Analytical techniques for Reverse Engineering of Reference products for the development of generic Oral Solid Dosage Forms

Authors

  • Harsha Kathpalia VES College of Pharmacy
  • Aditi Venkatesh
  • Tammannavar Venkatesh
  • Dr. Atul Kaushik

Abstract

Economical and speedy surrogates are cruces for successful generic product development. With value-driven drug development being key for generic pharmaceutical companies, pacing up innovator product characterization is an effective way to compete with heightened costs and pressures for bioequivalent surrogates. Generic product manufacturers characterize the Reference Listed Drug by reverse engineering techniques that serves as the basis for submission of the Abbreviated New Drug Application. Reverse Engineering is a systematic deformulation technique that is classified into three segments: (i) Characterization of small (non-complex) APIs- by determining morphology (including particle size distribution, solid-state and, crystal habit) (ii) Categorisation and analysis of complex APIs (peptides, polymeric compounds), (iii) Assessment of Excipients by Q1/Q2 evaluation. As of today, there is no prescribed step-by-step methodology for the process of reverse engineering. This review summarizes essential analytical processes for the successful deformulation and characterization of the Reference Listed Drug product.

Keywords:

API characterization, Deformulation, Excipient characterization, Generic Pharmaceutical Products, Reference Listed Drug Characterization, Q1-Q2-Q3 sameness

DOI

https://doi.org/10.25004/

References

Pharmaceutical Formulation Development. Malvern Panalytical. https://www.malvernpanalytical.com/en/industries/pharmaceuticals/pharmaceutical-formulation-development.

Research C for DE. Drugs@FDA Glossary of Terms. FDA; 2023.

ANDA Regulatory Pathway: Q1/Q2(Q3) Deformulation & Equivalence. Element. https://www.element.com/nucleus/2022/q1-q2-q3-deformulation-equivalence.

Narang AS, Boddu SHS, editors. Excipient Applications in Formulation Design and Drug Delivery. Cham: Springer International Publishing; 2015. https://doi.org/10.1007/978-3-319-20206-8.

Deformulation (re-engineering). AgfaLabs. https://www.agfa.com/agfa-labs/analytical-services/deformulation-re-engineering/.

Drug Approval Package: Renvela (Sevelamer Carbonate) NDA #022127s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022127s000TOC.cfm.

Drug Approval Package: Welchol (Colesevelarn Hydrochloride) NDA #21-141 & 21-176. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-141_welchol.cfm.

Research C for DE. ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin Guidance for Industry 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/andas-certain-highly-purified-synthetic-peptide-drug-products-refer-listed-drugs-rdna-origin.

Jiang X. Navigating Q1/Q2 for Complex Generics. https://accessiblemeds.org/sites/default/files/2019-11/Xiaohui_%28Jeff%29_Jiang_GRxBiosims2019.pdf.

Thomas LC. Modulated DSC® Paper #7 Characterization of Pharmaceutical Materials. n.d.

Byrn S, Pfeiffer R, Ganey M, Hoiberg C, Poochikian G. Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations. Pharm Res. 1995; 12:945–54. https://doi.org/10.1023/A:1016241927429.

Tishmack PA, Bugay DE, Byrn SR. Solid-State Nuclear Magnetic Resonance Spectroscopy-Pharmaceutical Applications. J Pharm Sci. 2003; 92:441–74. https://doi.org/10.1002/jps.10307.

Miyamae A, Koda S, Kitamura S, Okamoto Y, Morimoto Y. X-ray Crystallographic Characterization of two Polymorphs of 8-(2-Methoxycarbonylamino-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)-imidazo[1, 2-a]pyridine. J Pharm Sci. 1990;79:189–95. https://doi.org/10.1002/jps.2600790302.

Hirsch CA, Messenger RJ, Brannon JL. Fenoprofen: Drug Form Selection and Preformulation Stability Studies. J Pharm Sci. 1978;67:231–6. https://doi.org/10.1002/jps.2600670227.

Niazi S. Thermodynamics of Mercaptopurine Dehydration. J Pharm Sci. 1978;67:488–91. https://doi.org/10.1002/jps.2600670413.

Antoncic L, Copar A. Preparation of telmisartan salts with improved solubility. WO2006050921A2, 2006.

Salt Selection in Drug Development. https://www.pharmtech.com/view/salt-selection-drug-development.

EP Monograph for Hygroscopicity. 2021. n.d.

Vapour Sorption and Surface Analysis - Solid State Characterization of Pharmaceuticals. Wiley Online Library. https://onlinelibrary.wiley.com/doi/10.1002/9780470656792.ch8.

Microscopic Techniques for the Analysis of Micro and Nanostructures of Biopolymers and Their Derivatives. Polymers. https://www.mdpi.com/2073-4360/12/3/512.

Spectroscopic Methods in Solid‐state Characterization - Characterization of Pharmaceutical Nano and Microsystems. Wiley Online Library. https://onlinelibrary.wiley.com/doi/abs/10.1002/9781119414018.ch2.

