Batch-made manufacturing

A few years ago, a customer filed suit against a nationally known manufacturer of automotive brake fluid for supplying faulty merchandise. When the company s control chemist went before the jury with his detailed quality control records, he was able to prove that the allegedly faulty batch made two years earlier met all the requirements established for this product. The plaintiff lost his case. 

Shellac, boiled linseed oil, resins, paraffin wax, beeswax, litbographic varnish and acaroid resin are used in various pyrotechnic formulations. Similarly chlorinated rubber powder has also been used successfully as a binder. Some of tbe waxes and resins which are of natural origin are still popular and are in use. In order to improve quahty and avoid batch-to-batch variation, manufacturers of pyrotechnics are moving from natural binders to man-made binders. 

In addition to data gathering, QA will want the validation batches made entirely by the production department. When this stipulation is satisfied, it will be demonstrated that the process control is independent of the technical background of the operating personnel. This kind of approach demonstrates that the manufacturing process will support the soon-to-be-marketed product s volume demands. This approach also allows QA to have a baseline activity with which it can compare future audit activities. 

For APIs, stability data should be generated on a minimum of one pilot-scale batch made using equipment of the same design and operating principle as the manufacturing-scale equipment (with the exception of scale). 

Another division of the factors can be made into mixture-related, quantitative (continuous), or qualitative (discrete) factors (4,5,16,18,24). A mixture-related factor in CE is usually related to a mixture of solvents, for example, the composition of the background electrolyte solution. A quantitative factor can vary on a continuous scale, for example, the buffer pH, the electrolyte concentration, the additive concentration, the capillary temperature, or the voltage. A qualitative factor, on the other hand, varies on a discrete nominal scale, for example, batch or manufacturer of a reagent, solvent, or capillary. 

Product specifications will also evolve during development (see Table 8.4). In the early stages, testing is typically performed on only a small number of samples due to the small scale of manufacture available. There may only be one or two product batches made to support Phase I and early Phase II studies. The specification limits also tend to be wide, due to the limited data available. The specification limits are tightened as more information is gained from testing more batches, and the scale of manufacture is increased. 

The EPA has further categorized violations as one-day or per-day violations. The per-day violations can easily add up to millions of dollars because each day of violation can be penalized separately. The ERPs specify which types of violations are per-day and which are one-day. Generally, penalties for violations relating to manufacturing are based on the volume of each batch made. The date of the violation is the date the batch is completed. The EPA will assess per-day violations when there is an imminent hazard, or when there was an intent to disregard TSCA. 

Written procedures should be provided for all changes from one chemical reaction to another, and a comprehensive list of all products and raw materials handled, with their physical and chemical properties, should be kept on the plant. This is particularly relevant to batch plants manufacturing a range of products. If a product is made only infrequently, people who are new to the plant may be unfamiliar with it. (See also case histories Al 87-90, pages 191-192.)... 

A typical example of a chemical reaction in need of control is the sulfation of a fatty alcohol to produce a surfactant (surface active agent.) In traditional batch-mode manufacturing, the chlorosulfonic acid is added to the alcohol, reacted, and then the mixture is made basic with sodium or ammonium hydroxide. The concentration of the sulfated product is assayed (usually by titration) and any necessary dilution made. Then the color, viscosity, percentage sulfate, pH, etc. are measured This is a clear case in... 

As it pertains to batch selection, site-specific stability has been the subject for discussion between FDA and industry. Site-specific means that stability batches are manufactured at the proposed manufacturing site. The site-specific stability is to assure that the batches used for expiration date determination will be representative of the batches made for commerce. Although site-specific stability testing has typically been implemented for years, it is not an absolute requirement from all authorities. It is recommended that the requirements for site-specific stability be determined for each country prior to initiation of the registration stability studies. 

Since API stability data are needed to support the three clinical phases, the selection of batches at each phase reflects the synthetic scheme and batch size used at that stage of development. In phase I studies, the batches used in the toxicological and clinical trials should be monitored. As the synthetic scheme and batch size evolve, batches made by the new process should be selected for stability testing and monitored for the duration of the phase II clinical trials. Knowledge about the API gathered in phases I and II should form the basis for the stability protocol for the API manufactured by the final synthetic process that will be used to support the phase HI clinical trials and the primary registration stability studies. 

Firmenich US has also performed studies with e-noses, but the results have not been disseminated to our knowledge. Merck used e-noses to discriminate between various flavours used in pharmaceutical formulations, obtaining a good correlation between GC, sensory panel and e-nose. Zhu et al. (2004) of Merck research Laboratories used the electronic-nose technique to qualitatively distinguish raspberry, red berry, strawberry, pineapple, orange, and cherry in placebo formulations. Raspberry flavour samples from different batches made by the same manufacturer, as well as freshly prepared and aged samples, were also distinguished by an electronic-nose. They used not only PCA and CA but also other methods such as Discrimination Function Analysis (DFA). 

Most manufacturing equipment should be made of stainless steel. The liming tanks, however, can be either concrete or wood (qv). Properly lined iron tanks are often used for the washing and acidification, ie, souring, operations. Most gelatin plants achieve efficient processes by operating around the clock. The product is tested in batches and again as blends to confirm conformance to customer specifications. 

Manufacture of ion-exchange resins has traditionaHy been a batch process. Significant progress was made more recentiy in the development of a continuous process for the manufacture of copolymer beads. However, as of this writing (ca 1994) is it not used by aH manufacturers. Moreover, those companies having continuous processing capabiHties do not use it for aH ion-exchange products. 

In the most common production method, the semibatch process, about 10% of the preemulsified monomer is added to the deionised water in the reactor. A shot of initiator is added to the reactor to create the seed. Some manufacturers use master batches of seed to avoid variation in this step. Having set the number of particles in the pot, the remaining monomer and, in some cases, additional initiator are added over time. Typical feed times ate 1—4 h. Lengthening the feeds tempers heat generation and provides for uniform comonomer sequence distributions (67). Sometimes skewed monomer feeds are used to offset differences in monomer reactivity ratios. In some cases a second monomer charge is made to produce core—shell latices. At the end of the process pH adjustments are often made. The product is then pumped to a prefilter tank, filtered, and pumped to a post-filter tank where additional processing can occur. When the feed rate of monomer during semibatch production is very low, the reactor is said to be monomer starved. Under these... 

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