaged, and the packaging materials used is another critical element for consideration. All Ansell sterile PPE is double or triple bagged in durable plastic packaging to reduce contamination and includes sterilisation indicators to show the PPE has been sterilised to a sterility Assurance Level (SAL) 10-6.
Certificates of Irradiation (Gamma) or Certificates of Processing (EtO) per product lot number can be downloaded via our easy to use certificate tool on www.ansell.com/life-sciences/certificates to prove the PPE has been subjected to the full sterilisation process. All packaging clearly states expiry and manufacturing dates.
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Gmp Annex 1 Guidelines – The Rules Governing Medicinal Products In The European Union Volume 4 Eu Guidelines For Good Manufacturing Practice For Medicinal Products For Human And Veterinary Use
What is Annex 1?
A legally binding part of EU GMP, Annex 1 provides guidelines and information relating to the manufacture of sterile medicinal products.
When was the new version issued?
The new version of Annex 1 was published on 25th August 2022
When is the date of implementation?
25th August 2023 (one year from the date of publication)
What is the scope of Annex 1?
Annex 1 applies to all sterile medicinal products manufactured in the European Union and the UK, as well as those manufactured elsewhere and exported into the European Union and the UK and applies to:
• Finished products
• Active substances
• Packaging materials
• Products provided in any size and combination
• Any manufacturing process
• Any manufacturing technologies
• Any manufacturing scale, where the objective is to provide a sterile product
• The design and control of facilities, equipment, systems and procedures
What is the biggest contamination risk during aseptic processing?
Sources of contamination within a cleanroom include raw materials, packaging, equipment, fluids, tools, processes and the most significant source of contamination, people. Microorganisms are shed from hair, skin, eyes and mucus membranes (1).
When people move around they shed 10 times more particles than when they are sitting or at rest, hence the reason for clear guidelines on the correct controlled behaviour of personnel.
CLEANROOM GARMENT MATERIAL & CONSTRUCTION
Part 7 of Annex 1 outlines the requirements needed regarding personnel numbers, behaviours, skills and clothing. A precise contamination control strategy needs to ensure that the PPE they’re wearing is suitably assessed and monitored.
Outlined in the IEST-RP-CC003.4 standard - Garment system consideration for cleanrooms and other controlled environments, lists six types of non-woven fabrics for use in cleanrooms and other controlled environments, and describes each fabric as follows:
A nonwoven fabric typically made from polypropylene in a
relatively open structure. More commonly used in bouffant
caps, shoe covers etc. This type of non-woven fabric does
not demonstrate high barrier performance.
A laminate structure made from polypropylene
continuous fibres, SMS offer barrier protection
and comfort.
A nonwoven fabric made of high-density polyethylene
continuous fibres. Flash spun non-wovens have some
barrier properties and are splash-resistant to water.
A spunbonded layer laminated to nonporous films.
Demonstrates particle, blood and chemical barrier
properties but lacks air and moisture permeability.
Made from continuous polypropylene micro fibres and
used in composite structures of many types off face masks
because of its high filtration efficiency and repellence.
Melt blown fabric does not have adequate strength to be
used alone for garments.
A laminate made from a spunbonded layer and a
microporous film for improved barrier properties.
This laminate is a splash-resistant and a blood
barrier. Microporous film laminate is optimal for
use in surgical areas and critical environments.
• Electrostatic properties
• Biological properties
• Durability
• Comfort
• Particle filtration efficiency
• Microbial penetration
• Chemical compatibility
• Fluid resistance
Construction of cleanroom garments is another important consideration, and the IEST standard outlines recommendations for thread and seam structure. Seams for cleanroom garments should be joining seams to avoid free-air/particulate passage from the inside of the garment to the outside environment. The IEST standard recommends for the construction of cleanroom garments that they are constructed using a bound joining seam, as shown in Figure 1.
CLEANROOM GARMENT SELECTION & DONNING
As well as consideration for how the cleanroom garments are constructed and the type of material used, Annex 1 Parts 7.11 & 7.12 indicates what garments to wear in each cleanliness grade and how they should be worn and donned has been outlined in Part 7.13 & 7.14.
ANNEX 1 PART 7 - PERSONNEL
The clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way as to protect the product from contamination. When the type of clothing chosen needs to provide the operator protection from the product, it should not compromise the protection of the product from contamination. Garments should be visually checked for cleanliness and integrity immediately prior to and after gowning. Gown integrity should also be checked upon exit. For sterilised garments and eye coverings, particular attention should be taken to ensure they have been subject to the sterilisation process, are within their specified hold time and that the packaging is visually inspected to ensure it is integral before use. Reusable garments (including eye coverings) should be replaced if damage is identified, or at a set frequency that is determined during qualification studies. The qualification of garments should consider any necessary garment testing requirements, including damage to garments that may not be identified by visual inspection alone.
Part 7.12
Clothing should be chosen to limit shedding due to operators’ movement.