Banahan S, Byrne D. Methods of Particle Size Determination – A Review. 2019;1–25. https://www.innopharmatechnology.com/docs/default-source/eyecon2-whitepapers/methods-of-particle-size-determination.pdf.

Particle Analysis Techniques Compared. Microtrac. https://www.microtrac.com/applications/knowledge-base/different-particle-analysis-techniques-compared/.

Clarke PG. Low-Angle Light Scattering (LALS) for Molecular Weight Determinations by GPC/SEC Why Closer is Better. The Applications Book Viscotek Europe. 2003.

BET Specific Surface Area Testing. Particle Technology Labs. https://particletechlabs.com/analytical-testing/bet-specific-surface-area/.

Kaur A, Kale DP, Bansal AK. Surface characterization of pharmaceutical solids. TrAC Trends Anal Chem. 2021;138:116228. https://doi.org/10.1016/j.trac.2021.116228.

Particle Size & Particle Shape Analysis. Microtrac. https://www.microtrac.com/products/particle-size-shape-analysis/.

A basic guide to particle characterization. Malvern Whitepaper. 2015;1–24. https://www.cif.iastate.edu/sites/default/files/uploads/Other_Inst/Particle Size/Particle Characterization Guide.pdf.

Solid State Characterization of Commercial Crystalline and Amorphous Atorvastatin Calcium Samples. AAPS PharmSciTech. https://link.springer.com/article/10.1208/s12249-010-9419-7.

Measuring API Particle Size Distribution. Pharm Tech. https://www.pharmtech.com/view/measuring-api-particle-size-distribution.

Henson MJ, Zhang L. Drug Characterization in Low Dosage Pharmaceutical Tablets Using Raman Microscopic Mapping. Appl Spectrosc. 2006;60(8):906-11. https://doi.org/10.1366/000370206778998987.

Connor EF, Lees I, Maclean D. Polymers as drugs—Advances in therapeutic applications of polymer binding agents. J Polym Sci A Polym Chem. 2017;55:3146–57. https://doi.org/10.1002/pola.28703.

Sterns RH, Rojas M, Bernstein P, Chennupati S. Ion-Exchange Resins for the Treatment of Hyperkalemia: Are They Safe and Effective? J Am Soc Nephrol. 2010;21:733. https://doi.org/10.1681/ASN.2010010079.

Davidson MH. The use of colesevelam hydrochloride in the treatment of dyslipidemia: a review. Expert Opin Pharmacother. 2007;8:2569–78. https://doi.org/10.1517/14656566.8.15.2569.

EMEA Cholestagel Scientific Discussion. 2005;1–15. https://www.ema.europa.eu/en/documents/scientific-discussion/cholestagel-epar-scientific-discussion_en.pdf.

EMEA Renagel Scientific Discussion. 2005. https://www.ema.europa.eu/en/documents/scientific-discussion/renagel-epar-scientific-discussion_en.pdf.

Determination of Phosphate binding capacity in sevelamer carbonate, sevelamer hydrochloride by Ion Chromatography.

Berendt RT, Samy R, Carlin AS, Pendse A, Schwartz P, Khan MA, et al. Spontaneous carbonate formation in an amorphous, amine-rich, polymeric drug substance: Sevelamer HCl product quality. J Pharm Sci. 2012;101:2681–5. https://doi.org/10.1002/jps.23228

Holmes-Farley SR, Whitesides GM. Phosphate-binding polymers for oral administration. US Patent 5667775A. 1997.

CHMP, EMA. Constella, INN-linaclotide. 2012. https://www.ema.europa.eu/en/documents/assessment-report/constella-epar-public-assessment-report_en.pdf

USFDA. Draft guidance on linaclotide. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/psg/Linaclotide-Capsule-NDA-202811-Page-RC-12-2018.pdf

Luke MC. Equivalence of locally-acting drug products. 2017. https://www.fda.gov/media/105890/download

Koradia VS, Chawla G, Bansal AK. Comprehensive characterisation of the innovator product: targeting bioequivalent generics. J Generic Med. 2005;2:335–46. https://doi.org/10.1057/palgrave.jgm.4940086

Hydroxypropyl methylcellulose (SB-806M HQ) | Shodex HPLC columns and standards. 2024. https://www.shodex.com/en/dc/03/06/45.html

Whelan MR, Ford JL, Powell MW. Simultaneous determination of ibuprofen and hydroxypropylmethylcellulose (HPMC) using HPLC and evaporative light scattering detection. J Pharm Biomed Anal. 2002;30:1355–9. https://doi.org/10.1016/S0731-7085(02)00394-1

Ramírez B, Bucio L. Microcrystalline cellulose (MCC) analysis and quantitative phase analysis of ciprofloxacin/MCC mixtures by Rietveld XRD refinement with physically based background. Cellulose. 2018;25:2795–815. https://doi.org/10.1007/s10570-018-1761-z

