This article provides guidance for industry on how to comply with the pending American National Standard on excipient GMP, with a focus on risk assessment. This article is part of a special issue on solid dosage and excipients.
Mar 1, 2012 By:
Dale Carter Pharmaceutical Technology
The forthcoming American National Standard for GMP for pharmaceutical excipients, NSF 363, utilizes quality risk-management
principles to ensure that the implementation of this standard provides appropriate controls in manufacturing to produce excipients
that are safe, of appropriate quality, and of consistent composition (1). (See "The American National Standard for Excipient
GMP" in this issue for background details). The need to apply risk-management principles to excipient manufacture and use
was born out of the challenge of defining a clear and auditable standard that can be applied across the vast diversity of
excipient manufacturing processes, their raw-material sources, their chemical and physical properties, and their many end
users in different types of drug products. Attempts to define requirements in such areas as personnel hygiene, infrastructure,
or work environment, inevitably lead to clauses that may be appropriate for one excipient but not for others (e.g., indoor
operations versus outdoor multiacre facilities, multiuse facilities versus dedicated production lines).
The Joint International Pharmaceutical Excipient Council and Pharmaceutical Quality Group (IPEC–PQG) GMP Guide for Pharmaceutical
Excipients was used to develop NSF 363 (2). The standard addresses the aforementioned industry differences by discussing various
points for consideration during excipient manufacture as well as calling for a risk assessment. The American National Standard
Institute (ANSI) is expected to review and approve NSF 363 this year. This article provides guidance for industry on how to
comply with NSF 363 upon its pending approval, with a focus on risk assessment as part of excipient GMP.
NSF 363 requires risk assessments to support decisions and implement controls (see Tables I–IV). For example, Section 4.2.1
on Documentation requires incorporating quality risk-management principles into changes to the quality-management system (1).
The International Conference on Harmonization (ICH) Q9 Quality Risk Management guideline, a reference document for NSF 363, gives two primary principles: "The evaluation of the risk to quality should be
based on scientific knowledge and ultimately link to the protection of the patient" and "the level of effort, formality, and
documentation of the quality risk management process should be commensurate with the level of risk" (3).
Table III: NSF 363 sections requiring decisions based on risk assessment (Ref. 1).
These principles can help to frame a company's thought process when conducting and documenting risk assessment by focusing
the activity on the overall goal of protecting the patient. The principles direct the industry to use science when determining
the significance "of the probability of occurrence of harm and the severity of that harm" (1). It is also pointed out that
not all risks are equal, and therefore, each documented risk assessment may or may not provide the same level of detail or
Table IV: NSF 363 sections requiring risk controls as a result of risk assessment (Ref. 1).
NSF 363 adopts the same definition for risk assessment as found in ICH Q9, namely: "a systematic process of organizing information
to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the
analysis and evaluation of risks associated with exposure to those hazards" (3). In Q9, a hazard is a potential source of
harm and harm is "damage to health, including the damage that can occur from loss of product quality or availability" (3).
This definition highlights the difference between risk assessment for excipients and hazard analysis for food ingredients.
In Hazard Analysis and Critical Control Points (HACCP) plans used throughout the food industry, the focus lies on preventing
microbiological, chemical, or physical contamination that is reasonably likely to cause illness or injury. No consideration
is given to consistency of composition or functionality of the ingredient. Excipient manufacturers must assess the impact
of a change to excipient composition on its functionality and performance in the drug product, but only the user of the excipient
can adequately make this assessment. The excipient manufacturer understands the range of variability, in chemical composition
and physical properties, of its product and may communicate this to the user during qualification. The excipient manufacturer
is expected to use risk assessment to prevent deviations in the stated range of variability. For this reason, the excipient
manufacturer's documentation of its product's composition and variability provides crucial information for conducting an adequate
risk assessment. This information is also a requirement of NSF 363 Section 126.96.36.199 on Excipient Composition (1).