Manufacturing formulae

Manufacturing formulae should clearly indicate the product name, potency or strength, and exact batch size. It lists each of the starting raw materials required, and the quantity in which each is required. The processing instructions should contain step-by-step manufacturing instructions. The detail given should be sufficient to allow a technically competent person, unfamiliar with the process, to successfully undertake the manufacturing procedure. 

The manufacturing methods/process simulation include the following steps (see individual MFM [manufacturing formula and method] for media hll run) ... 

There should be a clear distinction between in-process controls and validation. In-process tests are performed during the manufacture of each batch using specifications and methods devised during the development phase. The aim is to monitor the process continuously and not exactly validate it. When a new manufacturing formula or method is adopted, steps should be taken to demonstrate its suitability for routine processing prior to the validation. The defined process using the materials and equipment specified should be shown to yield a product consistently of the required quahty. 

When any new manufacturing formula or method of preparation is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to yield a product consistently of the required quality. 

Proposed manufacturing formula, manufacturing instruction, in-process and final product specifications at the 100 X-batch size... 

Method of manufacture of the finished product—manufacturing formula, processes and validation, control during the manufacturing process. 

Short information concerning the methods of manufacture of the finished product, including the manufacturing formula, manufacturing processes and their validation in-process control. 

The names and quantities of all the ingredients, active and inactive, must correspond with the batch manufacturing formula stated in Annexure 11. 

Manufacturing formula and the process of preparation and conformity control ensuring the constant quality of the product through the different manufacturing stages. 

Fig.l The synthesis and variations performed in a process research validation shown schematically. HV stands for performed according to the manufacturing formula. The example shown illustrates the first step of the chemical synthesis. Circles show the variations of the two parameters tested in the validation (LiCl and TOBO are internal names for chemicals used in the synthesis, eq stands for equivalent)... 

The original manufacturing formula (HV) and five variations are performed in the first step of the synthesis. Six samples are analysed. The results of these six analyses are used to assess the validation of this process step. In this case validation of the analytical method is a prerequisite for any decision that is made about the validity of the process. This information is needed before the process research chemist can start variations of the process otherwise it is possible that the data received cannot be assessed. The difficulty of assessing the data of the process validation results from the fact that the data is influenced by the analytical method and the uncertainty of the chemical process. If the uncertainty of the analytical method is larger or in the same range as the variations of the chemical process, assessment of the data is not possible. 

Together with the customer it was decided to perform the analysis according to option 2. The samples were analysed in one analytical run. The result is shown in Table 3. The result of the estimation compares well with the found results. The found uncertainty is smaller than the estimation. Assessment of the results of the validation of the manufacturing formula becomes easier from the customers point of view because the customer is able to deceide if a variation of his result is related to his process or to the uncertainty of the analytical method. Additionally, the influence of the individual contributions to uncertainty becomes smaller because of the uncertainty propagation. Therefore, the difference between the estimated and found uncertainty becomes smaller with an increasing number of parameters that influence uncertainty. 

Even after an application has been approved and the product has been marketed, consideration should be given to the effects of changes in the manufacturing formula or manufacturing process. Bioequivalence of the product and the stability properties may be affected. Appropriate studies will therefore need to be conducted, and applications for the changes will need to be submitted as necessary. 

Good documentation constitutes an essential part of the quality assurance system. Clearly written documentation prevents errors from spoken communication and permits tracing of batch history. Specifications, Manufacturing Formulae and instructions, procedures, and records must be free from errors and available in writing. The legibility of documents is of paramount importance. 

Manufacturing Formulae, Processing and Packaging Instructions state all the starting materials used and lay down all processing and packaging operations. 

Formally authorised Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. They are often combined in one document... 

A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and Processing Instructions. The method of preparation of such records should be designed to avoid transcription errors. The record should carry the number of the batch being manufactured. 

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