The risk assessment for excipients associated with their use in drug-product formulation and use can only be adequately performed
by the drug-product manufacturers. Generalizations around the route of administration, the function of the excipient in the
formulation, and the characteristics of the type of API can be useful in identifying potentially high-risk excipients. However,
many excipients can have multiple functions, in multiple formulations, and are used with different types of APIs. Just because
an excipient manufacturer can point to a drug-product formulation where their excipient presents a lower risk does not mean
the excipient will be of lower risk in other formulations.
It's crucial that the excipient manufacturer clearly communicate its expectations for the route of administration for the
final drug product using its excipient to avoid additional risks. In most cases, excipient manufacturers do not have adequate
experience and knowledge of the use and function of their excipients in all user formulation and drug-product manufacturing
processes. Certain assumptions are necessary for the excipient manufacturer to design appropriate controls into their processes,
but these assumptions should be transparent and clearly open for the user's evaluation.
Excipient makers and users should each use risk-management principles to prevent failures in the final drug product. Risk
assessment will not identify the extent of GMP required for a particular excipient but will serve to strengthen the processes.
The engineering design, process control, and GMPs form the prerequisite controls necessary to reduce the infinite possibility
for failures to a smaller and more manageable number from whence risk assessment can serve to focus our attention toward the
few opportunities for failure in the absence of heightened control. Well-functioning GMPs have layers of checks and balances
built into the procedures and processes to ensure that a single lapse at one point will likely not result in failure or necessitate
a withdrawal of product.
Overall, risk assessment provides a tool to evaluate the status quo and find the opportunities to make the good better. Risk assessment brings an obligation for action to protect the patient
because once a significant risk is identified, it cannot be ignored.
Regulatory bodies and excipient users may benefit from focusing their limited resources on higher-risk excipients as determined
from a risk assessment based on available information. Assigning a higher risk to an excipient that in reality has a lower
risk when sourced from a specific manufacturing facility due to advanced engineering and the unique processes utilized carries
little consequence to the patient or drug manufacturer.
The opposite result of designating an excipient a lower risk when in actuality significant risk exists due to the particulars
of its manufacturing process or facility introduces potential to harm the patient and drug maker. In the interest of patient
safety, excipient risk characterizations must come from a proper and complete risk assessment, including consideration of
the specific manufacturing locations and supply chains.
Pending IPEC guideline. IPEC–Americas is developing a guideline for excipient risk management in conjunction with the global IPEC Federation. This
guide will explore risk management from both the makers' and users' perspective. The guide will outline the process, structure,
and documentation necessary to demonstrate the effective application of risk management principles. The current ANSI NSF 363
stand-alone excipient GMP draft standard, and EXCIPACT ISO 9001 Annex Certification Standard for Excipient GMP, require documented
risk assessments at several points to justify the application of certain GMP controls (3, 4). These standards are scheduled
to become publically available in 2011 and the IPEC Excipient Risk Management guideline will be a helpful reference for companies
seeking GMP certification to either of these proposed standards.
W. Busch, DowWolff Cellulosics; L. Calhoun, King Pharmaceutical/Pfizer; G. Collins Jr., RT Vanderbilt; D. Fillar, Perrigo;
F. Flynn, RT Vanderbilt; J. Garofalo, Avantor Performance Materials; R. Green, CP Kelco; S. Hernadez, Ashland Aqualon; L,
Herzog, Asahi Kasei; D. Klug, sanofi-aventis; F. Murphy, Dow Chemical; B. McCarter, EMD Chemicals; P. Merrell, Jost Chemical;
L. Milano, Genentech; RC Moreton, FinnBrit Consulting; C. Perini, ISP; D. Schoneker, Colorcon; I. Silverstien, IBS Consulting
in Quality; R. Sulouff III, Ashland Aqualon; A. Van Meter, Dow Chemical; P. Zawislak, Ashland Aqualon.
W. Dale Carter is chair of the International Pharmaceutical Excipients Council of the Americas (IPEC–Americas) and director of global quality-silica
with Huber Engineered Materials in Atlanta, GA, tel. 678.247.2735.
1. ICH, Q9 Quality Risk Management (Geneva, November 2005).
2. J. Orloff, Pharm. Technol.
35 (2) 38–40 (2011).
3. ANSI NSF 363 (September 2009).
4. EXCIPACT ISO 9001 (in development). EXCIPACT is a consortium of industry bodies including IPEC-Americas, IPEC–Europe,
PQG, EFCG, and FECC.