Design and construction
1. Equipment for manufacturing operations of active substances or intermediates thereof shall meet the following conditions:
(a)
be of appropriate design and adequate size, and suitably located and qualified for its intended use;
(b)
be cleaned, sanitised, where appropriate and maintained;
(c)
be constructed so that contact surfaces do not alter the quality of the products beyond the established specifications for the active substance;
(d)
be used within its qualified operating range.
2. Major equipment and permanently installed processing lines used during the production of active substances or intermediates thereof shall be appropriately identified.
3. Substances required for the operation of equipment used in manufacturing operations, such as lubricants, heating fluids or coolants, shall not come into contact with the active substances or intermediates thereof. Deviations from this requirement shall be evaluated to check whether there are no detrimental effects to the fitness for purpose of the active substances or intermediates thereof. Wherever possible, food grade lubricants and oils shall be used during the operation of equipment used in manufacturing operations.
4. Closed or contained equipment shall be used when appropriate. Where open equipment is used, or equipment is opened, appropriate precautions shall be taken to minimise the risk of contamination.
5. The manufacturer shall ensure that up-to-date drawings are kept for equipment used in manufacturing operations and critical installations such as instrumentation and utility systems.
Maintenance and cleaning
1. Manufacturers shall establish:
(a)
schedules and procedures, including assignment of responsibilities, for the maintenance of equipment used in manufacturing operations;
(b)
written procedures for cleaning of equipment and its subsequent release for use in the manufacture of active substances and intermediates thereof.
2. The cleaning procedures shall be sufficiently detailed to allow cleaning of each type of equipment in a reproducible and effective manner, and shall include the description of the following:
(a)
assignment of responsibilities for cleaning of equipment;
(b)
cleaning schedules, including, where appropriate, sanitising schedules;
(c)
the methods and materials, including dilution of cleaning agents used to clean equipment;
(d)
instructions for disassembling and reassembling each article of equipment to ensure proper cleaning, where appropriate;
(e)
instructions for the removal or obliteration of previous batch identification;
(f)
instructions for the protection of clean equipment from contamination prior to use;
(g)
inspection of equipment for cleanliness immediately before use, if practical;
(h)
the maximum time that may elapse between the completion of processing and equipment cleaning, where appropriate.
3. Equipment and utensils shall be cleaned, stored, and, where appropriate, sanitised or sterilised to prevent contamination or carry-over of a material that would alter the quality of the active substances or intermediates thereof beyond the established specifications of the active substances or intermediates thereof.
4. Where equipment is assigned to continuous production or campaign manufacture of successive batches of the same active substance or intermediate thereof, equipment shall be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants.
5. Equipment which is not assigned to continuous production or campaign manufacture of successive batches of the same active substance or intermediate thereof shall be cleaned between production of different materials to prevent cross-contamination.
6. Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents shall be defined and the reasons for choosing them shall be documented.
7. Equipment shall be identified as to its contents and its cleanliness status.
Calibration
1. Manufacturers shall ensure that the following requirements are met:
(a)
control, weighing, measuring, monitoring and test equipment that is critical for ensuring the quality of the active substances or intermediates thereof is calibrated in accordance with written procedures and an established schedule;
(b)
equipment calibrations are performed using standards which ensure traceability to certified standards, where available;
(c)
records of the calibrations referred to in point (b) are kept;
(d)
the calibration status of equipment that is critical to the quality of the active substances or intermediates thereof is known and verifiable;
(e)
instruments that do not meet calibration criteria are not used.
2. Deviations from certified standards of calibration on critical equipment shall be investigated to determine the potential impact on the quality of the active substances or intermediates thereof manufactured using the concerned equipment since the last successful calibration.
Computerised systems
1. Computerised systems related to the good manufacturing practices for active substances shall be validated, taking into account the diversity, complexity and criticality of the computerised system.
2. Appropriate installation qualification and operational qualification shall demonstrate the suitability of computer hardware and software to perform assigned tasks.
3. Commercially available software that has been qualified shall not require the same level of testing as non-commercially available software. Where an existing computerised system is not validated at the time of installation, a retrospective validation shall be conducted if appropriate documentation is available.
4. Computerised systems shall have controls preventing unauthorised access, changes to data and omissions in data. All changes in data shall be recorded and reviewed in the audit trail.
5. Written procedures shall be available for the operation and maintenance of computerised systems.
6. Where critical data are entered manually, an additional check on the accuracy of the entry shall be performed by a second operator or by the system itself.
7. Incidents related to computerised systems potentially affecting the quality of the active substances or intermediates thereof, or the reliability of records or test results, shall be recorded and investigated.
8. Changes to the computerised system shall be made in accordance with a change control procedure and shall be formally approved, documented and tested, where appropriate. Records shall be kept of all changes to the computerised system., including modifications and enhancements made to the hardware, software and any other critical component of the system. Those records shall demonstrate that the computerised system is maintained in a validated state.
9. A back-up system shall be in place to prevent computerised system breakdowns or failures resulting in the permanent loss of records.
10. Data protection shall be ensured for all computerised systems.
11. In addition to the computerised system, data may be recorded by a different means.
Source: EUR-Lex (Publications Office of the EU), © European Union, reuse permitted under Commission Decision 2011/833/EU.
