The EU GMP Guide, Annex 1: Manufacture of Sterile Medicinal Products, is now in effect.

This legally binding, updated guide includes further clarifications and additional instructions for sterile manufacturing of medicinal products. As of August 2023, manufacturers are now required to review pharmaceutical quality systems and procedures for the manufacture of sterile products using Quality Risk Management principles to adopt their own Contamination Control Strategy (CCS).  The key requirements centre on the design, control of facilities, maintenance, equipment and reducing the risk of contamination from personnel within a sterile environment. 

Cleanroom Design and Maintenance

Annex 1 now puts far greater emphasis on “Quality by Design”. Consideration must be given to the importance of materials used along with the addition of barrier technology to maintain Grade A conditions.

Design of Cleanrooms

Design is crucial and should include the following: airlocks (section 4.12), filters (section 4.14), Restricted Access Barrier Systems (RABS) (section 4.18) Isolators (section 4.21) and change rooms. 

Validation

The disinfection process will now need to be validated demonstrating the suitability and effectiveness of the products chosen and how they are used (section 4.34).

Disinfectants Annex 1

Cleaning and Disinfection

Cleaning first to physically remove dirt particles and chemical contamination from surfaces with a Neutral Detergent has been expanded to include a second stage – the use of a disinfectant in order to kill any microbiological contamination (section 4.33).  In addition, Annex 1 now requires you to introduce a sporicidal disinfectant so that you are rotating a broad spectrum and a sporicidal agent.

Cleanroom consumables

Annex 1 states that apparel must be worn 'to protect the product from contamination'. Manufacturers must ensure that the apparel they are using is of an appropriate quality with garments being visually checked before, and after gowning, prior to entering the controlled area. The required apparel is dependent on the classification of your working area:

Classification A & B

Grade A signifies a critical area for high-risk operations or for making aseptic connections by providing initial air protection.  Grade B represents its preparation area. 

Classification C & D

Grade C/D signifies cleanrooms used for less critical stages in the manufacture of aseptically filled sterile products. In addition may also be used for the preparation/filling of terminally sterilized products. 

A. Headwear

Head gear/beard Snoods: (Section 7.13ii) sterile headgear which must enclose all hair (including facial hair).

Recommended for: Grade C and D 

B. Goggles

Sterile eye coverings such as goggles are required and should fit the around the face completely (Sections 7.13i & 7.14). 

Recommended for: GMP Grade A/B

C. Face Masks

Face masks should be worn along with sterile eye coverings to cover and enclose all facial skin and prevent shedding of droplets and particles (Section 7.13i).

Recommended for:  GMP Grade A/B

D. Gloves

Powder-free rubber or plastic sterile gloves (Section 7.13i).

Recommended for:  GMP Grade A/B.  (Section 7.13iv) Gloves and facemask may be required in Grade C and D areas when performing activities considered to be a contamination risk

E. Disinfectants

The use of a disinfectant in order to kill any microbiological contamination has been introduced as a second stage to preliminary cleaning (Section 4.33).

Recommended for:  GMP Grade A/B

F. Garments

Low linting disposable garments strategically folded to aid aseptic donning (Section 7.11).

Recommended for:  GMP Grade A/B and C. Operators must wear single or two-piece trousers and high collar tunics (in Grade C) and general protective suit (in Grade D)

G. Undergarments

Dedicated garments should be worn under a sterilized suit (Section 7.13i).

Recommended for:  GMP Grade A/B and C

H. Socks

Dedicated cleanroom socks are required (Section 7.14).

Recommended for:  GMP Grade A/B and C 

I. Overshoes

Sterile footwear should be worn with trousers tucked inside footwear (Section 7.13ii).

Recommended for: GMP Grade A/B. Disinfected footwear should be worn recommended for: Grade C and D

J. Shoes

Sterile footwear should be worn with trousers tucked inside footwear (Section 7.13ii).

Recommended for: GMP Grade A/B. Disinfected footwear should be worn recommended for: Grade C and D

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EXAMPLE OF AN ANNEX 1 CLEANROOM GOWNING AREA

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EXAMPLE OF AN ANNEX 1 CLEANROOM WORK AREA

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