Excipients also are an important area for regulation and related standards. Several recent developments include the launch
of EXCiPACT, a draft FDA guidance to limit use of certain phthalate-based excipients, and proposed revisions to European excipients
guidelines on labeling with respect to pediatric provisions.
. In late January 2012, EXCiPACT, a new, voluntary international certification scheme, was launched. It was designed and developed
to ensure that cGMP and current good distribution practices (cGDP) standards are being used in the manufacture and supply
of pharmaceutical excipients. The scheme is a product of a mulitstakeholder effort, which included participation from the
European Fine Chemicals Group (EFCG), the International Pharmaceuticals Excipients Council (IPEC) of the Americas, IPEC–Europe,
the European Association of Chemicals Distributors, and the Pharmaceutical Quality Group.
The EXCiPACT scheme provides independent certification of manufacturers and suppliers of pharmaceutical excipients as a means
of ensuring patient safety through supplier quality while minimizing overall supply-chain costs. The EXCiPACT standards act
as annexes to ISO standards 9001, 19011, and 17021. Suppliers who do not hold ISO 9001 certification will be able to obtain
an equivalent certificate through the forthcoming US national standard (ANSI–NSF 363), which also uses the EXCiPACT cGMP and
cGDP standards, according to an EFCG analysis.
In March 2012, FDA issued a draft guidance Limiting the Use of Certain Phthalates as Excipients in CDER-Regulated Products to provide the Center for Drug Evaluation and Research's thinking on the potential human health risks associated with exposure
to dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) (1). In particular, the draft guidance recommends that the
pharmaceutical industry avoid the use of these two specific phthalates as excipients in CDER-regulated drug and biologic products,
including prescription and nonprescription products. The draft guidance does not address the use of DBP or DEHP in other types
of FDA-regulated products or exposure to DBP or DEHP due to the presence of any of these compounds as an impurity, including
as a result of leaching from packaging materials. The comment period for the draft guidance ends May 31, 2012.
Phthalates are found in certain pharmaceutical formulations, primarily as a plasticizer in enteric coatings of solid oral
drug products to maintain flexibility (1). According to FDA's draft guidance, DBP and DEHP have been shown to be developmental
and reproductive toxicants in laboratory animals. While the data in humans are less clear, epidemiological studies suggest
that certain phthalates may affect reproductive and developmental outcomes. Although the human data are limited, FDA has determined
that there is evidence that exposure to DBP and DEHP from pharmaceuticals presents a potential risk of developmental and reproductive
toxicity and suggests that safer excipient alternatives to DBP and DEHP are available and should be used (1).
Pediatric considerations for excipients.
In March 2012, EMA issued a concept paper to gain public input regarding revisions to its excipient guidelines on labeling
and packaging to include safety concerns for pediatric populations and pregnant women (2). The current excipient guideline
was last revised in July 2003 and does not address safety concerns regarding excipients as they relate to pediatric populations
as had been addressed in other European regulations covering pediatric populations for pharmaceuticals (3, 4).
"It is important to note that the safety of excipients can affect children differently than adults due to the ongoing
organ development and incomplete maturation depending on the age," stated EMA in its concept paper (2). EMA also noted in
its concept paper that pregnant women are not covered in the excipient guidelines and that "safety labeling is needed for
products intended for use in this population to ensure the safety of the unborn child(ren)" (2).
The public comment period ends at the end of May 2012. EMA also said in its concept paper that the labeling of several excipients
are specified for a limited number of routes of administration and additional routes of administration need to be added. Also,
the guidelines need to be expanded to include additional excipients (2). The draft revised guideline is expected to be released
for a six-month month external consultation in the third quarter of 2013 to the first quarter of 2014. After the external
consultation, the final guideline is expected to be available within 6–12 months.
Patricia Van Arnum is a executive editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, firstname.lastname@example.org
1. FDA, Draft Guidance for Industry: Limiting the Use of Certain Phthalates as Excipients in Center for Drug Evaluation and Research-Regulated
Fed. Reg. 77 (42), 12852 (2012).
2. EMA, Concept Paper on the Need for Revision of the Guideline on Excipients in the Label and Package Leaflet of Medicinal Products
for Human Use (CPMP/463/00) (Feb. 6, 2012).
3. EC, Guidelines: Medicinal Products for Human Use: Safety, Environment and Information: Excipients in the Label and Package Leaflet
of Medicinal Products for Human Use (Brussels, July 2003).
4. EC Regulation No. 1901/2006, Pediatric Regulation (Brussels, Dec. 2006).