The SAT of a new air handling unit closes with no open punch list items. At PQ, however, the grade C room next to the entry airlock fails to hold the expected differential once the pass-box is cycled at the frequency the shift really uses. The supplier produces the airflow calculation and demonstrates compliance with the specification, which asked for "adequate pressurisation towards adjacent areas" without stating under which conditions the differential had to hold, against which value, and with which instrument. Contractually nobody is wrong; in GMP terms the qualification cannot be closed.
This is the typical way a poorly written URS moves a technical problem from design into qualification, where fixing it costs far more. The URS (User Requirement Specification) is the document in which the site states what the installation must do, under which conditions, and how that will be verified. It is not a wish list, nor a restatement of Annex 1: it is the contractual basis of the tender, the technical basis of the design and the documentary basis of the qualification. The same requirements are traced in DQ, revisited at FAT and SAT, verified in IQ, OQ and PQ. The full route is in the Cleanrooms & HVAC Systems hub.
Why the URS decides the qualification outcome
An ambiguous requirement triggers a predictable chain. In the tender it produces bids that cannot be compared, because two suppliers price the same sentence with different architectures and instrumentation. In qualification it cannot generate an acceptance criterion: either the protocol verifies something else, or a deviation closes a gap that already existed in the URS. In operation it becomes recurring cost. Annex 15 places the URS at the start of the qualification cycle (3.2) and requires lifecycle traceability.
The regulatory frame the URS has to carry
| Source | Status and date | What it actually binds |
|---|---|---|
| Annex 1, EudraLex Vol. 4 | C(2022) 5938 final, in application since 25 August 2023; only clause 8.123 deferred to 25 August 2024 | Grades A/B/C/D (4.4), airlocks (4.12–4.13), pressurisation and airflow visualisation (4.14–4.15), qualification (4.25), requalification (4.32) |
| Annex 15, EudraLex Vol. 4 | 2015 revision, operational since 1 October 2015 | URS, DQ, FAT/SAT, IQ, OQ, PQ, change control. The word "commissioning" does not appear in the text |
| Chapters 3 and 5, EudraLex Vol. 4 | Operational since 1 March 2015 | 3.12 requires effective ventilation with control of temperature, humidity and filtration; 5.21 lists the technical measures against cross-contamination. No figures |
| ICH Q9(R1) | Step 4 on 18 January 2023 | Risk management methodology; Annex II.4 applies it to facilities and utilities. No HVAC design parameter |
| 21 CFR 211.42(c)(10) and 211.46 | In force | Require HEPA-filtered air under positive pressure, temperature and humidity control, monitoring and filtration, with no numerical value |
| ISO 14644-4 (2022), ISO 14644-5 (2025), WHO TRS 1010 Annex 8 (2018) | Voluntary standards and guidance | Method, not GMP acceptance criteria. TRS 1010 Annex 8 (§6.2) points to HEPA of at least class H13 to EN 1822 or equivalent [GUIDANCE] |
Structuring the URS section by section
Intended use, products and process
State what is manufactured, which operations are open and exposed, and what the risk profile is: without that, neither the grade nor the segregation level can be justified. State the operating modes and the maximum number of operators, because Annex 1 defines the "in operation" state in terms of the people carrying out or simulating routine work (4.29(ii)).
Rooms: zoning, classification, finishes, flows
State the GMP grade of each room and the occupancy state in which the limits apply, never a flat equivalence with an ISO class: Annex 1 grades are regulatory categories defined by particulates, microbiological limits, airflow, differentials and gowning, while ISO 14644-1 classes rest on particle concentration alone. Adjacency logic is covered in zoning and classification. Specify the finish criteria (4.5–4.9) and the separation between PAL and MAL required by 4.12.
HVAC: airflow, pressure cascade, filtration, temperature and humidity
The URS states performance, not solutions: grade and reference state, expected clean up period, airflow direction, differentials with their verification conditions, temperature and humidity with their origin, filter class with standard and edition. The cascade is covered in airflow and pressure cascades. Avoid the most common error: specifying air changes per hour as a regulatory requirement. Annex 1 contains no ACH requirement; air change rates are derived to achieve the required classification and clean up.
