Finished product testing

Manufacturing validation data, which should aim to identify the critical process steps, especially for nonstandard manufacturing processes such as for new dosage forms, should be discussed in the development pharmaceutics section of the application. Validation data may be accepted based on closely related products. In-process control tests and acceptance limits should be included for any aspect where conformity with the finished product tests cannot otherwise be guaranteed (e.g., mixing, granulation, emulsification and nonpharmacopeial sterilization processes). 

Records include materials transfer records, batch records, materials/inter-mediates/finished product test records, shipping records, water test records, and environmental test records. They provide an audit trail for reviewing all the information related to the production of any batch of drug product. The data are required to be reviewed for product release. 

FDA inspectors are instructed to look for any differences between the process filed in the application and the process used to manufacturer the bio/clinical batch. Furthermore, one of the main requirements of a manufacturing process is that the process will yield a product that is equivalent to the substance on which the biostudy or pivotal clinical study was conducted. Validation of the process development and scale-up should include sufficient documentation so that a link between the bio/clinical batches and the commercial process can be established. If the process is different after scale-up, the company has to demonstrate that the product produced by a modified process will be equivalent, using data such as granulation studies, finished product test results, and dissolution profiles. 

C.02.016 (Packaging Material Testing), C.02.019 (Finished Product Testing), and... 

Correspondences in Canadian GMP Code In the Canadian GMP code [12] issues related to holding and distribution are covered in the interpretations of regulations C.02.004 (Premises), C.02.011 (Manufacturing Control), C.02.012 (Manufacturing Control), and C.02.019 (Finished Product Testing). Correspondences to regulation... 

A. Walsh et al., Development and validation of automated methods for finished product testing, Pharm. Technol. Eur., 24(3), 134, 2000. 

As discussed, the manufacture of suspensions presents additional problems, particularly in the area of uniformity. The development data should address the key compounding and filling steps that ensure uniformity. The protocol should provide for the key in-process and finished product tests, along with their specifications. For oral solutions, bioequivalency studies may not always be needed. However, oral suspensions, with the possible exception of some of the over-the-counter antacids, usually require a bioequivalency or clinical study to demonstrate their effectiveness. Comparison of product batches with the biobatch is an important part of the validation process. Make sure there are properly written protocol and process validation reports and, if appropriate, data for comparing full-scale batches with biobatch available during FDA inspection. 

Biobatch manufacturing Inspection to determine the establishment s compliance with cGMP requirements, including a data audit of the specific batches on which the application is based (e.g., pivotal clinical, bioavailability, bioequivalence, and stability) is a field office responsibility. CDER scientists are responsible for the review and evaluation of the records and data submitted in the application, including the components, composition, batch instructions, in-process and finished product test points, and... 

The statistical analysis performed during the in-process control and finished product test is verified by other authorized personnel prior to release. 

Conventional quality control procedures for finished product testing encompass three basic steps ... 

Finished Product Test Data Stability Reports Process Validation Report... 

In-process testing and acceptance criteria Finished product testing and acceptance criteria Test method references Formulation... 

Critical process steps are operations performed during dosage-form manufacture that can contribute to variability of the end product if not controlled. Since each type of dosage form requires different machinery and unit operations to produce the end product, the critical process steps will also differ. For each product considered suitable for retrospective validation, a list of these steps must be compiled following careful analysis of the process by technically competent persons. In a similar manner, in-process and finished-product tests should be screened to identify those that may be of some value. As a rule, tests in that the outcome is quantitative will be of greatest interest. 

Lot-to-lot differences in the purity of the therapeutic agent must be considered when evaluating in-process and finished-product test results. In addition to potency such qualities as particle size distribution, bulk density, and source of the material will be of interest. Such information should be available from the raw material test reports prepared by the quality control laboratory for each lot of material received. The physical characteristics of the excipients should not be overlooked, especially for those materials with inherent variability. Metallic stearates is a classic example. In such instances, the source of supply is desirable information to have available. 

Once this has been done, one can proceed to actual product testing utilizing these parameters and their specifications to validate that the process will produce acceptable product. The testing can be conducted on samples during the manufacture (in-process tests) or on the finished product (finished product tests). Each product may have its own idiosyncrasies requiring special tests, but generally the in-process and finished product tests that would be required for all solid dosage forms in process validation are as follows. 

Acknowledging that validation is an intimate part of development, considerations for each major phase of the development activities will be reviewed. This review starts with studies of the drug substance and progresses through finished product testing. 

Validation of a process often results in the reduction of in-process and finished-product testing requirements. Process controls established during validation may prove sufficient to assure product quality without excessive quality markers throughout the process. 

Changes should also be correlated with the statistical data available from stability, inprocess, and finished-product testing. The statistical data should be examined for trends in specification test results. Where trends are found (e.g., increases or decreases in potency, decreases in stability) the change control records should be evaluated to determine whether or not changes have occurred that might be responsible for the shifts in QC trends and analytical results. 

Another example might be where a specific batch is not in question but rather a number of consecutive batches across a specific time frame. Imagine a situation in which a number of batches were manufactured. All met in-process and finished-product testing, and they were released to inventory... 

An important piece of information typically contained in an APR is the number of out-of-specification (OOS) results identified over the course of the year for (in-process and finished-product) testing related to any single product. While this is valuable information, it maybe of further use to more frequently evaluate the OOS trends relate to high-volume products. 

Finished product test results to include content uniformity, assay, hardness, friability, etc. 

Amount of Data To validate the manufacturing process, the manufacturer has to design and specify in the protocol the use of data sheets to keep information about the control of product specifications from each batch in-process as well as finished-product tests. Some formats are common to different products, though each type of product has some specific information to be kept on special sheets. Thus, the amount of data varies from one type of product to another [6]. 

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