Annex 1 is here!

The new GMP regulations coming out of the European Union will have a big impact on pharmaceutical manufacturers. How will it affect cleaning and disinfection protocols?

Find out

What is Annex 1?

EU Annex 1 was first issued in 1972 to offer guidance for the manufacture of Sterile Medicinal Products. It has been over a decade since the annex has been reviewed, and in that time there have been significant changes in the industry.

Hover on circles to learn notable changes in the sterile manufacturing industry

Technology & methodology

• RABS • Isolators • Rapid microbiological methods • Water for injection preparation

Regulations

• •

ICH Q9 for Quality Risk Management ICH Q10 describing Pharmaceutical Quality Systems

What’s different?

Contamination Control Strategy

Cleaning and Disinfection

Disinfectant Rotation

Detergents and Disinfectants

Is your company prepared?

Learn more

One of the main documentary requirements is a Contamination Control Strategy (CCS).

Contamination Control Strategy

What is a CCS?

How to execute your CSS

As a minimum a CCS will include

What if I don’t have one?

The CCS is a site-wide strategy for the control of contamination, microorganisms, endotoxins/pyrogens and particles. It should consider all aspects of contamination control with ongoing and periodic reviews resulting in updates within the pharmaceutical quality system where appropriate. In summary its all of the measures needed to achieve the intent of Annex 1.

What is a CCS?

Did you know?

Your CSS must be an holistic living document, continuously reviewed and kept up-to-date throughout the lifecycle of the facility. It can be single or separate related documents.

How to execute your CSS

For established facilities it probably already exists but not defined exactly as a CCS but maybe across different documents which need to be linked together.

What if I don’t have one?

Design of both plant and process Premises and equipment Personnel Utilities Raw material controls Product containers and closures Vendor approval Outsourced services Process risk management Process validation

Process validation Validation of sterilization process Preventative maintenance Cleaning and disinfection Monitoring systems

Prevention mechanisms trend analysis, investigations CAPA

Continuous improvement based on the information derived above

As a minimum a CCS will include

There are approx. 45 times the annex states that a particular requirement, measurement or validation should be documented in a site’s CCS.

New and added definitions

Guidance

Throughout the Annex, the term “cleaning” has been replaced with "cleaning and disinfection" reflecting that current best practice treats cleaning and disinfection as two distinct activities trying to achieve different things.

Cleaning and Disinfection

Cleaning

“A process for removing contamination e.g. product residues or disinfectant residues”

Disinfection

“The process by which the reduction of the number of microorganisms is achieved by the irreversible action of a product on their structure or metabolism, to a level deemed to be appropriate for a defined purpose.”

Decontamination

“The overall process of removal or reduction of any contaminants (chemical, waste, residue or microorganisms) from an area, object or person. The method of decontamination used (e.g. cleaning, disinfection, sterilization) should be chosen and validated to to achieve a level of cleanliness appropriate to the intend use of the item decontaminated.”

Sporicidal agent

“An agent that destroys bacterial and fungal spores when used in sufficient concentration for specified contact time. It is expected to kill all vegetative microorganisms.”

Did you know?

Alcohols and hydrogen peroxide are the only two disinfectants that truly leave no residue.

Prior cleaning

For disinfection to be effective, prior cleaning to remove surface contamination should be performed.

Multiple disinfectants

More than one type of disinfecting agent should be employed to ensure that where they have different modes of action, their combined usage is effective against bacteria and fungi.

Sporicidal agent

Disinfection should include the periodic use of a sporicidal agent.

Residues

Cleaning programs should effectively remove disinfectant residues.

Monitoring

Monitoring should be undertaken regularly in order to assess the effectiveness of the disinfection program and to detect changes in types of microbial flora (e.g. organisms resistant to the disinfectant currently in use).

The disinfection process should be validated. Validation studies should demonstrate the suitability and effectiveness of disinfectants in the specific manner in which they are used and on the type of surface material, or representative material if justified, and should support the in-use expiry of prepared solutions.

