UKAS accredited calibration laboratory No. 10723

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What EU GMP and the Orange Guide require of temperature

If you hold a manufacturer's licence, the law requires you to follow GMP (Human Medicines Regulations 2012, regulation 37), and the detail is the EU GMP Guide, which the MHRA reproduces in the Orange Guide. For temperature that means special storage conditions provided, checked and monitored (Chapter 3, 3.19), instruments calibrated at defined intervals (3.41), rooms and chambers qualified and kept qualified (Annex 15), stability chambers monitored against ICH tolerances, a validated monitoring system (Annex 11) and records kept intact for the whole retention period (Chapter 4).

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Updated 19 October 2026Reviewed by Jake Farrow, Managing Director

At a glance

What it asks

What inspectors cite

MHRA GMP inspections citing each area, 2019

Of 258 GMP inspections in MHRA's 2019 deficiency data, this many cited each clause at least once. Storage and calibration are rarely Critical, but each comes up at about one inspection in six or seven.

Inspections citing the clause, 2019
Annex 15 qualification and validation117
Annex 11 computerised systems95
3.41 calibration41
3.19 storage conditions38

Our count from MHRA's 2019 GMP deficiency spreadsheet (258 inspections). One inspection can cite several clauses. MHRA has published no GMP deficiency data since 2019.

HMR reg 37, C17

The Orange Guide, and which text applies

What it says

Regulation 37(2) of the Human Medicines Regulations 2012 requires a manufacturer's licence holder to comply with the principles and guidelines of GMP, and 37(6) to maintain the staff, premises and equipment needed. The Orange Guide (Rules and Guidance for Pharmaceutical Manufacturers and Distributors) is the MHRA's compilation of the EU GMP Guide as applied in the UK, UK legislation and MHRA guidance; the Green Guide is the separate book for distributors. Under regulation C17(3), the EU guidelines as they applied immediately before 31 December 2020 continue to apply unless the MHRA replaces them. The MHRA's 2020 note says Great Britain uses those versions and Northern Ireland the current EU texts.

What it means on site

Most procedures cite the Orange Guide, but inspectors quote the clause, so cite the clause (for example Chapter 3, 3.19). Great Britain applies the EU guidelines as they stood on 31 December 2020 unless the MHRA replaces them (reg C17(3)), and the MHRA has adopted some later texts for GB: the 2022 Annex 1 has applied since 25 August 2023 (MHRA Orange Guide update). Under reg 43(1)(b), Northern Ireland wholesalers follow the current Commission GDP; Northern Ireland manufacturers should confirm the current position with the MHRA. For later texts not yet adopted, such as the 2025 Annex 11 and Chapter 4 drafts, check the MHRA's position before relying on them.

How to evidence it

  • Your manufacturer's licence and the activities it covers
  • A register of the GMP texts and versions your procedures cite
  • A note of how you apply texts adopted after 2020, and who confirmed it

GMP 3.19, 5.7

Storage: provided, checked and monitored

What it says

Storage areas should be clean, dry and maintained within acceptable temperature limits, and where special storage conditions are required (for example temperature or humidity) they should be provided, checked and monitored (3.19). All materials and products should be stored under the conditions established by the manufacturer (5.7): intermediates and bulk (5.41), finished product in quarantine (5.63) and after release (5.65). Quarantine and rejected, recalled or returned stock need marked, segregated areas (3.21, 3.23), and QC needs adequate storage for samples (3.27).

What it means on site

Chapter 3 doesn't say mapping, but MHRA inspectors have linked 3.19 to a mapping study to decide where probes go, and the deficiency data show what goes unwatched: a receiving bay with a 32 °C limit and no monitoring, alarms set at 18 °C to 26 °C for products needing 2 °C to 25 °C, and capsule shells stored outside their humidity range.

