Manufacturing and Process Controls

Due to the nature of the SMB process, in-process samples of the unwanted enantiomer and the enantiopure drug substance can be sampled at controlled times during the continuous process to assess the enantiomeric and chemical purity. One can monitor the process without system shutdown by diverting either the extract or the raffinate streams. Further monitoring of the receiving tanks can also be accomplished. 

The guidance document requires calculation of actual yields and percentages of expected yields. The yield should be recorded at the conclusion of each phase of manufacturing of an API. The expected yield and ranges are established during process validation or from a pilot-scale production run [66]. 

For a continuous SMB process, the specific identified amount or batch produced is defined by unit of time in such a way that ensures a homogeneous material and quality within specified limits. In the case of a continuous SMB production run a batch is defined by the amount produced in a fixed time interval. A time limitation during manufacturing using SMB is established by the same fixed time interval as the batch. The duration of the production phase is thus established, which does not affect the quality of the drug substance [66]. 

The design of the system must take into account possible variation of critical control parameters that could affect performance. The maximum performance of the process should be defined by a reasonable safety margin. In order to comply with cGMP guidelines, established validation protocols, and parameters should allow the process to achieve reproducible purity and yield under stressed conditions. This implies that the industrial SMB system must be stressed to simulate worst-case conditions for process validation. 

In addition, the protocol should specify a sufficient number of process runs to prove consistency of the process, and provide an accurate measure of variability among successive runs. The number of batches should depend on the extent of validation and complexity of the process or importance of any process changes. Furthermore, the protocol should address the quality of materials used in the process from starting materials to new and recovered solvents, and evidence of the performance and reliability of equipment and systems. 

---

With the passing of time and looking ahead these material and equipment variabilities continually are reduced due to improvement in their manufacturing and process control... 

Determination of the range for each critical process parameter expected to be used during routine manufacturing and process control. Data to substantiate the ranges for critical process parameters generally should be obtained from laboratory- or pilot-scale batches, unless a specific parameter can only be determined from a production-scale batch. 

Spath, D., Braun, M., and Hagenmeyer, L. (2006). Human factors and ergonomics in manufacturing and process control. In G. Salvendy (Ed.), Haruibook of Human Factors and Ergonomics (pp. 1597-1626). Upper Saddle River, NJ John WUey Sons. 

Augsburger, L. L. and Hoag, S. W. Pharmaceutical Dosage Forms Tablets, 3rd ed.. Manufacture and Process Control. Vol. 3. Informa Healthcare Press, New York, 2008. 

Manufacture and Processing. Mononitrotoluenes are produced by the nitration of toluene in a manner similar to that described for nitrobenzene. The presence of the methyl group on the aromatic ring faciUtates the nitration of toluene, as compared to that of benzene, and increases the ease of oxidation which results in undesirable by-products. Thus the nitration of toluene generally is carried out at lower temperatures than the nitration of benzene to minimize oxidative side reactions. Because toluene nitrates at a faster rate than benzene, the milder conditions also reduce the formation of dinitrotoluenes. Toluene is less soluble than benzene in the acid phase, thus vigorous agitation of the reaction mixture is necessary to maximize the interfacial area of the two phases and the mass transfer of the reactants. The rate of a typical industrial nitration can be modeled in terms of a fast reaction taking place in a zone in the aqueous phase adjacent to the interface where the reaction is diffusion controlled. 

The Toxic Substances Control Act (TSCA) was enacted in 1976 to identify and control toxic chemical ha2ards to human health and the environment. One of the main provisions of TSCA was to estabUsh and maintain an inventory of all chemicals in commerce in the United States for the purpose of regulating any of the chemicals that might pose an unreasonable risk to human health or the environment. An initial inventory of chemicals was estabhshed by requiring companies to report to the United States Environmental Protection Agency (USEPA) all substances that were imported, manufactured, processed, distributed, or disposed of in the United States. Over 50,000 chemical substances were reported. PoUowing this initial inventory, introduction of all new chemical substances requires a Premanufacturing Notification (PMN) process. To be included in the PMN are the identity of the new chemical, the estimated first year and maximum production volume, manufacture and process information, a description of proposed use, potential release to the environment, possible human exposure to the new substance, and any health or environmental test data available at the time of submission. In the 10 years that TSCA has been in effect, the USEPA has received over 10,000 PMNs and up to 10% of the submissions each year are for dyes (382)... 

Shear strength is measured via a simple single overlap shear specimen of standard dimensions (Fig. 9). In contrast to its simple appearance, the forces in a thin-adherend shear specimen can be quite complex due to the inherent offset loading of the specimen and subsequent bending in the substrates. The single overlap shear test is anything but a pure shear test, but the configuration is easy to manufacture, simple to test and is firmly entrenched in the industry as a primary examination technique for materials qualifications, inspection and process control. 

