Drug substance

Griesser and Burger (1999) compiled the information regarding 559 polymorphic forms, solvates (including hydrates) of dmg solids at 25 °C in the 1997 edition of 

A survey by this author of the 1 October 2000 release of the CSD ( 225 000 entries) yielded 6353 hits for the qualifier form , 1045 hits for the qualifier phase 528 hits for the qualifier polymorph , 201 hits for the qualifier modification , 28 342 hits for the qualifier solvate and21 132 hits for the qualifier hydrate . Of course, the last two numbers give no indication of whether the materials are polymorphic and none of these statistics indicate the instances for which the structures of more than one form have been determined. The data for hydrates and solvates from the CSD may be considered quite reliable, since molecules of solvation are usually positively identified in the course of a crystai structure determination. The frequency of polymorphs, however, is likely to be underestimated, since many crystal structures of polymorphic systems, or what later are discovered to be polymorphic systems, are reported without making note of that fact. If the structure of only one member of a polymorphic family has been reported, then there may not be any reference to the polymorphism in the CSD. References to drugs discovered prior to 1971 that form solvates have been compiled, along with a separate summary of the thermomicroscopic behaviour of drug hydrates by Byrn et al. (1999). 

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McPhiUips in M. E. Goldberg, ed.. Pharmacological and Biochemical Properties of Drug Substances, Vol. 1, American Pharmaceutical Association,... 

G. A. Biewei, in K. Floiey, eA, Analytical Profiles of Drug Substances, Vol. 8, Academic Press, New York, p. 179. 

Guidelinesfor Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances, Office of Drug Evaluation and Research (HFD-100), FDA, RockviUe, Md., 1987, pp. 3, 4. 

A related substance of quinapril, 3-methyl-a-(2-phenylethyl)-l,4-dioxo-1,3,4,6,11,1 lfl-hexahydro-2//-pyrazino[l,2-A]isoquinoline-2-acetic acid, was determined by a HPLC method in drug substance (00MI55). 

J. V. Posluszny and R. Weinherger, Detemiination of drug substances in biological fluids by diiect injection multidimensional liquid chromatography with a micellar cleanup and reversed-phase clnomatography , Chem. 60 1953-1958(1988). 

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]. 

Market Exclusivity Newly Approved Drug Substances... 

In order to illustrate an example of process design for the manufacture of enantiopure drug substances on an industrial SMB system, consider manufacturing 10 ton/ year of an enantiopure drug. The racemic drug by definition is a 50 50 mixture of each enantiomer (products A and B). The goal is to process enantiopure drug substances in order to obtain 99 % purity for both the extract and the raffinate. 

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. 

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]. 

SMB is now accepted as a real production tool. For instance, the Belgium pharmaceutical company U.C.B. Pharma announced recently the use of SMB for performing multi-ton scale purification of an enantiopure drug substance. The concept of large-scale purification of enantiomers using chromatographic techniques has moved from a dream to a reality within the last few years. 

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. 

From the position of the FDA, acceptance of SMB as a viable tool for cGMP manufacturing of enantiopure drug substances, there shall be no compromise, it must be properly engineered, and follow established guidelines. 

International Conference on Harmonisation Draft Guidance on Specifications Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products Chemical Substances Notice, Fed Regist. Docket No. 97D-0448, 1997. 

HHS/FDA International Conference on Harmonisation Stability Testing of New Drug Substances and Products Guideline Availability Notice, Federal Register, September 22, 1994... 

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