How to evidence it

  • Storage conditions for each material and product, from the specification
  • A drawing linking each monitoring probe to a mapped extreme
  • Alarm limits for each area that match the product, with their reasoning
  • Monitoring records for receiving, quarantine, released and rejected stock

GMP 3.41, Part II 5.30 to 5.35

Calibration: defined intervals, and a look back on failure

What it says

Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods, with adequate records (3.41). Installation qualification includes calibration of instrumentation (Annex 15, 3.9). For APIs, Part II adds traceable standards (5.31), calibration status known and verifiable (5.33), failed instruments taken out of use (5.34) and deviations investigated for their effect since the last successful calibration (5.35).

What it means on site

The interval is yours to define; an MHRA Inspectorate blog reply (Sara Berry, 26 February 2018, on the 2016 mapping blog) says "the general expectation is that equipment should be calibrated annually". The gap is usually the look back: when a probe fails, nobody reviews the readings, releases and stability pulls that relied on it since its last good calibration.

How to evidence it

  • A calibration certificate for each monitoring probe, in date and traceable
  • Acceptance criteria for each calibration, reviewed and signed
  • The interval for each instrument and why
  • For any failure, the impact assessment back to the last good calibration

Annex 15, sections 3, 4 and 11

Qualification, mapping and requalification

What it says

Facilities, equipment and utilities are qualified through a lifecycle from the user requirements specification (3.2) through design (3.3), installation (3.8 and 3.9), operational qualification testing upper and lower limits or worst case (3.11), and performance qualification under normal conditions (3.14). They should then be evaluated at an appropriate frequency to confirm they remain in control (4.1); a fixed requalification period must be justified and gradual change considered (4.2). Changes are assessed for their effect on validation, calibration and requalification (11.4).

What it means on site

Annex 15 never uses the word mapping; a mapping study, empty and loaded, is the usual evidence that a room or chamber holds its range throughout. Common gaps are a contractor's mapping the company never approved, and racking moved or a unit replaced with no assessment of the old map. Annex 1's fixed 6 and 12-month intervals are for cleanrooms, not storage.

How to evidence it

  • URS, DQ, IQ, OQ and PQ for each room, cold room and chamber
  • Mapping protocols approved before the study, and reports approved after it
  • The requalification interval for each, with its justification
  • Change control records that assess the effect on mapping and calibration

GMP 6.29, ICH Q1A(R2)

Stability chambers: qualified, and monitored to ICH

What it says

Equipment for the ongoing stability programme, stability chambers among others, should be qualified and maintained under Chapter 3 and Annex 15 (6.29), with ICH conditions in the protocol (6.30). ICH Q1A(R2) sets the conditions, for example 25 °C ± 2 °C/60% RH ± 5% RH, 30 °C ± 2 °C/65% RH ± 5% RH, 40 °C ± 2 °C/75% RH ± 5% RH, 5 °C ± 3 °C and −20 °C ± 5 °C, and says actual temperature and humidity should be monitored. Door-opening spikes are accepted; equipment-failure excursions are assessed and reported if they could affect results; excursions beyond tolerance for over 24 hours go in the study report.

What it means on site

A chamber's own display is a controller, not an independent record. A failure on Friday night found on Monday has already passed the 24-hour line, and the batches on that shelf may hold years of data for the marketing authorisation.

How to evidence it

  • Qualification and mapping for each chamber, at its set conditions
  • Independent temperature and humidity records for every condition
  • Alarm limits inside the ICH tolerances, and the delays you set
  • Excursion assessments, and the study reports that describe them

Annex 11, MHRA data integrity

The monitoring system: validated for your use

What it says

Computerised systems used in GMP should be validated under Annex 11 (Annex 15, principle): risk-based validation across the lifecycle (4), data accessible throughout the retention period with restores checked (7), an audit trail of GMP-relevant changes that is regularly reviewed (9), periodic evaluation (11) and access restricted to authorised people (12). The MHRA's data integrity guidance says vendor validation data in isolation from your configuration and intended use is not acceptable (6.19), and administrator rights should not sit with people who generate or review the data (6.16).

What it means on site

Older monitoring software often runs on one PC with shared logins and no audit trail review. A cloud platform moves the hosting, not the accountability: you still assess the supplier, approve your reliance on its testing and qualify your configuration.

