Packaging materials, stability study testing

The evolution and optimisation of a formulation is an experimental stage that will be conducted on small batches of the material. For a drug with a tablet weight of 250 mg, test batches would t)rpically be 0.5-1 kg, providing up to 4000 tablets for analysis, performance testing and initial stability studies. Similar scales will be used in the optimisation of the product s packaging. 

The application (or Type II DMF) should include a detailed description of the complete container closure system for the bulk drug substance as well as a description of the specific container, closure, all liners, inner seal, and desiccant (if any), and a description of the composition of each component. A reference to the appropriate indirect food additive regulation is typically considered sufficient to establish the safety of the materials of construction. The tests, methods, and criteria for the acceptance and release of each packaging component should be provided. Stability studies to establish a retest period for bulk drug substance in the proposed container closure system should be conducted with fillers or desiccant packs in place (if used). Smaller versions that simulate the actual container closure system may be used. 

The key elements of an inspection are to ensure that the facility is capable of fulfilling the application commitments to manufacture, process, control, package, and label a drug product following GMP the adequacy and accuracy of analytical methods submitted, to ensure that these methods are proper for the testing proposed correlation between the manufacturing process for clinical trial material, bioavailability study material, and stability studies and submitted process that the scientific data support full-scale production procedures and controls that only factual data have been submitted and that the protocols are in place to validate the manufacturing process. 

Approved packaging is normally selected after completing package performance qualification testing as well as product compatibility and stability studies. Since in most cases (exceptions transdermal delivery systems, diagnostic tests, and medical devices) packaging is not intimately involved in the manufacturing process of the product itself, it differs from other factors, such as raw materials. 

Stability protocol for accelerated and long-term studies, including all the information in the phase 2 stability protocol (tests, analytical procedures, time points for each of the tests, and duration of the study) plus temperature and humidity conditions and a detailed description of the material under investigation, including packaging... 

However, a SIM during formulation development involves more than the above four steps, since the formulation development is a dynamic process where the formulation is optimized as the clinical program moves further along the development process. To continue the list from above, the following three steps must be added to the Ust (5) compatibility studies with excipients, (6) stability trending (variables would be temperature, humidity, and packaging material), and (7) mass balance for assay. An analytical chemist must revisit the separation of all components in the related substances method after steps 3,5, and 6 to ensure that the test method is truly a SIM. 

ICH guidelines ° describe and discuss stability issues and testing requirement for NCEs and macromolecules. These guidelines provide manufacturers and CSOs with acceptance specifications for accelerated and long-term stability studies. In addition to the drug substance and drug product, stability assessment is frequently conducted on raw materials, key intermediates, formulation excipients, and packaging materials. 

With the exception of BA studies that are not conducted for the stability studies, all the above-mentioned tests are performed after storing the product in the package material to declare that products of acceptable quality after the manufacturing. In vitro... 

Stability testing A brief description of the stability study and the test methods used to monitor the stability of the drug product packaged in the proposed container/closure system and storage conditions should be submitted. Preliminary tabular data based on representative material may be submitted. Neither detailed stability data nor the stability protocol need to be submitted. 

Once several batches of raw materials have been reviewed and tested to demonstrate that they will conform with the functional and quality requirements, the full excipient and packaging specifications can be finalised. Excipient and pack performance should be evaluated from a stability evaluation of the product and feedback from experience in clinical trials. Ideally, the specifications should be finalised for the start of Phase III clinical trials. If for some reason, the excipient or packaging material has to be changed for Phase III supplies, then some or all of the steps involved in the selection of materials, compatibility and stability studies may have to be repeated. 

Provisional specifications have been created for all packaging components, and these are subsequently used to clear all materials through a QC plus type operation prior to use in any tests, irrespective of whether these are feasibility or formal stability studies. Procedures should include (for plastics) material identification (by IR, UV, differential scanning calorimetry (DSC), etc.), physical assessment including dimensions and functional tests, and should be of greater technical and scientific depth than the QC procedures used for subsequent regular incoming production materials (hence the use of the phrase QC plus ). 

Accelerated stability tests provide a means of comparing alternative formulations, packaging materials, and/or manufacturing processes in short-term experiments. As soon as the final formulation and manufacturing process have been established, the manufacturer carries out a series of accelerated stability tests which will enable the stability of the drug product to be predicted and its shelf-life and storage conditions determined. Real-time studies must be started at the same time for confirmation purposes. Suitable measures should be taken to establish the utilization period for preparations in muitidose containers, especially for topical use. 

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