Drug substances development

In November 1997, the Department of Health and Human Services along with the International Conference on Harmonisation (ICH) released a draft guidance for the selection of test procedures, which included chiral drugs. For the development of an enantiopure drug substance, acceptable criteria shall include, if possible, an enan-tioselective assay. This assay should be part of the specification for the identification of an enantiopure drug substance and related enantioenriched impurities [16]. 

Preparative chromatography has been used for chiral separations for years, but examples of multi-kg separations (and hence larger ones) were rare until recently. The development of SMB techniques (both hardware and simulation software) has made major breakthroughs in this field. The ability of SMB as a development tool has allowed the pharmaceutical manufacturer to obtain kilo grams quantities of enantiopure drug substances as well benefit from the economics of large-scale production. 

Chemical development Proof of structure and configuration are required as part of the information on chemical development. The methods used at batch release should be validated to guarantee the identity and purity of the substance. It should be established whether a drug produced as a racemate is a true racemate or a conglomerate by investigating physical parameters such as melting point, solubility and crystal properties. The physicochemical properties of the drug substance should be characterized, e.g. crystallinity, polymorphism and rate of dissolution. 

The development of the most appropriate route for administration is influenced by a number of factors, including the location of the target within the body, the desired speed and duration of the therapeutic effect and the properties and characteristics of the drug substance. 

Manufacturing process The descriptions of the manufacturing steps for the drug substance and product should include process flow diagrams and discussions of critical scale-up steps and process development history and process validation activities, together with assessment of the equivalence or differences in batches used for various studies. 

Drug substance/drug product purity, potency, and other testing Drug substance/drug product stability testing Method development, validation, and transfer Drug product formulation development... 

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

Product specification documents and analytical test methods—In preclinical development, these are important documents and they evolve along with the development phases. Drug substances and products for clinical trials are tested based on these documents, and so are the stability samples. It is critical to ensure that the analyst will perform the right tests against the right specifications with the correct version of the test method. Therefore a mechanism must be in place to control these documents. This can be done manually or with TIMS. A manually controlled system would require the analyst to sign out hard copies of the documents from a central location. After the testing is done, the analyst would have to return these controlled documents to the... 

The Pharmacopoeial Forum fulfills a vital role in promoting industry-wide communication between those involved with quality assurance, the development of standards and analytical methods. It contains an up to date list of official USP Reference Substances, with current and recently changed lot numbers. Reference Substances not yet available and those under development are also described. The publication acts as an international open forum in which scientists are invited to express their views, suggestions, ideas and comments regarding new drug standard development and revisions to existing monographs. Pharmacopoeial Forum is published, on a subscription basis, six times a year, back issues are available for USP website see Table 84. 

Incompatibilities have also been observed in solid dosage forms. A typical tablet contain binders, disin-tegrants, lubricants and fillers. Compatibility screening for a new drug should consider two or more excipients from each class. Serajuddin et al. have developed a drug-excipient compatibility screening model to predict interactions of drug substances with excipients [49],... 

Stability of a drug substance and product is monitored throughout the development and clinical phases. This monitoring requires stability-indicating assay methodology, and this is a subject that is separate from performulation per se. In most instances, the major, feasible decomposition products are identified early [51], and as such it is known if the pathways are hydrolytic, oxidative, or photochemical. 

Because of today s myriad regulations, the NDA submission has become a compilation of information that could be compared in size with any one of the well-known encyclopedias. Before 1962, only a few volumes were necessary for an NDA submission [11]. Today it is not uncommon for this justification to consist of as many as 200 volumes of information (see Table 2). It is important for the pharmacy and medical practitioner to have some sensitivity to the many requirements and high cost placed on manufacturers who develop and market new drugs (especially new drug substances) today. 

The development pharmaceutics section should also include consideration of possible overdosing of the active ingredient that might arise from normal use of the dosage form—e.g., deposition of drug substance from a metered dose inhalation product in the mouth. 

---