The shape and size distribution of crystalline nanoparticles prepared by acid hydrolysis of native cellulose | Biomacromolecules. 2024. https://pubs.acs.org/doi/10.1021/bm700769p

Newman RH. Estimation of the lateral dimensions of cellulose crystallites using 13C NMR signal strengths. Solid State Nucl Magn Reson. 1999;15:21–29. https://doi.org/10.1016/S0926-2040(99)00043-0

HPLC-ELSD determination of sodium lauryl sulphate and polysorbate in nebivolol drug product and different formulation products. Int J Pharm Sci Res. 2015. https://ijpsr.com/bft-article/hplc-elsd-determination-of-sodium-lauryl-sulphate-and-polysorbate-in-nebivolol-drug-product-and-different-formulation-products/

Haq N, Siddiqui N, Alam P, Shakeel F, Alanazi F, Alsarra I. Estimation of sodium lauryl sulphate concentration in marketed formulations by stability indicating ‘green’ planar chromatographic method. Chiang Mai J Sci. 2018;45:1531–42.

Sugisawa K, Kaneko T, Sago T, Sato T. Rapid quantitative analysis of magnesium stearate in pharmaceutical powders and solid dosage forms by atomic absorption: Method development and application in product manufacturing. J Pharm Biomed Anal. 2009;49:858–61. https://doi.org/10.1016/j.jpba.2009.01.004

Arai T, Hosoi Y. Determination of magnesium stearate in pharmaceutical preparations using derivatization with 2-nitrophenylhydrazine and HPLC. Yakugaku Zasshi. 2005;125:299–305. https://doi.org/10.1248/yakushi.125.299

Riby P, Dey D, Patel T, Wande A. The use of ICP-OES and ICP-MS in the assessment of magnesium stearate levels on tablets. J Pharm Pharmacol. 2009;61:A113–4.

Ion exchange chromatography TECH TIP #62. 2007. www.thermo.com/pierce.

Carr JD, Swartzfager DG. Complexometric titration for the determination of sodium ion. Anal Chem. 1970;42:1238–41. https://doi.org/10.1021/ac60293a025

Zhu L, Seburg RA, Tsai EW. Determination of surface-bound hydroxypropylcellulose (HPC) on drug particles in colloidal dispersions using size exclusion chromatography: A comparison of ELS and RI detection. J Pharm Biomed Anal. 2006;40:1089–96. https://doi.org/10.1016/j.jpba.2005.09.014

United States Pharmacopeia. Mannitol. In: The United States Pharmacopeial Convention; 2015. https://www.usp.org/sites/default/files/usp/document/harmonization/excipients/mannitol.pdf

Risley DS, Yang WQ, Peterson JA. Analysis of mannitol in pharmaceutical formulations using hydrophilic interaction liquid chromatography with evaporative light-scattering detection. J Sep Sci. 2006;29:256–64. https://doi.org/10.1002/jssc.200500253

Jones SA, Martin GP, Brown MB. Determination of polyvinylpyrrolidone using high-performance liquid chromatography. J Pharm Biomed Anal. 2004;35:621–4. https://doi.org/10.1016/j.jpba.2004.01.024

Pedersen G, Kristensen HG. Quantitative analysis of povidone (PVP) in drug–PVP matrix using multicomponent analysis. Drug Dev Ind Pharm. 1999;25:69–74. https://doi.org/10.1081/DDC-100102143

Berggren J, Frenning G, Alderborn G. Compression behaviour and tablet-forming ability of spray-dried amorphous composite particles. Eur J Pharm Sci. 2004;22:191–200. https://doi.org/10.1016/j.ejps.2004.03.008

Sebhatu T, Ahlneck C, Alderborn G. The effect of moisture content on the compression and bond-formation properties of amorphous lactose particles. Int J Pharm. 1997;146:101–14. https://doi.org/10.1016/S0378-5173(96)04777-1

De Bleye C, Sacré P-Y, Dumont E, Netchacovitch L, Chavez P-F, Piel G, et al. Development of a quantitative approach using surface-enhanced Raman chemical imaging: First step for the determination of an impurity in a pharmaceutical model. J Pharm Biomed Anal. 2014;90:111–8. https://doi.org/10.1016/j.jpba.2013.11.026

Lakio S, Vajna B, Farkas I, Salokangas H, Marosi G, Yliruusi J. Challenges in detecting magnesium stearate distribution in tablets. AAPS PharmSciTech. 2013;14:435–44. https://doi.org/10.1208/s12249-013-9927-3

Published

30-01-2025
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“Analytical Techniques for Reverse Engineering of Reference Products for the Development of Generic Oral Solid Dosage Forms”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 17, no. 1, Jan. 2025, https://doi.org/10.25004/.

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How to Cite

“Analytical Techniques for Reverse Engineering of Reference Products for the Development of Generic Oral Solid Dosage Forms”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 17, no. 1, Jan. 2025, https://doi.org/10.25004/.

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