Controls, alarms, records
State which parameters are critical, who measures them, and what happens to the data. Annex 1 requires pressure differential indicators and, for the differentials identified as critical in the CCS, continuous monitoring and recording with alarms (4.16): the URS must define the criticality criteria, not just list sensors. Audit trail, access control and backup derive from Annex 11 and belong in the URS as testable requirements, as discussed in BMS, EMS and data integrity.
CQV, documentation and lifecycle
State the supplier deliverables and the verification methods: as-built detail, TAB protocols, turnover documentation, access for filter changes, permanent measuring points, critical spares. Annex 1 (4.32) sets a maximum requalification interval of 6 months for grades A and B and 12 months for grades C and D [REQUIREMENT]: this drives the instrumentation designed in from the start.
Where a number in a URS legitimately comes from
Every figure written into a URS needs four attributes: source, justification, owner and review date. Without them it is indefensible in an inspection. There are three legitimate origins.
- Regulatory or compendial. The value appears in a binding text or in guidance and is cited with clause and nature: the minimum 10 Pa differential between adjacent rooms of different grade (Annex 1 4.14) [GUIDANCE], stated in the text itself as a guidance value; the 0.36–0.54 m/s range at the working position for unidirectional airflow (4.30) [GUIDANCE], open to departure with scientific justification in the CCS; the clean up period of less than 20 minutes (4.29(iii)) [GUIDANCE], still to be determined in qualification.
- Product or process. The value follows from product stability, process technology or the ergonomics of the operation: the justification is a product document, not a standard.
- Site. The value is set by the site on its own qualification and monitoring history and must be declared as such.
A value taken from non-European guidance must be qualified as such: FDA guidance documents do not establish legally enforceable obligations, they describe the Agency's current thinking. The 2004 aseptic processing guidance recommends, by way of example, at least 10–15 Pa between adjacent rooms of different classification with doors closed [GUIDANCE], describes at least 20 air changes per hour as typically acceptable for ISO 8 supporting rooms only [GUIDANCE], and reports 0.45 m/s ± 20 % as a typical value in a footnote [GUIDANCE]. None of these transfers into a European URS without stating its origin and assessing applicability.
Bad wording and verifiable rewrites
| Faulty wording | Why it is a problem | Verifiable rewrite |
|---|---|---|
| "Adequate pressurisation" | No value, no condition, no method: it cannot produce an acceptance criterion | For each adjacency: target and minimum value, verification state, instrument and observation period |
| "Grade A equivalent to ISO 5" | The equivalence does not exist: grades are multi-parameter, ISO classes are particle-only | State the required GMP grade and cite the ISO standard separately as a methodological reference |
| "Air changes in line with industry standard" | No binding ACH standard exists and Annex 1 contains none | Specify the expected outcome and leave sizing to the supplier, with the calculation shown at DQ |
| "Filters to EN 1822" | The series is partly withdrawn: only EN 1822-1:2019 remains valid for classification | Cite the class to EN 1822-1:2019 and, separately, the method standard for field integrity testing |
| "Reliable and easy to maintain system" | Unmeasurable adjectives: no test can demonstrate compliance | Filter access from the unclassified side, minimum service clearances, duty/standby where risk analysis requires |
| "Recovery time below 20 minutes as required by regulation" | Turns a guidance value into a binding one and conflates clean up period with the recovery test | State the clean up period as a parameter determined in qualification, citing 4.29(iii) |
Requirement, rationale, verification method
| Requirement | Rationale | Verification method |
|---|---|---|
| Airflow direction between adjacent rooms of different grade, demonstrated under the declared operating conditions | Annex 1 4.14 and 4.15 [REQUIREMENT] | Airflow visualisation study at rest and in operation |
| Differentials continuously monitored and recorded for the room pairs the CCS identifies as critical | Annex 1 4.16 [REQUIREMENT]; criticality follows from site QRM [QRM] | Functional verification at OQ of the sensor-recording-alarm chain |
| Terminal filter class to EN 1822-1:2019, with field integrity testing after installation | Annex 1 4.1 [REQUIREMENT] requires appropriate efficiency; the class is justified on QRM | Factory certificate plus installed filter system leakage test at IQ/OQ |
The URS as an output of risk management
ICH Q9(R1) treats QRM as a continuum of formality: not every decision needs the same methodological apparatus, but every one needs consistency and traceability. Annex II.4 applies QRM to facilities, equipment and utilities, including plant zoning and qualification scope. In URS terms that means three things: segregation and grade follow from a documented analysis of the exposed operations, not from site habit; parameter criticality is a risk decision that has to be justified; and subjectivity has to be acknowledged, because a URS copied from the last project built is the textbook bias Q9(R1) asks teams to manage.
