Drug product manufacturing

Although the API is designed to provide efficacy, without a properly controlled manufacturing process the API will not be formulated and delivered correctly. Drag product manufacture can be complicated and varied, but most processes have three components. 

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Drug substance/drug product manufacturing process development, validation, and transfer... 

While LIF monitoring is established in other manufacturing industries, it is relatively new within the pharmaceutical industry. The application of real-time intrinsic LIF for the manufacture of pharmaceuticals in general can be broken in to three areas (i) classic (small molecule) final drug product manufacturing (ii) biopharmaceutical prodnct manufacturing and (iii) factory operational applications. 

The first demonstration of solid state fluorescence of API dates back to 1961, while its in-line use for final drug product manufacturing was not demonstrated until recently." While in its infancy as a process analytical technology for real-time monitoring and product parametric real-time release, the applications identified and in some instances demonstrated include (i) blend endpoint API content nniformity detection " (ii) segregation monitoring or API content at various process critical control points and (iii) at-line tablet content uniformity determination. The fundamentals of solid-state luminescence spectroscopy for pharmaceutical solids has been covered by Brittain."... 

Evaluation of extrusion-spheronization for drug product manufacturing has focused on two main areas ... 

Pilot Scale Batch — A batch of a drug substance or drug product manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is larger. 

Production Batch — A batch of a drug substance or drug product manufactured at production scale by using production equipment in a production facility as specified in the application. 

Protection from microbial contamination is provided by maintaining adequate container integrity after the packaging system has been sealed. An adequate and validated procedure should be used for drug product manufacture and packaging. 

Each manufacturer of a packaging component sold to a drug product manufacturer should provide a description of the quality control measures used to maintain consistency in the physical and chemical characteristics of the component. These measures generally include release criteria (and test methods, if appropriate) and a description of the manufacturing procedure. If the release of the packaging component is based on statistical process control, a complete description of the process (including control criteria) and its validation should be provided. 

This test is intended for drugs being dispensed on prescription, but it has also been applied to the drug product manufacturer s container closure system. If the container closure system has an inner seal, it should be removed before testing. The results from this study reflect the contributions to water vapor permeation through the container and through the seal between the container and the closure. 

The drug product manufacturer must establish the reliability of the supplier s analyses through appropriate validation of the supplier s test results at appropriate intervals per [21 CFR Part 211.84(d)(2)]. The reliability of the analyses need not be established at the time the application is submitted. However, the specification should indicate that the tests that will be performed once the reliability of the supplier s results has been established in accordance with cGMPs, prior to marketing the drug product. 

While the COA is the excipient manufacturer s responsibility, once the material is received, it is the drug product manufacturers responsibility to verify the product and ensure that it is properly tested, handled, and stored. Upon receipt of a shipment, each lot of excipient will be withheld from use until the lot is sampled, tested, or examined according to the written procedures. The quality control (QC) personnel will examine each container for (i) manufacturer s name, (ii) manufacturer s lot number, (iii) leaks or spills, (iv) contamination, (v) breached containers, (vi) proper labeling, and (vii) material safety data sheet and determined material hazards. 

With the globalization of the supply system and more open markets, traceability is required to enable everyone in the drug manufacture s supply chain to control and investigate any problems that may arise in one of their products, which may be caused by or linked to any excipient. A traceability system is required by cGMP. Cell excipients should be traceable and the drug product manufacturer may need to trace the origin of the excipient to assess whether it is appropriate for the intended use or not. 

To compare the rate and extent of absorption of the drug product for which the manufacture has been changed, as defined in this guidance, to the drug product manufactured prior to the change. 

In vitro dissolution should be shown to be independent of dissolution test conditions after change is made in drug product manufacturing. 

The various preparation processes and technologies used in drug product manufacture also can effect product safely, stability, and performance, e.g., compression during tablet manufacture. The principal processes used in dosage form manufacture arc as follows. 

Phase I Strategies for Drug Product Manufacturing of V ter-lnsoluble... 

Relatively low upfront investment in time and resources for developing a market image drug product manufacturing process. 

Drug product manufacturing process poorly understood Development of clinical manufacturing process and its... 

PHASE I STRATEGIES FOR DRUG PRODUCT MANUFACTURING OF WATER-INSOLUBLE NEW CHEMICAL ENTITIES... 

The transition from Phases II to III for drug product manufacturing is a very critical step as the formulation scientists and the process scientists are diligently working to optimize the composition and the process. The formulation and the process go hand-in-hand. The clinical supply requests tend... 

Most drug product manufacturers use the same excipients, and usually in relatively high concentrations in the drug product when compared to the concentration of the API. The manufacture of excipients therefore often involves continuous processing. A continuous process is one in which material (both raw and/or in-process) is added continually as the finished product is removed for... 

To Support Product Development. In addition to supporting the use of clinical trial materials, stability studies are carried out on both the API and different formulations in different container-closure systems to guide the development of the final formulation and container-closures. Stability studies may be carried out on either the formulation to be marketed or a representative formulation to evaluate different API suppliers, drug product manufacturing processes and sites, and drug product container-closures. 

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