Collectively, the combination of appropriate facilities, equipment, documentation, manufacturing practices and quality control procedures provide a basis for effective product and process control. This is illustrated in Figure 11.10. 

Sec. 820.70 Production and process controls - Address production procedures and process controls, changes to the process, environmental controls, clothing and hygiene of personnel, prevention of contamination, suitability and layout of buildings, equipment qualification, maintenance, periodic inspection, and adjustment, removal of unwanted manufacturing materials from devices and automated (computer controlled) processes... 

The manufacturing and quality control departments face higher costs because they have to eliminate process and measurement variability, even if they are already operating at the technological limit. They will have to add people to their staffs to mn all of the investigations and handle the additional paperwork (because malicious intent is suspected, peers and supervisors have to sign off at every step to confirm that each SOP was strictly adhered to whether the SOPs made sense, scientifically speaking, or were installed to satisfy formalistic requirements is of no interest here). 

Several commercial companies now offer process compatible NMR systems. These systems are either low resolution based on relaxation time measurements or high resolution Fourier Transform spectral measurements. The low resolution systems are manufactured by Process Control Technologies (www.pctnmr.com) and Progression, Inc. (www.progression-systems.com). Progression s systems... 

Deskbook Issue of Chemical Engineering Instrumentation and Process Control, Sept. 11, 1972 (lists equipment manufacturers). 

The principles of quality assurance are commonly related to product and process control in manufacturing. Today the field of application greatly expanded to include environmental protection and quality control within analytical chemistry itself, i.e., the quality assurance of analytical measurements. In any field, features of quality cannot be reproduced with any absolute degree of precision but only within certain limits of tolerance. These depend on the uncertainties of both the process under control and the test procedure and additionally from the expense of testing and controlling that may be economically justifiable. 

Recent advances in mass spectrometry (MS) techniques have radically changed the analysis of biomolecules. MS has become the analytical method of choice for discovery and characterization of molecules with therapeutic value. Technological breakthroughs in the discovery area are now increasingly applied in the process development held and have recently entered the production process in manufacturing and quality control (QC) areas. In this presentation, after a review of the current state of the art, we would like to demonstrate how MS methods are influencing the development and manufacturing of therapeutic molecules. 

Production and Process Controls Critical Manufacturing Steps, Equipment Identification, In-Line and Bulk Testing, Actual Yield, Personnel Habits... 

The growing nse of more complex PAT (versus the historically used simple univariate sensors such as pressure, temperature, pH, etc.) within manufacturing industries is driven by the increased capabilities of these systems to provide scientihc and engineering controls. Increasingly complex chemical and physical analyses can be performed in, on, or immediately at, the process stream. Drivers to implement process analytics include the opportunity for live feedback and process control, cycle time reduction, laboratory test replacement as well as safety mitigation. All of these drivers can potentially have a very inunediate impact on the economic bottom line, since product quality and yield may be increased and labor cost reduced. 

The manufacture and processing of the protein microarray should be conducted in such a manner that the arrayed proteins remain in their native and active state. For most proteins, this usually means the hydrated state in order to avoid surface denaturation. For antibody arrays which are perhaps more forgiving than other proteins, it has been our experience that while these could be stored cold and dry, it is most important to rehydrate them prior to use. This process is in sharp contrast to the preparation of nucleic acid arrays in which strand melting or denaturahon is necessary to achieve optimal binding to the solid support. While the hybridization process is well understood and can be controlled under thermodynamic principles, the folding and renaturation of proteins on planar (microarray) surfaces is under study. 

Title I - Control of Toxic Substances - includes provisions for testing chemical substances and mixtures, manufacturing and processing notices, regulating hazardous chemical substances and mixtures, managing imminent hazards, and reporting and retaining information. 

Another important aspect related to both process technology and equipment design is the need for yield management and process control techniques embedded in the tools, which will have to provide accurate and reliable means for avoiding yield losses in manufacturing and contributing to overall improvement. From this point of view, it is expected that standards in equipment and in characterization techniques will be developed or implemented if already available. 

Willig, S. H. (2001), Production and process controls, in Swarbrick, J., Ed., Good Manufacturing Practices for Pharmaceuticals A Plan for Total Quality Control from Manufacturer to Consumer, Marcel Dekker, New York, pp. 99-138. 

Good manufacturing practice is that part of the quality management system (QMS) that is concerned with the production and quality control of medicinal products (drugs) for human and veterinary use. It includes documentation, personnel training, facility, equipment, and process controls for the manufacture of pharmaceuticals. 

---