Part 7.13 A description of typical clothing required for each cleanliness grade is given below:
i. Grade B (including access / interventions into grade A):
appropriate garments that are dedicated for use under a sterilised suit should be worn before gowning (see paragraph 7.14). Appropriately sterilised, non-powdered, rubber or plastic gloves should be worn while donning the sterilised garments. Sterile headgear should enclose all hair (including facial hair) and where separate from the rest of the gown, it should be tucked into the neck of the sterile suit. A sterile facemask and sterile eye coverings (e.g. goggles) should be worn to cover and enclose all facial skin and prevent the shedding of droplets and particles. Appropriate sterilised footwear (e.g. over-boots) should be worn. Trouser legs should be tucked inside the footwear. Garment sleeves should be tucked into a second pair of sterile gloves worn over the pair worn while donning the gown. The protective clothing should minimize shedding of fibres or particles and retain particles shed by the body. The particle shedding and the particle retention efficiencies of the garments should be assessed during the garment qualification. Garments should be packed and folded in such a way as to allow operators to don the gown without contacting the outer surface of the garment and to prevent the garment from touching the floor.
ii. Grade C:
Hair, beards and moustaches should be covered. A single or two-piece trouser suit gathered at the wrists and with high neck and appropriately disinfected shoes or overshoes should be worn. They should minimize the shedding of fibres and particles.iii. Grade D:
Hair, beards and moustaches should be covered. A general protective suit and appropriately disinfected shoes or overshoes should be worn. Appropriate measures should be taken to avoid any ingress of contaminants from outside the clean area.
iv. Additional gowning including gloves and facemask may be required in grade C and D areas when performing activities considered to be a contamination risk as defined by the CCS.
Part 7.14
Cleanroom gowning should be performed in change rooms of an appropriate cleanliness grade to ensure gown cleanliness is maintained. Outdoor clothing including socks (other than personal underwear) should not be brought into changing rooms leading directly to grade B and C areas. Single or two-piece facility trouser suits, covering the full length of the arms and the legs, and facility socks covering the feet, should be worn before entry to change rooms for grades B and C. Facility suits and socks should not present a risk of contamination to the gowning area or processes.
BARRIER TECHNOLOGIES
Annex 1 places considerable emphasis on barrier technology to separate the operator from the product to maintain Grade A conditions. This can be accomplished using RABS and Isolators:
Annex 1 Part 4.18
Isolators or RABS, which are different technologies, and the associated processes, should be designed to provide protection through separation of the grade A environment from the environment of the surrounding room. The hazards introduced from entry or removal of items during processing should be minimized and supported by high capability transfer technologies or validated systems that robustly prevent contamination and are appropriate for the respective technology.Annex 1 Part 4.21
The materials used for glove systems (for both isolators and RABS), should be demonstrated to have appropriate mechanical and chemical resistance. The frequency of glove replacement should be defined within the CCS.Solution
Our clean and sterile Nitrile RABS and Isolator glove range comprises of gloves, mittens and sleeve/glove systems. 100% water leak tested for glove integrity and resistant to VHP, IPA and disinfectants for in situ sanitizing.
Other RABS and Isolator glove materials available are CSM, NRL, Neoprene, EPDM & EPDM+ the most suitable material will be dependent on the applications and can be decontaminated by autoclaving, VHP or IPA**.
CHOOSING THE RIGHT RABS/ISOLATOR GLOVE MATERIAL
Nitrile is a synthetic, non-solvent based, FDA approved polymer and is an ideal alternative to CSM, EPDM and latex, where the risk of latex allergies is a concern. With excellent anti-static properties, preventing the buildup of static electricity, nitrile is ideal for use with flammable liquids and powders. It can also be sanitised by Gamma Irradiation, Vapourised Hydrogen Peroxide (VHP) and Isopropyl Alcohol (IPA) and non-sterile options can also be washed, processed and packaged within a cleanroom environment, ensuring the gloves are an ultra-low contamination risk before being introduced into the isolator glove box.
WHY CHOOSE BIOCLEAN™ NITRILE ISOLATOR/RABS GLOVES?
CHEMICAL PERMEATION RESULTS TABLE - BIOCLEAN™ GGL & CGL
*ASTM F739 - Breakthrough of the test chemical is deemed to have occurred when the permeation rate has reached 0.1 μg/cm2 /min. **EN 16523-1: 2015 (formerly EN374-3) - Breakthrough of the test chemical is deemed to have occurred when the permeation rate has reached 1.0 μg/cm2 /min.
ANSELL STERILE PORTFOLIO
Our extensive portfolio of sterile garments, gloves, goggles and facemasks detailed below ensure you meet all the guidelines set out in Annex 1 Part 7.
PACKAGING & STERILISATION PROCESS
How PPE is packaged, and the packaging materials used is another critical element for consideration. All Ansell sterile PPE is double or triple bagged in durable plastic packaging to reduce contamination and includes sterilisation indicators to show the PPE has been sterilised to a sterility Assurance Level (SAL) 10-6.
Certificates of Irradiation (Gamma) or Certificates of Processing (EtO) per product lot number can be downloaded via our easy to use certificate tool on www.ansell.com/life-sciences/certificates to prove the PPE has been subjected to the full sterilisation process. All packaging clearly states expiry and manufacturing dates.
For more information, visit www.ansell.com
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