In-Process Assays, In-Process Controls, and Specifications

In-process controls (IPCs) are essential to make high-quality products, to conduct operations productively, and to facilitate troubleshooting. The managers of manufacturing facilities rely upon IPCs to ensure that processes run effectively, efficiently, consistently, and productively. IPCs are crucial for process validation, and processes must be validated for permission to sell drugs for use in humans. IPCs are established to guide operations to prepare APIs and drug products that meet the critical quality attributes (CQAs) accepted by the FDA and other regulatory authorities. IPCs are part of the Chemistry, Manufacturing & Controls (CMC) section of New Drug Applications (NDAs) and are part of the current good manufacturing practices (cGMPs) that must be followed to prepare material for use in humans. In-process assays can determine an acceptable operating “space” in the Quality by Design (QbD) approach favored by the FDA; IPCs can help keep processing within acceptable ranges. Some common in-process assays are shown. Understanding the critical details behind in-process assays can lead to developing rapid, effective in-process analyses. Process analytical technology (PAT) and quality by design (QbD) are discussed as the currently favored approach to generating process data and controlling operations. A sample list of product specifications is provided.

[1]  Hans-Jürgen Federsel,et al.  Facing chirality in the 21st century: Approaching the challenges in the pharmaceutical industry. , 2003, Chirality.

[2]  P. Westerduin,et al.  A Mechanistic Insight into a Simple C−N Bond Formation via SN2 Displacement: A Synergistic Kinetics and Design of Experiment Approach , 2010 .

[3]  J. Wasylak,et al.  The Process Development of Ravuconazole: An Efficient Multikilogram Scale Preparation of an Antifungal Agent(1) , 2009 .

[4]  A. R. Tatchell,et al.  Vogel's Textbook of Practical Organic Chemistry , 1996 .

[5]  D. T. LEWIS,et al.  Spot Tests in Organic Analysis , 1961, Nature.

[6]  Rick Mullin.  A NEW COURSE FOR A MAVERICK BUYER , 2011 .

[7]  S. Wittenberger,et al.  An improved synthesis of pyran-3,5-dione: application to the synthesis of ABT-598, a potassium channel opener, via Hantzsch reaction. , 2006, The Journal of organic chemistry.

[8]  G. W. Anderson,et al.  A reinvestigation of the mixed carbonic anhydride method of peptide synthesis. , 1967, Journal of the American Chemical Society.

[9]  David Q. Liu,et al.  A Systematic Method Development Strategy for Determination of Pharmaceutical Genotoxic Impurities , 2010 .

[10]  D. O'grady,et al.  A Review of the Use of Process Analytical Technology for the Understanding and Optimization of Production Batch Crystallization Processes , 2005 .

[11]  Gary Francis GlaxoSmithKline Breen,et al.  The Development of a Manufacturing Route for the GPIIb/IIIa Receptor Antagonist SB-214857-A. Part 2: Conversion of the Key Intermediate SB-235349 to SB-214857-A , 2003 .

[12]  Andrew Nguyen,et al.  Process Development of 5-Fluoro-3-[3-[4-(5-methoxy-4-pyrimidinyl)-1- piperazinyl]propyl]-1H-indole Dihydrochloride , 1997 .

[13]  Kapa Prasad,et al.  A Practical Enantioselective Synthesis of a Novel Peptide Deformylase Inhibitor , 2006 .

[14]  Lawrence X. Yu.  Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control , 2008, Pharmaceutical Research.

[15]  Sushil K. Srivastava,et al.  Removal of Palladium from Organic Reaction Mixtures by Trimercaptotriazine , 1997 .

[16]  Rick Mullin.  PAYING ATTENTION TO MANUFACTURING: Consortia aim to BRIDGE THE GAP between drug development and manufacturing with a technology and engineering focus , 2011 .

[17]  G. Steele,et al.  An In-Line Study of Oiling Out and Crystallization , 2005 .

[18]  Robert E Gawley,et al.  Do the terms "% ee" and "% de" make sense as expressions of stereoisomer composition or stereoselectivity? , 2006, The Journal of organic chemistry.

[19]  F. Sistare,et al.  Process Analytical Technology: An Investment in Process Knowledge , 2005 .

[20]  J. Suffert.  Simple direct titration of organolithium reagents using N-pivaloyl-o-toluidine and/or N-pivaloyl-o-benzylaniline , 1989 .

[21]  J. A. Wachter,et al.  An Investigation of Solvent-Mediated Polymorphic Transformation of Progesterone Using in Situ Raman Spectroscopy , 2000 .

[22]  J. Wiss,et al.  Safety Improvement of a Grignard Reaction Using On-Line NIR Monitoring , 2005 .

[23]  Sanjay Mahadeo Gade,et al.  Counting On Process I Analytical Technology , 2010 .

[24]  P. K. Owens,et al.  Strategies for the investigation and control of process-related impurities in drug substances. , 2007, Advanced drug delivery reviews.

[25]  T. Laird.  Is Your Yield Truly Quantitative , 2011 .

[26]  G. W. Anderson,et al.  RACEMIZATION BY THE DICYCLOHEXYLCARBODIIMIDE METHOD OF PEPTIDE SYNTHESIS , 1958 .

[27]  Alan S. Futran,et al.  Investigations of Pd-catalyzed ArX coupling reactions informed by reaction progress kinetic analysis. , 2006, The Journal of organic chemistry.