How to evidence it

  • A URS, risk assessment and qualification records for the monitoring system
  • The supplier assessment and the quality and technical agreement
  • Audit trail reviews, with the reviewer and date
  • A periodic evaluation of the validated state

Annex 1 (2022) 4.16, 5.2, 9

Sterile sites: monitoring in the URS, alarms trended

What it says

Critical pressure differences should be continuously monitored and recorded with an instant warning, and any alarm delay assessed and justified in the contamination control strategy (4.16). Equipment monitoring requirements belong in the URS and are confirmed during qualification, and alarm events are acknowledged and evaluated for trends (5.2). The monitoring programme includes temperature and relative humidity (9.2), controlled within ranges that suit the product, process and people (9.6), with the trending approach defined (9.11) and a root cause investigation when action limits are exceeded (9.13).

What it means on site

Annex 1 doesn't mention calibration or audit trails; those come from Chapter 3 and Annex 11. Particle counts and cleanroom classification follow ISO 14644 and usually sit on a dedicated environmental monitoring system, separate from storage monitoring.

How to evidence it

  • The contamination control strategy, with alarm delays justified
  • URS entries for each monitored parameter, confirmed in qualification
  • Alarm trend reviews and their actions
  • Investigations for action-limit breaches

GMP 4.1, 4.10 to 4.12

Records: intact for the whole retention period

What it says

Controls should keep records intact throughout the retention period (4.1, 4.10). Batch documentation is kept for one year after expiry of the batch or at least five years after QP certification, whichever is longer (4.11). Critical documentation, including raw data relating to validation or stability that supports the marketing authorisation, is kept while the authorisation remains in force (4.12). For APIs, Part II sets one year after expiry, or three years after complete distribution for retest-dated APIs (6.13). For investigational products, batch documentation is kept five years after the last trial using the batch ends.

What it means on site

Chapter 4 doesn't name temperature records, so decide which records support a batch's release or a stability study and keep them with that documentation. Stability chamber data can need keeping for as long as the product is on the market.

How to evidence it

  • Your retention schedule, with the clause behind each period
  • Proof that archived monitoring data, with its audit trail, still opens
  • Your exit plan if you change monitoring supplier

Annex 15 section 6, Annex 16 1.5

Shipping and certification

What it says

Products should be transported under the conditions in the marketing authorisation or label (Annex 15, 6.1), with routes defined, seasons considered (6.2), and risks such as delays and failure of monitoring devices assessed (6.3); critical environmental conditions should be continuously monitored and recorded unless otherwise justified (6.4). The QP takes storage and transport conditions into account before certifying a batch (Annex 16, 1.5.3). For investigational products, the EU shipping guideline says temperature monitoring of transport and storage is necessary and the records are reviewed at delivery.

What it means on site

Shipping lanes are often validated once and never revisited, and MHRA has cited air shipments with no justification for leaving loggers out of some pallets. If excursions repeat, they are no longer unexpected deviations.

How to evidence it

  • Route risk assessments and shipping qualification
  • Temperature records for each shipment, reviewed at delivery
  • Excursion investigations, and the QP's decision

In the inspector's words

Questions to be ready for

The kind of questions an inspector, assessor or auditor puts. If you can answer each with a record, you're ready.

  1. “Show me the mapping for this store. Why are the probes where they are?”
  2. “This room was re-racked last year. Where is the change control, and what did it say about the mapping?”
  3. “When was this stability chamber last requalified, and how did you choose that interval?”
  4. “This probe failed calibration. What did you review, and back to when?”
  5. “Who can change an alarm limit here, and where would I see that they did?”
  6. “Show me the last excursion in this chamber. Is it in the study report?”
  7. “How do you know the vendor's validation covers how you use the system?”

