Page 303 - Chiral Separation Techniques

282 10 The Use of SMB for the Manufacture of Enantiopure Drug Substances: From …

ues to establish policies to control market exclusivity as it applies to cGMP guide-
lines defined for the development and manufacture of enantiopure drug substances.
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 pro-
duction.
Process validation is the procedure that allows one to establish the critical operat-
ing parameters of a manufacturing process. Hence, the constraints imposed by the
FDA as part of process control and validation of an SMB process. The total indus-
trial SMB system, as described, is a continuous closed-loop chromatographic pro-
cess, from the chromatographic to recycling unit and, with the use of numerical sim-
ulation software allows the pharmaceutical manufacturer rapidly to design and
develop worst-case studies.
From the position of the FDA, acceptance of SMB as a viable tool for cGMP man-
ufacturing of enantiopure drug substances, there shall be no compromise, it must be
properly engineered, and follow established guidelines.

References

[1] FDA’s Policy Statement on the Development of New Stereoisomeric Drugs (Stereoisomeric Drug
Policy) Fed. Regist. (1992) 57 FR22249.
[2] Agranat, I. and Cancer, H., Drug Discover Today, 4 No. 7, (1999) 313–321.
[3] Crosby, J. (1997) in Chirality in Industry II: Developments in the Commercial Manufacture and
Application of Optically Active Compounds (Collins, A.N., Sheldrake, G.N. and Crosby, J., eds),
pp 1–10, Wiley.
[4] Committee for Proprietary Medicinal Product (1993) Note for Guidance: Investigation of Chiral
Active Substances III/3501/91.
[5] Daniels, J.M., Nestmann, E.R. and Kerr, A. Drug Inf. J., 31, (1997) 639–646.
[6] Blumenstein, J.J. (1997) in Chirality in Industry II: Developments in the Commercial Manufacture
and Application of optically Active Compounds (Collins, A.N., Sheldrake, G.N. and Crosby, J.,
eds), pp 11–18, Wiley.
[7] Shindo, H. and Caldwell, J., (1995) Chirality, 7, 349–352.
[8] Francotte, E., J. Chromator. A., 666 (1994) 565–601.
[9] Welch, C.J., J. Chromatogr. A, 666 (1994) 3–26.
[10] 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.
[11] Draft Guidance for Industry on Manufacturing, Processing, or Holding Active Pharmaceutical
Ingredients; Availability; Notice, Fed Regist. Docket No. 98-0193, 1998.
[12] Current Good Manufacturing Practice for Finished Pharmaceuticals, Sampling and Testing of In-
Process Materials and Drug Products, (1998), CFR, Title 21, Part 211, Volume 4, Section 2ll.l10.
[13] Zamani, K., Conner, D.P, Weems, H.B., Yang and Cantilena, L.R, Chirality, 3, (1991) 467–470.
[14] Okerholm, R.A., Weiner, D.L., Hook, R.H., Walker, B.J., Biopharm. Drug Dispos., 2,
(1981)185–190.