1. Purpose
The purpose of this guideline is to define the general requirements and to provide guidance for the calibration and maintenance of instruments, equipment, facilities, utilities/services and systems.
2. Scope and Applicability
This guideline applies to all instruments, equipment and systems, to be used for GMP activities in R&D and Operations, Manufacturing Functions. It is applicable to all Operational Manufacturing Functions, including API Manufacture, Formulated Product Manufacture, Manufacturing Service Systems, (e.g. water, steam, HVAC, gases,) Packaging activities, QC activities, Monitoring equipment, test equipment, storage and distribution. For simplicity this guideline uses ‘item’ as a generic term including any of the foregoing or any sub-part. The guideline is concerned with the calibration and maintenance requirements of GMP.
3. Definitions
3.2.1 Accuracy
The accuracy of a procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found.
3.2.2 Adjustment (of a measuring instrument – ISO 17025)
Operation of bringing a measuring instrument into a state of performance suitable for its use.
3.2.3 Calibration (ISO 17025)
Set of operations that establish, under specified conditions, the relationship between values of quantities, indicated by a measuring system, or values represented by a material measure or a reference materials, and the corresponding values realized by standards.
3.2.4 Calibration Master Schedule
Information within a controlled document defining agreed calibration and maintenance requirements for GMP critical items. A schedule arising from the initial review of item criticality and kept current in the light of subsequent changes to equipment and facilities. Suitable forms of controlled documents include SOPs, equipment qualification documentation, Service level agreements or critical instrument lists – if this information exists in such suitable controlled documents it is not necessary to generate a separate document.
3.2.5 Critical Items
Items which have been assessed to impact on product quality, safety and efficacy or otherwise present an unacceptable hazard if the equipment or its protective system should fail, and where failure or malfunction could lead to danger to life, significant harm to any person or to the environment.
3.2.6 Engineering (may also be known as maintenance management)
A dedicated Engineering department responsible for establishing and/or maintaining a system of planned preventative maintenance and for delivering or coordinating the required calibration and maintenance activities. Alternatively, depending upon organization structure these responsibilities may be carried by appropriately nominated persons within the ‘line’ function rather than by a dedicated engineering function.
3.2.7 FMEA
Failure modes effect analysis.
3.2.8 Maintenance (EN 13306)
Combination of all technical, administrative and managerial actions during the life cycle of an item intended to retain it in, or restore it to, a state in which it can perform the required function (EN 13306, 2.1).
3.2.9 National standard (ISPE: GAMP)
Standard recognized by a national decision to serve, in a county, as the basis for assigning values to other standards of the quantity concerned.
3.2.10 Process Owner
A nominated person with responsibility for the operation of a specified process.
3.2.11 RCM
Reliability centered maintenance.
3.2.12 Test equipment (ISPE: GAMP)
Instrument or device used to calibrate other instruments, which is traceable back to accepted national standards. The test equipment should have precision, accuracy, and repeatability that is higher than that of the instrument being calibrated.
3.2.13 Traceability (ISPE: GAMP)
Property of the result of a measurement or the value of a standard whereby it can be related to stated references, usually national or international standards, through an unbroken chain of comparisons all having stated uncertainties.
3.2.14 Unscheduled maintenance (corrective maintenance EN 13306)
Maintenance carried out after a fault recognition and intended to put an item into a state in which it can perform a required function.
