Regulatory Update: The IPEC Novel Excipient Safety Evaluation Procedure - Pharmaceutical Technology

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Regulatory Update: The IPEC Novel Excipient Safety Evaluation Procedure
The authors, representing the International Pharmaceutical Excipients Council, propose a new evaluation procedure, including tiered toxicology testing for excipients.


Pharmaceutical Technology
Volume 33, Issue 11, pp. 72-82

The expert committee's review of Solutol HS 15

BASF novel excipient, Solutol HS 15, a non-ionic solubilizer, was developed to fulfill an unmet need for a safe and effective excipient for parenteral and solid oral dose formulations containing poorly soluble APIs. Chemically, Solutol HS 15 is composed of polyglycol mono- and di-esters of 12-hydroxy-stearic acid and contains approximately 30% polyethylene glycol. Solutol HS 15 is listed as Macrogol 15 hydroxystearate in the European Pharmacopoeia (PhEur). The excipient has been used in approved drugs in some countries, including Canada and Argentina. Even though the Solutol HS 15 drug-master file (DMF) was filed with FDA in January 1992 (DMF #9501), it has not yet been used in FDA-approved drugs because of its novel excipient nature and absence of FDA-review status.

In 2007, IPEC–Americas Safety Committee Chair Jay Goldring, recognizing the urgent industry need for an excipient that meets the requirements in formulations containing poorly soluble APIs, selected Solutol HS 15 solubilizer as the subject for the first NEEC review. The expert committee's report would then be reviewed by FDA for consistency with its own review process.

As defined in the IPEC–Americas procedure in the previous section of this article, BASF entered into an agreement with Aclairo PDG to develop an independent safety evaluation of Solutol HS 15. To accomplish this, BASF prepared a package of information containing safety and chemistry information. The package included the following items:
  • Technical information containing a summary of chemistry, manufacturing, and controls (CMC) information
  • BASF's safety expert report on Solutol HS 15
  • Reports of all acute, subchronic, reproductive, and genotoxicity studies conducted by BASF for Solutol HS 15 under different routes of administration
  • Safety evaluation assessment report for Solutol HS 15 conducted by the European Medicines Agency
  • Safety expert report of a related BASF solubilizer excipient Cremophor (Polyoxyl 35 Castor Oil: NF Polyoxyl 40 Hydrogenated Castor Oil NF)
  • FDA IID information for use of Cremophor in 15 FDA-approved drugs
  • List of other excipients with related chemistry derived from the FDA IID.

The package also included a cover letter requesting that Aclairo PDG evaluate the information submitted and provide an independent safety evaluation for Solutol HS 15.

The independent safety evaluation procedures were coordinated and led by Dr. Osterberg. Aclairo conducted an independent safety assessment using two other distinguished toxicologists. The six-month evaluation implemented all the steps of the review process described above. At the conclusion of the process, the expert committee issued an independent safety evaluation of Solutol HS 15 to BASF.

Following this process, BASF submitted a package to the IPEC–Americas Safety Committee Chair. This package included a cover letter from BASF that requested review and consideration for submission to FDA under the IPEC Novel Excipient Safety Evaluation Procedure, a safety expert report from Aclairo PDG and all the documents submitted to Aclairo PDG outlined in the previous paragraphs in this section. The BASF submission was forwarded to FDA by the IPEC-Americas Safety Committee. FDA provided its review letter of Solutol HS 15 to the committee which then informed BASF of the agency's findings.

After receiving feedback, BASF approached the United States Pharmacopeia (USP) for consideration of an official monograph for Solutol HS 15 on the following grounds: FDA review of this excipient, monograph status in PhEur, and use in approved drugs in some countries outside the US. USP informed BASF that, as required by their procedure for development of official monographs, they consulted the compendial group at FDA. USP then requested that BASF submit materials for monograph development. Efforts by BASF and USP led to the publication of Polyoxyl 15 Hydroxystearate (Solutol HS) NF monograph in the January/February 2009 issue of the USP Pharmacopeial Forum.


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