Documentation system
1. A documentation system that is adequate to achieve the objectives of the quality management system shall be established and maintained.
2. The documentation system shall cover in a comprehensive manner the instructions and specifications related to the manufacture of active substances and intermediates thereof, as well as other documentation relevant to the quality management system and shall ensure that records are made of the activities which may directly or indirectly affect the quality of the active substances or intermediates thereof. The documentation system shall specify the retention period for each of the documents or records.
3. All production, control, and distribution records of a batch shall be retained for at least 1 year after the expiry date of the batch.
4. By derogation from paragraph 3, records for active substances with retest dates shall be retained for at least 3 years after the batch is completely distributed.
5. The content of documents shall be unambiguous and be kept up to date.
6. Documentation may be kept in a variety of forms and the requirements set out in this Chapter are applicable irrespective of form. Where electronic, photographic media, video recording or other data processing systems are used, the relevant systems shall be validated first to ensure that such systems are adequate to appropriately store the data during the required period of storage.
7. Suitable retrieval equipment and a means to produce hard copies shall be readily available in case reduction techniques such as microfilming or electronic records are used to retain specifications, instructions, procedures or records.
8. During the retention period, the documents and records shall be readily available at the establishment where the activities described in those documents and records occurred.
9. Electronic signatures on the documents and records shall be authenticated and secure.
Specifications
1. Specifications shall be established and laid down for:
(a)
raw materials;
(b)
intermediates;
(c)
active substances;
(d)
labelling and packaging materials.
2. Specifications shall be established for any other materials used during the production of active substances and intermediates thereof that could critically impact the quality of active substances and intermediates thereof.
3. Acceptance criteria shall be established and documented for in-process controls.
Equipment cleaning, maintenance and use records
1. Records of major equipment use, cleaning, sanitisation and sterilisation and maintenance shall be kept. Those records shall include:
(a)
the date and, if appropriate, the time;
(b)
product, and batch number of each batch processed in the equipment;
(c)
the person who performed the cleaning and maintenance.
2. Individual equipment records are not required for equipment dedicated to manufacture of only one active substance or intermediate thereof, provided that batches follow in traceable sequence.
3. Records of major equipment use, cleaning, sanitisation or sterilisation, and maintenance may either be part of the batch record or kept separately.
Records for raw materials, intermediates, active substance labelling and packaging materials
1. Adequate records shall be kept to enable the entire history of a batch to be traced.
2. Receipt and batch processing records shall be kept for each delivery of materials used in the manufacturing, including raw materials, intermediate as well as labelling and packaging materials. Those records shall include:
(a)
the name of the manufacturer of the delivered material;
(b)
identity and quantity of each delivery of each batch of raw materials, intermediates or labelling and packaging materials for active substances;
(c)
the name of the supplier;
(d)
the supplier’s identification number;
(e)
the identification number allocated upon receipt and the date of receipt;
(f)
the results of any test or examination performed and the conclusions thereon;
(g)
records tracing the use of materials;
(h)
documentation of the examination and review of active substance labelling and packaging materials for conformity with established specifications;
(i)
the final decision regarding rejected raw materials, intermediates or active substance labelling and packaging materials.
3. Master labels shall be maintained for comparison to issued labels.
Master production instructions
1. Master production instructions for each active substance and intermediate thereof shall be prepared, dated, and signed by one person and independently checked, dated, and signed by a person in the quality unit.
2. The master production instructions referred to in paragraph (1) shall include:
(a)
the name of the active substance or intermediate thereof being manufactured and an identifying document reference code, if applicable;
(b)
a complete list of raw materials and intermediates designated by names or codes sufficiently specific to identify any special quality characteristics;
(c)
an accurate statement of the quantity or ratio of each raw material or intermediate to be used, including the unit of measure. Where the quantity is not fixed, the calculation for each batch size or rate of production shall be included. Variations to the quantities of raw materials or intermediates used shall be included where they are justified;
(d)
the production location and major production equipment to be used;
(e)
detailed production instructions, including:
—
sequences to be followed,
—
ranges of process parameters to be used,
—
sampling instructions and in-process controls with their acceptance criteria, where appropriate,
—
time limits for completion of individual processing steps and the total process, where appropriate,
—
expected yield ranges at appropriate phases of processing or time,
—
where appropriate, special notations and precautions to be followed, or cross references to these,
—
the instructions for storage of the active substance or intermediate thereof to assure its suitability for use, including the labelling and packaging materials and special storage conditions with time limits, where appropriate.