4. Responsibilities
It is the responsibility of line management/process owner to:
– Ensure SOPs are in place to support the requirements of this guideline
– To ensure a Service Level Agreement/contract or shared SOP, defining the calibration and maintenance support provided, is in place with the Engineering function and/or other relevant calibration service providers
– Approve calibration master schedules which record commitments to the calibration and maintenance of critical items and manage changes throughout the item lifecycle
– Identify the critical parameters, the process variables, and to derive acceptable limits
– Approve calibration and maintenance results
– Investigate the cause and GMP implications of non-conforming conditions and deviations
It is the responsibility of Engineering, or the line, to:
– Ensure a calibration master schedule is developed in cooperation with relevant experts as defined in local procedures
– conduct calibration and maintenance according to local SOPs , and local work schedules
– To inform the equipment owner of any non-conforming conditions Approve the detailed calibration and maintenance procedures prepared for the items
– Approve calibration and maintenance work conducted by contractors to verify the acceptance criteria have been met
– retain calibration and maintenance records
It is the responsibility of Quality Assurance to:
– approve SOPs for calibration and maintenance
– approve calibration master schedules for GMP critical items/preventative maintenance to ensure limits are appropriately defined and regulatory requirements are met
– review, in collaboration with line/engineering, the implications of out of tolerance results following calibration and/or maintenance activities according to local procedures
– verify that the capabilities of external providers of calibration and maintenance are assured
5. Guideline
SOPs must exist which describe the overall calibration and maintenance program Including:
– identification of critical items requiring calibration and maintenance
– establishing calibration and maintenance requirements and review during item lifecycle
– description of the workflow for calibration and maintenance
– management of ‘out of tolerance’ conditions and remedial actions
– requirements for trend reviews (e.g. calibration failures, maintenance frequencies)
– prevention from use of ‘un-calibrated’ and ‘out of service’ items
– acceptance of items as suitable for use
– use of contractor calibration and maintenance providers
– documentation requirements
Calibration and maintenance activities are key components of the codes of good pharmaceutical manufacturing practice and therefore must be conducted by staff with appropriate training and will be the subject of self-inspection programs/ audits, as defined in local procedures. Written procedures may also include details of how calibration and maintenance is conducted in support of other legislation such as Safety Health and Environment requirements.
5.1 Critical items
Written procedures will describe the processes for review of inventory items (and their function) and agreeing which are critical and require calibration and maintenance. This must include review of an inventory of equipment that is prepared during initial qualification of a facility or laboratory as well as consideration of subsequent changes and additions to facilities, systems and laboratories. The rationale used for classification of items as critical will be documented in local SOPs. A suitable rationale for declaring an item as critical is if it has the potential to;
– affect the safety, quality or efficacy of a product
– alter the physical, chemical or biological properties of a product
– and/if testing/certification/maintenance is a local mandatory requirement (e.g. pressure vessel testing)
Alternative rationales for determining criticality, such the ‘direct impact’ approach described in the ISPE/GAMP Good Practice Guide: Calibration Management may also be acceptable.
5.2 Determination of detailed Calibration and maintenance requirements
Written procedures will describe the process for defining the calibration and preventative maintenance details of critical items. At initial review this will be based upon
– the manufacturers recommendations (including both scope of work and suggested limits)
– user experience from qualification of the item
– regulatory expectations
– specific product or process requirements
– the impact of failure upon business performance
Reviews will be conducted by relevant experts (e.g. functional expert, engineering, quality assurance) as defined in local procedures. Reviews will agree and document;
– the acceptable maintenance and/or calibration frequency for each item
– for critical instruments the instrument range and calibration accuracy
– operating range and process tolerance (where appropriate)
– required checks to confirm conformance with standards
– required preventative maintenance requirements
The review scope must include those test instruments used in the calibration program and make provision for assurance of their accuracy, including calibration externally where appropriate. Agreements on calibration and maintenance requirements (Calibration Master Schedules) will be recorded in controlled documents and will be formally approved by the relevant functions according to local procedures. Documentation held locally must be sufficiently detailed to enable traceability Of critical item location, unique identity and the person responsible. Local procedures will define the approach required for documenting the qualification of test equipment. The application of risk management tools (eg RCM and FMEA) in the determination of maintenance requirements is considered good practice, and if used should be defined, or referenced, in local procedures
5.3 Periodic review and change management
Procedures must be in place to highlight adverse trends in calibration and maintenance of critical items. This may be included as part of documented reviews of broader scope, such as periodic trend reviews of deviations and Lab investigation reports, validation reviews etc. Adverse trends must result in appropriately documented corrective actions, which may include changes to agreed calibration and maintenance frequency or scope. Conversely reviews which indicate good performance of an item may result in justification of a reduced frequency. Procedures for making changes (excluding like for like replacement) to validated facilities etc must ensure calibration and maintenance requirements are addressed according to this guideline, including the updating of relevant schedules.
