Pharmaceutical drug products stability studies are important for establishing the shelf life of the products. Stability studies can be performed for finished drug substances and drug products with the real time, intermediate and accelerated storage conditions. All stability study guidelines are mentioned in ICH, FDA, EMEA and WHO guidelines. Hold time study data shall give the assurance the maximum allowable hold times for bulk and in-process drug products.
- Generally, one lot can be used for validating hold times if any inconsistency results were observed then another two lots can be used for this study. Although there are no specific regulations or guidance documents on bulk product hold times, GMP dictates that hold times should be validated to ensure that in-process and bulk products can be held, pending the next processing step, without any adverse effect to the quality of the material. Hold time study provides the re-assurance of the quality at each in-process stage.
ALSO READ: SOP for Hold Time Study in Pharmaceuticals
Hold Time Stability Study
- In drug product development, hold time stability is an important tool for establishing the in-process hold time. Hold time study is evaluated for each stage in the product manufacturing.
- Hold time study can demonstrate how much time is suitable for holding the blend or bulk stage before processing to the next stage. When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product. Hold time study results should meet the product specifications.
- Hold time studies are performed during the product development, i.e scale-up stage and commercial validation stages. Before starting the hold study, the formulation scientist needs to select the critical stages (where the study is required), time points and tests.
- Hold time can be considered as the established time period for which materials (dispensed raw materials, intermediates and bulk dosage form awaiting final packaging) may be held under specified conditions and will remain within the defined specifications.
- Hold‑time studies establish the time limits for holding the materials at different stages of production to ensure that the quality of the product does not produce results outside the acceptance criteria during the hold time. The design of the study should reflect the holding time at each stage.
Manufacturers should gather sufficient data to demonstrate that a product:
- Remains stable before processing to the next stage.
- Meets the acceptance criteria for the finished product.
- Meets its stability specifications.
- The quality and stability of starting materials, intermediate products, bulk and finished products should be ensured at all stages of manufacture.
- Maximum allowable hold times should therefore be established for starting materials, intermediate products, bulk and finished products on the basis of tests related to storage conditions. Data to justify the hold time can be collected during development on pilot scale batches, during process validation, or as part of a deviation with appropriate testing.
- Manufacturers may use a flow chart to review the manufacturing procedure of a product and then break up the critical stages of the manufacturing process on the basis of the time duration required for the particular processing stage and the impact of the time period with reference to environmental conditions and storage conditions.
Generally, for oral solid dosage forms, the following stages should be considered:
- Binder preparation to granulation.
- Wet granulation to drying
- Dried granules to lubrication/blending
- Lubrication/blending to compression
- Compression to coating
- Aqueous coating solution preparation to coating
- Coating to packing.
- Hold times should be established where materials, intermediate, bulk or finished products are stored for extended periods. Risk assessment (product specific) may further assist manufacturers to determine which stage, tests, intervals and storage periods should be considered for a hold time study.
- How to conduct and perform Hold Time Study for Tablets, Liquid Orals, Ointments, and Creams are detailed in the below link.
- Examples of stages and tests that may be considered, based on risk assessment and specific product needs.
ALSO READ: Hold Time Study Protocol
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