Batch production and control records
1. Batch production records shall be prepared for each active substance and intermediate thereof. Those batch production records shall:
(a)
for each batch include the complete information referred to in paragraph 2;
(b)
be checked before issuance of the record to assure that it is the correct version and a legible accurate reproduction of the appropriate master production instruction;
(c)
include a reference to the master production instructions being used, in case that batch production record is produced from a separate part of the master production instruction;
(d)
be numbered with a unique batch or identification number and dated and signed when issued. In continuous production, the product code together with the date and time may serve as the unique identifier until the final number is allocated.
2. Batch production and control records shall include:
(a)
dates and, where appropriate, times of production and control;
(b)
identification of major equipment (e.g. reactors, dryers, mills, etc.) used;
(c)
specific identification of each batch, including weights, measures, and batch numbers of raw materials, intermediates, or any reprocessed materials used during manufacturing;
(d)
results recorded for critical process parameters;
(e)
samplings performed;
(f)
signatures of the persons performing and directly supervising or checking each critical step in the operation;
(g)
in-process and laboratory test results;
(h)
yield at appropriate phases or times;
(i)
description of packaging and labelling of the active substance or the intermediate thereof;
(j)
the representative label of active substance or intermediate thereof, if made commercially available;
(k)
any deviation from procedures and instructions or any unusual occurrence which could impact the manufacture or testing of the active substance, its evaluation, investigation conducted (if appropriate) or reference to that investigation if stored separately;
(l)
results of the release testing.
3. Written procedures shall be established and followed for investigating critical deviations from procedures and instructions or any unusual occurrence which could impact the manufacture or testing of the active substance or the failure of a batch of active substance or intermediate thereof to meet specifications. The investigation shall be extended to other batches that may have been associated with that deviation or failure.
Laboratory control records
1. Laboratory control records shall be prepared for each active substance. Those laboratory control records shall include complete data derived from all tests conducted to ensure compliance with established specifications and standards, including examinations and assays and in particular, the following aspects:
(a)
a description of samples received for testing, including the material name or source, batch number or other distinctive code, date of sampling, and, where appropriate, the quantity and date the sample was received for testing;
(b)
a description of or reference to each test method used;
(c)
a statement of the weight or measure of the sample used for each test as described by the method; data on or cross-reference to the preparation and testing of reference standards, reagents and standard solutions;
(d)
a complete record of all raw data generated during each test, in addition to graphs, charts, and spectra from laboratory instrumentation, properly identified to show the specific material and batch tested;
(e)
a record of all calculations performed in connection with the test, including, for example, units of measure, conversion factors, and equivalency factors;
(f)
a statement of the test results and how they compare with established acceptance criteria;
(g)
the signature of the person who performed each test and the dates when the tests were performed;
(h)
the date and signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.
2. Laboratory control records shall also include complete records on:
(a)
all modifications to an established analytical method;
(b)
periodic calibration of laboratory instruments, apparatus, gauges, and recording devices;
(c)
all stability testing performed on active substances;
(d)
out-of-specification investigations.
Batch production and laboratory control records review
1. Written procedures shall be established and followed for review and approval of batch production records referred to in Article 26 and laboratory control records referred to in Article 27, to ensure compliance of the active substance or intermediate thereof with established specifications before a batch is released.
2. Production and laboratory control records of non-critical process steps may be reviewed by qualified production personnel or other units following procedures approved by the quality unit.
3. All deviation, investigation, and out-of-specification reports shall be reviewed, as part of the batch record review, before the batch is released.
4. The quality unit can delegate the responsibility and authority for release of intermediates to the production unit, except for those intermediates dispatched outside the control of the manufacturer.
Source: EUR-Lex (Publications Office of the EU), © European Union, reuse permitted under Commission Decision 2011/833/EU.
