Production operations
1. Raw materials for manufacture of active substances or intermediates thereof shall be weighed or measured under appropriate conditions that do not affect their suitability for use.
2. Balances and measuring equipment shall be of an appropriate range and precision to ensure the accuracy of weighing operations.
3. Whenever a material is subdivided for later use in production operations, the container receiving the material shall be suitable and shall be identified so that the following information is available:
(a)
material name or item code;
(b)
receiving or control number;
(c)
weight or measure of material in the new container;
(d)
re-evaluation or retest date if appropriate.
4. Critical activities, including the critical weighing, measuring, or subdividing operations shall be verified or subjected to an equivalent control. Prior to use, the manufacturer shall ensure that its production personnel verifies that the materials are those specified in the batch record for the intended active substance or intermediate thereof.
5. Actual yields shall be compared with expected yields at designated steps in the production process. Expected yields with appropriate ranges shall be established based on previous laboratory, pilot scale or manufacturing data. Deviations in yield associated with critical process steps shall be investigated to determine their impact or potential impact on the resulting quality of the affected batches.
6. Any deviation in yield shall be documented and explained. Any critical deviation shall be investigated.
7. The processing status of major units of equipment shall be indicated either on the individual units of equipment or by appropriate documentation, computer control systems, or alternative means.
8. Materials to be reprocessed or reworked shall be appropriately controlled to prevent unauthorised use.
Time limits
Whenever time limits are specified in the master production instructions, those time limits shall be met to ensure the quality of active substances and intermediates thereof. Time limit deviations shall be documented and evaluated.
In-process controls and in-process sampling
1. Written procedures shall be established to monitor the progress and control the performance of processing steps that cause variability in the quality of active substances and intermediates thereof. In-process controls and their acceptance criteria shall be defined based on the information gained during the development stage or historical data.
2. The acceptance criteria and the type and extent of testing may depend on:
(a)
the nature of the intermediate or active substance being manufactured;
(b)
the reaction or process step being conducted;
(c)
the degree to which the process introduces variability in the quality of the active substance or the intermediate thereof.
3. Less stringent in-process controls may be appropriate in early processing steps, whereas more stringent controls may be appropriate for later processing steps (e.g. isolation and purification steps).
4. Critical in-process controls and critical process monitoring, including the control points and methods, shall be stated in writing and approved by the quality unit.
5. In-process controls may be performed by qualified personnel of the production department. The process may be adjusted without prior quality unit approval in case those adjustments are made within established limits approved by the quality unit. All tests and results shall be fully documented as part of the batch record.
6. Written procedures shall describe the sampling methods for in-process materials, intermediates and active substances. These procedures shall be designed to prevent contamination of the sampled material and of other intermediates or active substances. Procedures shall be established to ensure the integrity of samples after collection.
7. Out-of-specification investigations shall be performed.
8. By way of derogation from paragraph 7, out-of-specification investigations are not required for in-process tests that are performed for the purpose of monitoring or adjusting the process.
Blending batches of intermediates or active substances
1. Out-of-specification batches shall not be blended with other batches for the purpose of meeting specifications.
2. Each batch incorporated into the blend shall:
(a)
have been manufactured using an established process; and
(b)
have been individually tested and found to meet appropriate specifications prior to blending.
3. Acceptable blending operations include:
(a)
blending of small batches to increase batch size;
(b)
blending of tailings (e.g. relatively small quantities of isolated material) from batches of the same intermediate or active substance to form a single batch.
4. Blending processes shall be adequately controlled and documented and the blended batch shall be tested for conformity to established specifications, where appropriate.
5. The batch record of the blending process shall allow traceability back to the individual batches that compose the blend.
6. Where physical attributes of the active substance are critical (e.g. active substances intended for use in solid oral dosage forms or suspensions), blending operations shall be validated to show homogeneity of the combined batch. Validation shall include testing of critical attributes (e.g. particle size distribution, bulk density, and tap density) that may be affected by the blending process.
7. Where the blending may adversely affect stability, stability testing of the final blended batches shall be performed.
8. The expiry or retest date of the blended batch shall be based on the manufacturing date of the oldest tailings or batch in the blend.
Contamination control
1. Carryover of residual materials into successive batches shall not result in the carryover of degradants or microbial contamination that may adversely alter the established active substance’s impurity profile.
2. Production operations shall be conducted in a manner that prevents contamination of active substances or intermediates thereof by other materials.
3. Precautions to avoid contamination shall be taken for the handling of active substances after purification.
Source: EUR-Lex (Publications Office of the EU), © European Union, reuse permitted under Commission Decision 2011/833/EU.
