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EMA-Annex 1: sterility, proven.

From EMA-Annex 1 compliance to excellence in sterility assurance: the PBE Expert team designs, implements and demonstrates the contamination control strategy of your sterile facilities, all the way to inspection.

Talk to an ExpertSee the 13 levers

What changed in 2022

Five changes that matter.

Annex 1 governs the manufacture of sterile medicinal products. Its 2022 revision calls for fewer operator actions to monitor, and more risks eliminated by design.

Core standard

EMA-Annex 1

Manufacture of sterile medicinal products

EU GMP · EudraLex, Volume 4

2022 revision, in force since August 25, 2023

The official text(European Commission PDF, opens in a new tab)
  1. 01

    A strategy for the whole site

    The CCS covers premises, equipment, utilities, personnel, materials and processes.

  2. 02

    Risk first

    Quality risk management justifies every design choice and every monitoring limit.

  3. 03

    Barriers expected

    RABS and isolators protect the grade A zone; doing without them must be justified.

  4. 04

    Filters tested before use

    The integrity of the sterilizing filter is verified after sterilization and before use (PUPSIT), unless justified.

  5. 05

    Evidence, all the time

    Environmental monitoring, aseptic process simulations and trending demonstrate a state of control at all times.

What Annex 1 looks at

A vial, piece by piece.

Every part of an injectable vial falls under Annex 1. The PBE Expert team designs the line and the room so that each one is under control, then demonstrates it.

An injectable vial taken apart: the cap, the crimp seal, the stopper, the glass vial and a drop of product.
  1. The capEvery unit is inspected, one by one, before release.
  2. The crimp sealCrimped under grade A air; container closure integrity is demonstrated.
  3. The stopperSterilized, transferred without breaking the barrier, and protected until crimping.
  4. The glass vialWashed, depyrogenated and sterilized in validated cycles.
  5. The productSterile-filtered, with the filter tested before and after use; the aseptic process is validated by simulation.

EMA-Annex 1

Contamination, controlled by design, at every barrier, through monitoring, all the way to inspection.

The PBE Expert method

Thirteen levers, one strategy.

From the sterility assurance strategy all the way to inspection. At the end of the line, the detailed requirements: for each lever, what the team checks, its Annex 1 reference and its priority.

EMA-ANNEX 1 · CLEANROOM GRADES D TO APRESSURE CASCADE: 10–15 PA BETWEEN GRADES GRADE DGRADE CGRADE B HEPA FILTER · GRADE A 0,36 – 0,54 m/s

SAS, the sterility assurance strategy, covers the following twelve levers:

  1. QRM: Quality risk management
  2. CCS: Contamination control strategy
  3. CCbD: Contamination control by design
  4. Facility Design: design of the facilities
  5. HVAC: HVAC and clean utilities
  6. EMP: Environmental monitoring
  7. CDbD: Cleaning and disinfection by design
  8. RABS: RABS and isolators
  9. PUPSIT: Filter integrity before use
  10. APV/APS: Aseptic process simulation and validation
  11. AFV: Airflow visualization
  12. Audit Readiness: Preparing for audits and inspections

See the detailed requirementsHide the detailed requirements

Requirements · Gap analysis

EMA-Annex 1: the 13 levers of the PBE Expert method

Document no.
PBE-QA-A1-013
Revision
03
Category
Strategy
Page
1 of 4
Strategy
N°LeverWhat the team checksAnnex 1 ref. (§)PriorityVerified
Strategy
01SASSterility assurance strategyPBE methodThe whole sterile life cycle linked to the CCS, the risks and validationPrinciple; 2.1–2.6High
02QRMQuality risk managementRisk-based decisions, documented and reviewed2.2–2.6; ICH Q9Critical
03CCSContamination control strategyA living, site-specific document: prevent, detect, improve2.3–2.6Critical
Prepared byThe PBE Expert team
Reviewed byQuality assurance
StatusApproved

Requirements · Gap analysis

EMA-Annex 1: the 13 levers of the PBE Expert method

Document no.
PBE-QA-A1-013
Revision
03
Category
Design
Page
2 of 4
Design
N°LeverWhat the team checksAnnex 1 ref. (§)PriorityVerified
Design
04CCbDContamination control by designPBE methodRisks eliminated at the design stage, before procedures2.5 ; 3 à 9High
05SbDSterility by design and facility designPBE methodBarriers and complementary controls, not just the final testPrinciple; 8 and 9Critical
06HVACHVAC and room designConsistent grades, pressures, filtration and airflows4.14–4.17 ; 4.23–4.34Critical
07CDbDCleaning and disinfection by designPBE methodCleanable surfaces and equipment, with verifiable effectiveness2.5 ; 4.33–4.36Critical
08AFVAirflow visualizationSmoke studies under dynamic conditions, with worst-case interventions, on videoSection 4; FDA guidanceCritical
Prepared byThe PBE Expert team
Reviewed byQuality assurance
StatusApproved

