Annex 1 now comes with an official reading guide
By Daniele Calzolari, Service Area Manager Manufacturing Services, ProductLife Group
On 28 October 2026, PIC/S Recommendation PI 058-1, Interpretation of the Most Important Changes in the Annex 1 on the Manufacture of Sterile Products (2022), entered into force. It was prepared by experts of the PIC/S–EMA–WHO Joint Implementation Working Group on Annex 1 and formally adopted by all three bodies.
In Q&A form, it answers 79 questions across the Annex 1 chapters, from premises and utilities to aseptic process simulation and environmental monitoring. It replaces PI 032-2, the interpretation document issued in 2010 for the previous version of Annex 1.
PI 058-1 states that it does not introduce new GMP requirements. What it changes is the room for interpretation: its stated aim is harmonised inspection of the 2022 revision across PIC/S, EU and WHO jurisdictions. For manufacturers, a set of open debates becomes one reference their practices will be read against.
Three points stand out for anyone responsible for a Contamination Control Strategy.
1. The CCS is not only a sterile-manufacturing tool
The first question in the Scope section asks whether the CCS also applies to non-sterile products. The answer: yes, it can be applicable.
PI 058-1 gives the example of a company that makes no sterile products but operates grade C/D cleanrooms. It should still evaluate its contamination risks from process and product knowledge, and decide how to document them, for example in a summarising CCS document. Where a manufacturer chooses to apply Annex 1 guidance to non-sterile products, it should describe which principles it applied and how compliance is demonstrated.
This is not a new obligation. It is a clear direction: for non-sterile sites with classified areas, a structured contamination control strategy is the answer PI 058-1 points to when an inspector asks how contamination risks are managed. It also gives a common framework to sites running sterile and non-sterile operations side by side.
This interpretation is also consistent with the recent EMA/INS/GMP/161750/2026 “What are technical and organisational measures that should be taken into consideration to prevent microbial contamination of non-sterile medicinal products”, where EMA explicitly states that manufacturers of non-sterile medicinal products may consider applying principles from the Contamination Control Strategy described in Annex 1, based on a Quality Risk Management approach. The document confirms that contamination control is not limited to sterile manufacturing but should be applied, in a proportionate manner, whenever microbial contamination may impact product quality or patient safety.
2. A CCS has to prove it works, at least once a year
The 4.2 Section 2 – Principle asks how often the effectiveness of the CCS should be reviewed. The answer sets a floor: continued suitability must be assured on an ongoing basis, and the minimum review frequency is annual.
Effectiveness should be reviewed at least during management review, and again in case of significant change, deviation or a significant emerging problem. The CCS should also be covered by ongoing quality management and the periodic product quality review, with results actively checked for consistency with the strategy.
In practice, a CCS written once for the Annex 1 deadline is no longer enough. Questions worth asking now:
- Is the CCS on the management review agenda, with a defined owner?
- Do product quality reviews assess whether the CCS is still effective?
- Do environmental monitoring trends, APS results, deviations and CAPA feed back into the strategy?
- Which events trigger an out-of-cycle review, and are they written into change control and deviation procedures?
- Which indicators would show an inspector that the CCS is working, not just that it exists?
3. Risk-based means documented, not discretionary
Quality risk management runs through the whole document: roughly 30 of the 79 answers rely on a documented risk assessment or a QRM justification, usually recorded in the CCS. Some examples:
|
Area |
What PI 058-1 expects |
|
Existing facilities / legacy designs |
Where facilities or equipment cannot immediately comply with new Annex 1 requirements, a documented risk assessment should identify contamination risks, define interim mitigation measures and establish a justified remediation plan with appropriate timelines |
|
Isolators |
Automated functions and activities inside the isolator are part of the CCS risk assessment, at design or selection and over the equipment lifecycle |
|
Water for injection |
Sampling plans are commensurate with risk; points of use are selected by risk assessment |
|
Personnel qualification |
The scope of requalification activities after disqualification events should be risk-based and may include retraining, repeat gowning qualification and successful participation in APS before restoring independent cleanroom access. |
|
Filter integrity |
Where PUPSIT is not feasible, alternatives are acceptable only with a justified, comprehensive risk evaluation |
|
Extractables and leachables for SUS |
The need for additional extractables/leachables studies should be determined through a documented risk assessment considering product characteristics, route of administration, patient exposure, process conditions and the suitability of supplier-generated data |
|
Aseptic process simulation |
APS duration, campaign coverage, intervention frequency and any reduction of routine simulation activities must be supported by documented QRM demonstrating that aseptic process risks remain adequately challenged and controlled |
|
Environmental monitoring |
Monitoring points should be selected though a formal risk assessment on the basis of contamination risk, airflow patterns, interventions and process knowledge |
The examples throughout PI 058-1 consistently demonstrate that Quality Risk Management is expected to drive contamination-control decisions across facilities, equipment, utilities, processes and personnel practices. However, these decisions must be formally documented, scientifically justified and integrated within the Contamination Control Strategy rather than being based solely on operational experience or expert judgement.
What to do next: a gap assessment against PI 058-1
The most direct way to use PI 058-1 is to read your own practices against it before an inspector does. A structured gap assessment typically runs in five steps:
- Map the 79 Q&As against your sites, products and technologies, and set aside those that do not apply.
- Compare each relevant answer with current procedures and records, and classify the result: aligned, partially aligned, gap.
- Check the justifications. Wherever your practice relies on a risk-based choice, confirm the risk assessment exists, is current and is referenced in the CCS.
- Update the CCS and its review cycle: scope (including non-sterile areas where relevant), owner, annual review, triggers for out-of-cycle review, and effectiveness indicators.
- Prioritise remediation by patient and compliance risk, and track it through change control and CAPA.
How PLG can help
PLG experts in quality, engineering and digital manufacturing support sterile and non-sterile manufacturers across the topics PI 058-1 addresses:
- Gap assessment against PI 058-1, site by site, with a prioritised remediation plan
- CCS development for sterile and non-sterile operations, supporting the identification, evaluation and control of contamination risks through a structured and science-based approach.
- CCS effectiveness evaluation and review, supporting manufacturers with structured CCS effectiveness frameworks, either as standalone assessments or integrated within the CCS itself, to demonstrate through documented evidence that contamination control measures remain suitable, effective and continuously maintained over time.
- Quality risk management: facilitation and documentation of risk assessments supporting contamination-control decisions for facilities, personnel, utilities, single-use systems, environmental monitoring and aseptic process simulation.
- Facility design and qualification through PLG's Engineering Centre of Excellence, with contamination control built in from the first layout
- Digital manufacturing and data: connecting monitoring and quality data so CCS effectiveness can be shown, not only stated
PLG experts discussed these topics at the Pharma Microbiology Congress 2026 in Milan, where PI 058-1 was presented.
Planning an Annex 1 gap assessment or a CCS review? Talk to our experts.
Sources
- PIC/S PI 058-1, Interpretation of the Most Important Changes in the Annex 1 on the Manufacture of Sterile Products (2022), 28 October 2026
- PIC/S News: Adoption and entry into force of PI 058-1
- EMA/INS/GMP/161750/2026 “What are technical and organisational measures that should be taken into consideration to prevent microbial contamination of non-sterile medicinal products”