Validation

Prior cleaning

Multiple disinfectants

Sporicidal agent

Residues

Monitoring

Validation

Monitoring

Residue

Sporicidal agent

Multiple disinfectants

Prior cleaning

Validation

Monitoring

Cleaning programs should effectively remove disinfectant residues.

Residue

Disinfection should include the periodic use of a sporicidal agent.

Sporicidal agent

More than one type of disinfecting agent should be used to ensure effectiveness against all bacteria and fungi.

Multiple disinfectants

For disinfection to be effective, prior cleaning to remove surface contamination should be performed.

Prior cleaning

Rinse

Periodically

Routinely

Daily

Use everyday on all surfaces

Regulatory guidelines are currently not aligned on the subjection of disinfectant rotation and the number of disinfectants which need to be used. The new Annex repeats the guidance that more than one type of disinfectant should be used, it has added a qualifier:

Disinfectant Rotation

“...where they have different modes of action their combined usage is effective against all bacteria and fungi.”

How often should I rotate my disinfectants?

Disinfectants • HydroPure • CyChlor • IPA / Denatured Ethanol

Use based on room environment monitoring

Sporicide • ProChlor • PeridoxRTU

Detergent • NeutraKlean

Use to remove buildup residue or when needed.

Rinse • IPA • WFI • Water

Use after cleaning and disinfecting

Find the best disinfectant and cleaning products for your cleanroom

Disinfect Daily

Disinfect Periodically

Rinse

Typical Cleaning and Disinfection Program

Annex 1 states “More than one type of disinfecting agent should be employed to ensure that where they have different modes of action their combined usage is effective against bacteria and fungi. Disinfection should include the periodic use of a sporicidal agent.”

Disinfectant Rotation

Broad-Spectrum - Use everyday on all surfaces

• Contec CyQuanol (EPA registered) • PREempt Plus (EPA Registered) • PREempt RTU (EPA / Health Canada registered

Contec PeridoxRTU (EPA / Health Canada registered)

Sporicides – use periodically based on environmental monitoring or action point

Water for Injection Contec IPA Contec HydroKlean

After cleaning and disinfection (or wipe to dry instead)

Find the best disinfectant and cleaning products for your cleanroom! Contact Us

Annex 1 states that the CCS should be determined through risk management so the rotation and number of disinfectants used should also be based on a risk management approach

Made in-house versus purchased ready-made

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Same as previously, the annex states all disinfectants and detergents used in grade A and B areas should be sterile prior to use. Additionally, disinfectants used in grade C and D may also be required to be sterile when determined in the CCS.

Disinfectants and Detergents

Prepared by sterile product manufacturer

Where the disinfectants and detergents are diluted / prepared by the sterile product and manufacturer, this should be done in a manner to prevent contamination and they should be monitored for microbial contamination.

•

Dilutions should be kept in previously cleaned containers (and sterilized where applicable) and should only be stored for the defined period.

If the disinfectants and detergents are supplied “ready-made” then results from the C of A or C of C can be accepted subject to suitable vendor qualification.

Purchased “ready-made”

Monitoring

Validation

There is increased emphasis on disinfectant validation, the disinfection process needs to be validated not just the disinfectant. Validation will need to relate to the manner in which the disinfectant is used, sprays, wiping, presaturated wipes not just standard suspension testing of the disinfectant.

Microorganisms detected in the grade A and B areas should be identified to species level…Consideration should also be given to the identification of microorganisms detected in grade C and D areas…."

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Contec NeutraKlean Contec IPA

After maintenance or spills or periodically to remove built-up residues

Where existing control systems are in place and are appropriately managed, these may not require replacement but should be referenced in the CCS and the associated interactions between systems should be understood."

New facilities should start the CCS as soon as possible, ideally it forms part of the design process and is included in the URS and DQ documents.

So how many disinfectants do I need! Does this say I must rotate disinfectants with different modes of action? Is this because of resistance? What does periodic use mean?

Product containers and closures Vendor approval Outsourced services Process risk management Process validation

Validation of sterilisation process Preventative maintenance Cleaning and disinfection Monitoring systems

Did you know?

View Cleaning Webinar

View cleaning Webinar

View residue Webinar

View Residue Webinar