Requirements · Gap analysis

EMA-Annex 1: the 13 levers of the PBE Expert method

Document no.
PBE-QA-A1-013
Revision
03
Category
Barriers and process
Page
3 of 4
Barriers and process
N°LeverWhat the team checksAnnex 1 ref. (§)PriorityVerified
Barriers and process
09RABSRABS and isolator barriersBarrier, background environment, decontamination and interventions qualified4.18–4.22 ; 8Critical
10PUPSITFilter integrity before useFilter tested after sterilization and before use8.87Critical
11APV/APSAseptic process simulation and validationWorst case: durations, shifts, interventions; all aseptic controls validated, personnel included9.38–9.49; Annex 15Critical
Prepared byThe PBE Expert team
Reviewed byQuality assurance
StatusApproved

Requirements · Gap analysis

EMA-Annex 1: the 13 levers of the PBE Expert method

Document no.
PBE-QA-A1-013
Revision
03
Category
Monitoring and evidence
Page
4 of 4
Monitoring and evidence
N°LeverWhat the team checksAnnex 1 ref. (§)PriorityVerified
Monitoring and evidence
12EMPEnvironmental monitoringSampling points, frequencies and limits justified by risk9.1–9.37Critical
13ARAnnex-1 Audit Readiness: preparing for audits and inspectionsPBE methodCurrent, approved evidence, presented without delayPrinciple; ICH Q10Critical
Prepared byThe PBE Expert team
Reviewed byQuality assurance
StatusApproved

The path

From gaps to a successful inspection.

  1. 1

    Gap analysis

    Your facilities, processes and documents, compared against the 13 levers.

    Compliance audit
  2. 2

    Action plan and CCS

    Gaps ranked by priority, and your contamination control strategy written or reviewed.

    Quality assurance
  3. 3

    Design and upgrade

    Barriers, HVAC, flows and clean utilities designed to eliminate risks.

    Design
  4. 4

    Qualification and validation

    DQ, IQ, OQ and PQ, then aseptic process simulations.

    Qualification
  5. 5

    Inspection-ready

    Trained teams and up-to-date evidence, presented without delay.

    FormAction™
Two scientists in cleanroom gowning, at a microscope

Requirements and evidence

What the inspector checks, what we deliver.

RequirementThe inspector asks to seeThe PBE Expert team delivers
Contamination control strategyA site-specific, up-to-date CCS, linked to risks and monitoring resultsWriting or reviewing your CCS, lever by lever
Quality risk managementRisk assessments that justify the design and the limitsDocumented, reviewed risk assessments (FMEA)
Barrier technologiesQualified RABS or isolators, and controlled interventionsBarrier requirements (URS), design and qualification
Sterilizing filtrationFilter integrity tested before and after use, or the justificationAssessment and implementation of the test, or its justification
Aseptic process simulationWorst-case simulations: durations, shifts, interventionsDesign and follow-up of the simulations
Environmental monitoringJustified sampling points and limits, with trends trackedA risk-based monitoring plan

They passed inspection

Sterile facilities, approved.

All our projects

FormAction™

Your teams, ready for Annex 1.

Hands-on GMP FormAction™ courses, at your facility or in the classroom. PBE Expert is a CPMT-approved training organization: your costs are eligible expenses.

See the FormAction™ courses
An operator in full cleanroom gowning, holding a measuring instrument.

Frequently asked questions

Annex 1, in plain terms.

What is EMA-Annex 1?

It is the annex to the European Union’s good manufacturing practices that governs the manufacture of sterile medicinal products. Its revision, published by the European Commission in August 2022, has been in force since August 25, 2023.

Who does it apply to?

Manufacturers of sterile products, such as injectables, that sell in Europe or whose authorities follow EU or PIC/S GMP. Its principles can also guide the manufacture of non-sterile products.

What is a contamination control strategy (CCS)?

A site-specific document that defines all critical control points and assesses the effectiveness of all the controls (design, procedural, technical and organizational) and the monitoring used to manage contamination risks.

Do we have to replace our existing cleanrooms?

Not necessarily. Annex 1 requires every choice to be justified by risk. A gap analysis shows what can be kept, adapted or replaced, and in what order.

Where do we start?

With a gap analysis: the PBE Expert team compares your facilities, processes and documents against the 13 levers, ranks the gaps by priority and gives you an action plan.

Can PBE Expert train our teams?

Yes. Our GMP FormAction™ courses are given at your facility or in the classroom. PBE Expert is a CPMT-approved training organization: your costs are eligible expenses.

Keep exploringIndustriesPharmaceutical, vaccines and biotechnology, hospitals, fine chemicals, medical cannabis, food: the specific requirements of each regulated industry.

See alsoProjectsFormAction™

Let’s talk about your contamination control strategy.

A gap analysis, a CCS to write, an inspection coming up: the PBE Expert team has answers.

Talk to an Expert