Where JTF fits

Where JTF fits

We monitor your stores, cold rooms, stability chambers, QC fridges and freezers on one platform, run mapping studies for your qualification as a managed service, and provide calibration for every sensor we supply: traceable to national standards as standard, or UKAS accredited where you need it (temperature in our own UKAS accredited calibration laboratory No. 10723; other parameters through accredited partners). Sematics validates the platform under a validation lifecycle aligned to EU GMP Annex 11, and gives you the evidence for your supplier assessment; JTF qualifies the hardware it installs, and supports your URS, DQ and PQ. Your rooms, chambers and processes stay under your own validation plan. Our UKAS accreditation covers temperature calibration; mapping and monitoring are carried out to GMP and the protocol you approve.

Related

Keep reading

Questions

Common questions

Is the Orange Guide the law?

No. The law is the Human Medicines Regulations 2012, which make GMP a condition of the licence (regulation 37). The Orange Guide is the MHRA's compilation of the GMP guidelines and UK legislation, so it is what inspectors expect you to follow and the clause numbers inside it are the EU GMP numbers.

What is the difference between the Orange Guide and the Green Guide?

The Orange Guide is for manufacturers and distributors and contains the EU GMP Guide as applied in the UK as well as GDP. The Green Guide is the distributors' book: GDP, the Responsible Person and wholesale legislation.

Does Annex 15 tell us how often to remap?

No. It asks for evaluation at an appropriate frequency and for any fixed period to be justified (4.1 and 4.2). WHO gives three years as an example for storage areas, and ISPE's chamber guide moved to a risk-based review. Our recommendation is in the GMP guide.

Is there such a thing as a GMP-certified monitoring system?

No. Neither GMP nor Annex 11 certifies systems. You show the system is validated for your intended use with evidence: the supplier's validation, your assessment of it, and your own qualification of the configuration and use.

How long should we keep storage temperature records?

Chapter 4 doesn't name them. Keep those that support a batch's release with its batch documentation (one year after expiry or five years after certification, whichever is longer), and stability chamber records with the stability data for as long as the marketing authorisation stands (4.11 and 4.12). See how long to keep records.

We are in Northern Ireland. Is anything different?

The MHRA's 2020 note says Northern Ireland follows the current EU GMP texts, while Great Britain keeps those in force at the end of 2020 unless the MHRA replaces them. For investigational products, Northern Ireland follows Delegated Regulation 2017/1569 and Great Britain Directive 2003/94/EC.

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Sources

  1. The Human Medicines Regulations 2012, regulation 37 (manufacturing and assembly: the duty to comply with GMP)
  2. The Human Medicines Regulations 2012, regulation C17 (guidelines on GMP and GDP after 31 December 2020)
  3. Pharmaceutical Press: The MHRA Orange Guide (Rules and Guidance for Pharmaceutical Manufacturers and Distributors)
  4. EudraLex Volume 4, EU GMP Part I, Chapter 3: Premises and Equipment (in operation 1 March 2015)
  5. EudraLex Volume 4, EU GMP Part I, Chapter 4: Documentation (2011)
  6. EudraLex Volume 4, EU GMP Part I, Chapter 5: Production (in operation 1 March 2015)
  7. EudraLex Volume 4, EU GMP Part I, Chapter 6: Quality Control (in operation 1 October 2014)
  8. EudraLex Volume 4, EU GMP Part II: Basic Requirements for Active Substances used as Starting Materials (ICH Q7)
  9. EudraLex Volume 4, Annex 15: Qualification and Validation
  10. EudraLex Volume 4, Annex 1: Manufacture of Sterile Medicinal Products (2022, in operation 25 August 2023)
  11. EudraLex Volume 4, Annex 11: Computerised Systems
  12. EudraLex Volume 4, Annex 16: Certification by a Qualified Person and Batch Release
  13. ICH Q1A(R2) Stability testing of new drug substances and drug products (EMA scientific guideline; defines mean kinetic temperature)
  14. MHRA: 'GXP' Data Integrity Guidance and Definitions, Revision 1, March 2018 (PDF)
  15. MHRA: Good manufacturing practice inspection deficiencies (data sets to 2019)
  16. MHRA: Clinical trials for medicines, good manufacturing practice and radiopharmaceutical investigational medicinal products

This summary isn't official guidance. The source documents are what an inspector works from.

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