8. PRODUCTION AND IN-PROCESS CONTROLS

8. PRODUCTION AND IN-PROCESS CONTROLS
8.1 Production Operations
8.10 Raw materials for intermediate and API manufacturing should be weighed or measured under appropriate conditions that do not affect their suitability for use. Weighing and measuring devices should be of suitable accuracy for the intended use.
8.11 If a material is subdivided for later use in production operations, the container receiving the material should be suitable and should be so identified that the following information is available:
− Material name and/or item code;
− Receiving or control number;
− Weight or measure of material in the new container; and
− Re-evaluation or retest date if appropriate.
8.12 Critical weighing, measuring, or subdividing operations should be witnessed or subjected to an equivalent control. Prior to use, production personnel should verify that the materials are those specified in the batch record for the intended intermediate or API.
8.13 Other critical activities should be witnessed or subjected to an equivalent control.
8.14 Actual yields should be compared with expected yields at designated steps in the production process. Expected yields with appropriate ranges should be established based on previous laboratory, pilot scale, or manufacturing data. Deviations in yield associated with critical process steps should be investigated to determine their impact or potential impact on the resulting quality of affected batches.
8.15 Any deviation should be documented and explained. Any critical deviation should be investigated.
8.16 The processing status of major units of equipment should be indicated either on the individual units of equipment or by appropriate documentation, computer control systems, or alternative means.
8.17 Materials to be reprocessed or reworked should be appropriately controlled to prevent unauthorized use.
8.2 Time Limits
8.20 If time limits are specified in the master production instruction (see 6.41), these time limits should be met to ensure the quality of intermediates and APIs. Deviations should be documented and evaluated. Time limits may be inappropriate when processing to a target value (e.g., pH adjustment, hydrogenation, drying to predetermined specification) because completion of reactions or processing steps are determined by in-process sampling and testing.
8.21 Intermediates held for further processing should be stored under appropriate conditions to ensure their suitability for use.
8.3 In-process Sampling and Controls
8.30 Written procedures should be established to monitor the progress and control the performance of processing steps that cause variability in the quality characteristics of intermediates and APIs. In-process controls and their acceptance criteria should be defined based on the information gained during the development stage or historical data.
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Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
8.31 The acceptance criteria and type and extent of testing can depend on the nature of the intermediate or API being manufactured, the reaction or process step being conducted, and the degree to which the process introduces variability in the product’s quality. Less stringent in-process controls may be appropriate in early processing steps, whereas tighter controls may be appropriate for later processing steps (e.g., isolation and purification steps).
8.32 Critical in-process controls (and critical process monitoring), including the control points and methods, should be stated in writing and approved by the quality unit(s).
8.33 In-process controls can be performed by qualified production department personnel and the process adjusted without prior quality unit(s) approval if the adjustments are made within pre-established limits approved by the quality unit(s). All tests and results should be fully documented as part of the batch record.
8.34 Written procedures should describe the sampling methods for in-process materials, intermediates, and APIs. Sampling plans and procedures should be based on scientifically sound sampling practices.
8.35 In-process sampling should be conducted using procedures designed to prevent contamination of the sampled material and other intermediates or APIs. Procedures should be established to ensure the integrity of samples after collection.
8.36 Out-of-specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and/or adjusting the process.
8.4 Blending Batches of Intermediates or APIs
8.40 For the purpose of this document, blending is defined as the process of combining materials within the same specification to produce a homogeneous intermediate or API. In-process mixing of fractions from single batches (e.g., collecting several centrifuge loads from a single crystallization batch) or combining fractions from several batches for further processing is considered to be part of the production process and is not considered to be blending.
8.41 Out-Of-Specification batches should not be blended with other batches for the purpose of meeting specifications. Each batch incorporated into the blend should have been manufactured using an established process and should have been individually tested and found to meet appropriate specifications prior to blending.
8.42 Acceptable blending operations include but are not limited to:
− Blending of small batches to increase batch size
− Blending of tailings (i.e., relatively small quantities of isolated material) from batches of the same intermediate or API to form a single batch.
8.43 Blending processes should be adequately controlled and documented and the blended batch should be tested for conformance to established specifications where appropriate.
8.44 The batch record of the blending process should allow traceability back to the individual batches that make up the blend.
8.45 Where physical attributes of the API are critical (e.g., APIs intended for use in solid oral dosage forms or suspensions), blending operations should be validated to show homogeneity of the combined batch. Validation should include testing of critical attributes (e.g., particle size distribution, bulk density, and tap density) that may be affected by the blending process.
8.46 If the blending could adversely affect stability, stability testing of the final blended batches should be performed.
8.47 The expiry or retest date of the blended batch should be based on the manufacturing date of the oldest tailings or batch in the blend.
8.5 Contamination Control
8.50 Residual materials can be carried over into successive batches of the same intermediate or API if there is adequate control. Examples include residue adhering to the wall of a micronizer, residual layer of damp crystals remaining in a centrifuge bowl after discharge, and incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process. Such carryover should not result in the carryover of degradants or microbial contamination that may adversely alter the established API impurity profile.
8.51 Production operations should be conducted in a manner that will prevent contamination of intermediates or APIs by other materials.
8.52 Precautions to avoid contamination should be taken when APIs are handled after purification.