Clinical implications for substandard, nonproprietary medicines in multiple sclerosis: focus on fingolimod

Figures & data

Figure 1 The key requirements for the United States Food and Drug Administration.

Notes: These requirements must be fulfilled for the submission of a new drug application for proprietary versus nonproprietary medicines. Both types of medicines share requirements 1–8 (top panel), but have distinct requirements thereafter (bottom panel). Completion of all requirements bridges the differences between proprietary and nonproprietary medicines. Data from Dunne et al.³

Figure 2 The key differences between proprietary, nonproprietary, substandard, and counterfeit medicines, and substandard copies.

Note: Data from Johnston et al,² World Health Organization,⁴ US Food and Drug Administration,⁵ and Thaul.⁶
Abbreviation: HA, health authority.

Table 1 Examples of a link between quality parameters and their potential clinical impact

Category	Quality parameter	Potential impact
API quality and source	Presence of genotoxic or unknown impurities	Safety (side effects)
	Salt, polymorph, particle size, particle shape	Bioavailability
Medicinal product	API content (too high/low)	High content: safety (including toxicity)
		Low content: efficacy (subtherapeutic dose)
	In vitro dissolution, for example, oral products	Bioavailability, efficacy, and safety
	Excipients	Stability: safety
		Dissolution: efficacy
	Specifications analytical	Safety
Primary packaging	Material composition	Stability: safety
		Dissolution: efficacy and safety
Manufacturing	Process changes or quality by design not implemented	Dosage
	Content uniformity and batch-to-batch variability	Efficacy and safety
	Facility (good manufacturing practices)	Purity and sterility: safety

Note: Data from Johnston et al.²

Abbreviation: API, active pharmaceutical ingredient.

Table 2 Comparison of selected parameters for proprietary versus nonproprietary fingolimod

Parameter	Specification (source)	Nonproprietary fingolimod (%)	Proprietary fingolimod (%)
Assay fingolimod (HPLC)	90.0%–105.0% (proprietary specifications; USP generally acceptable: 90.0%–110.0% for oral drug products)	93.11	96.4
Individual unspecified degradation product (HPLC)	Not <0.5% (proprietary and ICH specifications)	7.575	<0.1
Total degradation products (HPLC)	Not <3.5% (proprietary specifications)	9.44	2.55
Content uniformity fingolimod (HPLC)	AV ≤15.0% at level 1 (Ph Eur, USP, JP)	AV 14.4	7.5
Dissolution rate fingolimod after 30 minutes (HPLC)	80% of the declared content (proprietary specifications)	92	96

Note: Data from Novartis Pharma AG, Basel, Switzerland (unpublished data, 2015).

Abbreviations: AV, acceptance value; HPLC, high-performance liquid chromatography; ICH, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use specifications; JP, Japanese Pharmacopeia specifications; Ph Eur, European Pharmacopeia specifications; USP, United States Pharmacopeia specifications.

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