Development of Taiwan’s strategies for regulating nanotechnology-based pharmaceuticals harmonized with international considerations

Figures & data

Form A – Chemistry, manufacturing, and controls (CMC) review checklist for nanotechnology^a-related pharmaceuticals

Notes: ^aNanotechnology: The understanding and control of matter at dimensions between approximately 1 to 100 nm, where unique phenomena enable novel applications. ^bNanoparticle: Nano-object with all three external dimensions at the nanoscale that is the size range from approximately 1 nm to 100 nm. Polymeric nanoparticle platforms are characterized by their physicochemical structures including solid nanoparticles, nanoshell, dendrimer, polymeric micelle, and polymer-drug conjugates. ^cDendrimer: A polymer in which the atoms are arranged in many branches and subbranches along a central backbone of carbon atoms. ^dLiposome: Vesicles composed of one or more bilayers of amphiphatic lipid molecules enclosing one or more aqueous compartments. ^eMicelle: Self-assembling nanosized colloidal particles with a hydrophobic core and hydrophilic shell currently used for the solubilization of various poorly soluble pharmaceuticals. ^fNanocrystal: Nanoscale solid formed with a periodic lattice of atoms, ions, or molecules. ^gMetal colloid: Metal nanoparticles in colloidal systems where the term colloidal refers to a state of subdivision. This implies that the molecules or polymolecular particles are dispersed in a medium and have at least in one direction a dimension roughly between 1 nm and 1 μm or, in a system, have discontinuities at distances of that order. For example, silver, gold, titanium dioxide, zinc oxide, and iron oxide.

Abbreviation: API, active pharmaceutical ingredient.

Form B – Methods used to characterize the nanomaterial

Notes: *Only common techniques are listed. Check relevant parts of the product. Justify if using other methods. ^#An abbreviation list is provided below. ^@These techniques will measure the average particle size, but can not necessarily distinguish between primary particles, aggregates, and agglomerates.

Abbreviations: AAS, atomic absorption spectroscopy; AFM, atomic force spectroscopy; AUC, analytic ultracentrifugation; BET, Buranuer–Emmett–Teller method; CHDF, capillary hydrodynamic fractionation; DLS, dynamic light scattering; DMA (1), differential mobility analyzer; DMA (2), dynamic mobility analyzer; DSC, differential scanning spectroscopy; ESA, electroacoustic spectroscopy; FFF, field flow fractionation; FTIR, fourier transform infrared spectroscopy; GE, gel electrophoresis; GPC, gel permeation chromatography; HPLC, high performance liquid chromatography; ICP-MS, inductivity coupled plasma mass spectrometry; ITC, isothermal titration calorimetry; LDE, laser doppler electrophoresis; MS, mass spectrometry (GCMS, gas chromatography-mass spectrometry; TOFMS, time-of-flight mass spectrometry; SIMS, secondary ion mass spectrometry, etc); NMR, nuclear magnetic resonance; PALS, phase analysis light scattering; RS, raman spectroscopy; SEM, scanning electron microscopy; SLS, static light scattering; SMA, scanning mobility particle sizer; SPM, surface probe microscopy (AFM, atomic force microscopy; STM, scanning tunneling microscopy; NSOM, near-field scanning optical microscopy, etc); TEM, transmission electron microscopy; TGA, thermal gravimetric analysis; UV-Vis, ultraviolet-visible spectrometry; XDC, X-ray disk centrifuge; XPS, X-ray photoelectron spectroscopy; XRD, X-ray diffraction.

Table 1 List of approved nanopharmaceuticals in Taiwan

Name	Type	Route of administration	Indication(s)	US FDA-approved date	Taiwan FDA-approved date
Lipodox (doxorubicin)	Liposome	Intravenous	Antineoplastic		1998/09
Visudyne (verteporfin)	Liposome	Intravenous	AMD	2000/04	2002/07
AmBisome (amphotericin B)	Liposome	Intravenous	Antifungal	1997/08	2002/03
Macugen (pegaptanib sodium)	Pegylation	Intravitreal	Neovascular, AMD in adults	2004/12	2007/06
Neulasta (pegfilgrastim)	Pegylation	Subcutaneous	Febrile neutropenia	2002/01	2011/09
PEG-Intron (peginterferon α-2b)	Pegylation	Subcutaneous	Chronic hepatitis C	2001/01	2001/06
Rapamune (sirolimus)	Nanocrystal	Oral	Immunosuppressant	2002/08	2002/01
Emend (aprepitant)	Nanocrystal	Oral	Antiemetic	2003/03	2004/05
Triglide (fenofibrate)	Nanocrystal	Oral	Antihyperlipidemia	2005/05	2004/10
Renagel (sevelamer hydrochloride)	Micronized	Oral	Control of hyperphosphatemia	2000/07	2003/07
Copaxone (glatiramer acetate)	Micronized	Subcutaneous	Relapsing-remitting multiple sclerosis	1996/12	2006/12
Invega Sustenna (paliperidone palmitate)	Nanocrystal	Intramuscular	Schizophrenia	2009/07	2011/04

Abbreviations: AMD, age-related macular degeneration; FDA, Food and Drug Administration.

Table 2 Comparison of nanopharmaceutical regulation between Taiwan and US/EU/Japan

Year	Taiwan	US/EU/Japan
2010	Abbreviated review process for new drug registration	US CDER: Reporting Format for Nanotechnology-related Information in CMC Review
	Draft: priority review mechanism for new drug registration	US FDA: Draft Guidance on Doxorubicin Hydrochloride
2011		EMA: Reflection Paper on Non-clinical Studies for Generic Nanoparticle Iron Medicinal Product Applications
2013	Drafting the guidance for technical review of CMC of the nanomedicines, including the following:	EMA: Joint MHLW/EMA Reflection Paper on the Development of Block Copolymer Micelle Medicinal Products
	CMC review checklist for nanotechnology-related pharmaceuticals	EMA: Reflection Paper on the Data Requirements for Intravenous Liposomal Products Developed With Reference to an Innovator Liposomal Product
	Draft guidance for technical review of CMC of the liposomal drug products, with an attachment of the current regulations for liposomal drug products, including new chemical entities, new administration routes, new indications, new combinations, new dosage forms, new doses, new dose units, and generic formulations	EMA: Reflection Paper on Surface Coatings: General Issues for Consideration Regarding Parenteral Administration of Coated Nanomedicine Products
		EMA: Draft Reflection Paper on the Data Requirements for Intravenous Iron-based Nanocolloidal Products Developed With Reference to an Innovator Medicine

Abbreviations: CDER, Center for Drug Evaluation and Research; CMC, chemistry, manufacturing, and controls; EMA, European Medicines Agency; EU, Europe; FDA, Food and Drug Administration; MHLW, Japanese Ministry of Health, Labour and Welfare.