5.4 Execution of the calibration and maintenance program
Calibration and maintenance programs must be conducted according to a written procedure detailing the management of required activities. This will include scheduling of work by the responsible line, Engineering unit or relevant service providers to ensure calibration and maintenance is carried out according to the frequencies and scopes agreed for individual facilities/laboratories.
The schedules maintained by the line or Engineering unit must be designed to enable identification of required frequency, due dates and status for calibration and maintenance activities. Where appropriate the procedure may detail the process for pre-approval of any ‘ad-hoc’ extension to calibration life including the persons responsible (Operations or R&D Manufacturing, Quality Assurance as appropriate).
Calibration and maintenance must be conducted according to written instructions specific to the work being performed. Such written instructions will be in the form of controlled documents approved by Engineering or the line, and must contain an appropriate level of detail to prevent ambiguity. Reference may be made to existing supplier/vendor/contractor documents as appropriate in order to avoid unnecessary duplication. Critical consumables must be specified where appropriate.
Where considered necessary instructions should include requirements for a post-calibration operational check (e.g. when verification of the operation of a probe, when its re-fitting to equipment after calibration, is considered complex). Instructions must be written in a manner that the work conducted avoids hazard to product or person. This may require inclusion of instructions for avoiding cross- contamination and also the specification of required lubricants and solvents. Wherever possible calibration must be performed using reference standards traceable to International standards.
5.5 Non-conformance and corrective action
Written procedures will describe the procedure to be followed when a critical item is found not to conform to requirements during recalibration and scheduled maintenance.
Procedures will define the persons responsible for investigating the failure (which will include Engineering, line management and Quality Assurance as appropriate). Investigation must include an assessment of the impact of the non-conformance, identification of any root causes and their corrective actions, as well as repair or re- calibration of the item concerned.
Procedures must include revision of schedules following an adverse review of the historic performance of the item. Procedures must define the actions to be taken in the event of the agreed calibration ‘window’ being exceeded. Where the non-conformance relates to the calibration of an item of test equipment the investigation must include a review of the implications of all calibrations performed.
5.6 Item Labeling and status
Inventory equipment items must be uniquely identified or labeled to facilitate the execution of the calibration and maintenance program.
Where appropriate this may require the labeling of constituent parts of a unit (for example multiple thermocouples within an autoclave may need to be uniquely identifiable to prevent ambiguity). Procedures must require that the status of the item be easily verified before its use.
The use of stickers indicating the status/expiry date or required re-calibration date is acceptable. Alternative systems (records, databases, status boards) are acceptable as long as they are designed to ensure that items which are ‘out of calibration’ are easily identified to prevent use.
Integrity sealing of critical instruments should be performed where appropriate. Items which require repair or are ‘out of service’ awaiting scheduled maintenance should be clearly identified to prevent their use.
5.7 Use of Contractors for calibration and maintenance
Local procedures will define the approach to management of calibration and maintenance performed by external contractors and calibration service suppliers, including requirements for contracts/service level agreements/shared SOPs.
This will include a list of company approved providers, specified means of assessing the competence of the provider and the scheduling of site calibration checks pre and post transportation to an external calibration lab (eg for calibrations requiring adjustment of units which are sealed by the manufacturer).
Procedures will also describe the provision of calibration and maintenance records or certificates by external contractors. This will include review of work performed to verify that it has been completed to an acceptable standard, and approval by the company indicating that the appropriate acceptance criteria have been met.
5.8 Calibration and maintenance records
Records will be kept of all calibration and maintenance performed including both scheduled work and also that arising from breakdown. Information will be sufficiently detailed to enable the implications of GMP non- conformances to be investigated (e.g Traceability of batches involved etc).
Local procedures must ensure that the current versions of relevant reference documents are used.
The calibration and maintenance records shall include the following information:
– unique identity of the item
– the date the calibration/adjustment/maintenance was performed.
– as-found readings, status or performance
– the As-left readings, status or performance
– identification of maintenance, spare parts or test equipment andstandards used
– identification of the procedure used
– signature of person performing calibration/maintenance following anyadjustment or maintenance activities
– review and acceptance by production line/Engineering
– indicate next steps to determine any product implications following any non-conforming adjustment or maintenance activities
– documents/records will be held or archived in accordance with corporate and regulatory expectations and must be retrievable as required by local procedures.