Worked example: Site Vega
"Site Vega" is a realistic but entirely fictitious example. The site is building a non-sterile area with two dispensing rooms, a granulation suite and an airlock block. The first URS draft asks for "grade D classification and differentials in line with normal practice". Review surfaces three problems. The product is hygroscopic, so relative humidity is not a comfort parameter but a process attribute, to be written with its own source and a justified band. Dispensing involves powder handling and the dominant risk is containment, not classification alone: the required airflow direction is the opposite of the one assumed by habit. The draft also failed to state the occupancy state in which the limits apply, making an acceptance criterion impossible to write. The second draft separates classification from containment, states the occupancy states, and moves the conflicting decisions into a formal risk assessment.
Where to fix the requirement: options and criteria
| Option | When it makes sense | Main risk | Weight |
|---|---|---|---|
| Prescriptive: the site fixes the solution | Site standardisation, interface with existing installations | The site takes technical ownership of the solution | |
| Performance-based: the site fixes the outcome | General case: classification, clean up, differentials, T and RH | Bids cannot be compared without verification conditions | |
| Delegated: the supplier proposes, the site approves at DQ | Detailed sizing, ductwork layout | Decision delays if the approval criterion is unwritten | |
| Deferred to qualification: value determined in the field | Parameters that depend on the final configuration | No contractual criterion without a stated expected band |
The weighting column is filled in by the project team according to system criticality: no universal weighting exists.
Levels of prescriptiveness
| Statement | Level | Source |
|---|---|---|
| Airlock and pass-box doors serving grade A and B areas must be interlocked | [REQUIREMENT] | Annex 1, 4.13 |
| Minimum 10 Pa differential between adjacent rooms of different grade | [GUIDANCE] | Annex 1, 4.14 (guidance value) |
| ISO 14644-4 and -5 as design and operations references | [STANDARD] | Voluntary standards |
| Criticality of continuously monitored parameters must be justified by risk analysis | [QRM] | ICH Q9(R1) Annex II.4; Annex 1, 4.16 |
| Filter access from the unclassified side | [GEP] | Good engineering practice |
| Every figure in a URS carries source, justification, owner and review date | [GUIDEGXP] | Editorial operating recommendation |
Completeness checklist
- State intended use, exposed operations and the maximum number of operators.
- Assign to each room its GMP grade and the applicable occupancy state.
- Specify airflow direction and differential verification conditions for every adjacency.
- Check that no ACH figure is presented as a regulatory requirement.
- Cite every standard with edition and year, confirming it is not withdrawn.
- Attach to every figure a source, an owner and a review date.
- Define the criticality criteria before listing sensors.
- Write the verification method and phase for each requirement.
- Include the Annex 11 data integrity requirements as testable entries.
- Freeze the baseline before the RFP and handle changes under change control.
Recurring errors and red flags
The first red flag is a URS quoting numbers without a source: if nobody knows where a figure came from, nobody will defend it. The second is a URS copied from an earlier project without revisiting the intended use. The third is confusion between classification, qualification and routine monitoring, which puts monitoring criteria inside qualification requirements. The fourth is a URS drafted by the supplier, which becomes a description of the offer. The fifth is the evaluative adjective standing in for a measurable quantity. The sixth is the absence of a frozen baseline. Checking these at tender stage is covered in supplier selection; the field outcome shows up in cleanroom qualification.
If this way of working on requirements is useful, The Pragmatic GMP collects technical analysis and verified regulatory updates for people who design and qualify pharmaceutical facilities.
Key takeaways
- The URS is both the contractual basis of the tender and the documentary basis of qualification.
- A requirement that cannot be verified produces traceability without evidence.
- Every figure needs a source, a justification, an owner and a review date.
- The current Annex 1 contains no air change rate requirement.
- GMP grades are not equivalent to ISO classes and need the applicable occupancy state.
- Parameter criticality is a risk decision that feeds the CCS.
- The URS baseline is frozen before the RFP and change-controlled thereafter.
