New excipient GMP requirements
Excipients come from a broad range of the chemical- and food-ingredient industries. Inorganic excipients usually begin with
the mining of minerals. Excipients whose starting material is grown on a farm or forest are often further processed into a
derivative through chemical reaction or fermentation. Synthetic excipients can be produced at the manufacturing site from
basic chemical starting materials, such as ethylene and acetylene. The one process common to all excipient manufacturing is
purification of the material to meet the requirements of a pharmaceutical ingredient. A key challenge of the NSF joint committee,
therefore, was to develop excipient GMPs that would be applicable to the diverse operational activities of the excipient industry.
Risk assessment.
NSF 363 represents the evolution of the joint IPEC–PQG GMP for Pharmaceutical Excipients (2) into an American National Standard
suitable for regulation by FDA. The most significant new requirement in NSF 363 not found in the joint IPEC–PQG guide involves
the use of risk management to ensure consistent excipient quality. For the purpose of the article, quality is taken to mean
consistent excipient composition and freedom from contamination. Risk assessment is defined in NSF 363 as "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" (1). (For details on conducting
and documenting risk assessments as required by the standard, please see the article "Conducting Risk Assessment in Support
of ANSI Excipient GMPs" in this issue.) The IPEC–PQG excipient GMP guide, as well as other IPEC guides, provide additional
resources for risk assessment. The purpose of the many risk assessments stipulated in NSF 363 is to identify risks to excipient
quality to assure control measures are commensurate with those risks (1). Several sections and clauses of the new standard
are explained below. Note that the term "Section" as used in this article refers to requirements that also contain enumerated
subordinate requirements referred to herein as "Clauses."
The first clause in NSF 363 to refer to risk is 4.2.1 (Quality Management System/ Documentation Requirements/General) where
the appropriate use of quality risk-management principles, defined as a systematic process for the assessment, control, communication,
and review of risks to the quality of the excipient across its life cycle, are to be used to evaluate changes to the quality
management system. Such changes include activities, operations, and processes that pose a risk to excipient quality. Also
in this clause is the requirement to document a risk assessment that justifies those other clauses of the standard that do
not apply to excipient manufacture and are thus not implemented.
Section 4.3 on Quality Management System/Change Control requires the implementation of risk assessment as a tool to determine
the impact of change involving the manufacture of the excipient. Here, IPEC–Americas has provided a guide as a basis for conducting
the risk assessment. Any change that may impact the consistent composition or performance of the excipient should be considered
potentially significant and the pharmaceutical customer should be notified as suggested in the IPEC guide for significant
change reporting (4).
Section 6 on Resource Management requires several risk assessments to identify the potential for contamination of the excipient.
For example:
- Clause 6.2.3 (Human Resources/Hygienic Practices) describes risk assessment to identify the potential for contamination of
the excipient by personnel and/or their activities. Where a risk to the excipient exists, the standard provides five measures
that may be taken to minimize said risk. The proposed control measures will be familiar to manufacturers who have implemented
excipient GMPs as noted in the IPEC–PQG guide (2).
- Clause 6.3.1 (Infrastructure/Buildings and Facilities) requires risk assessment to evaluate the threat to excipient contamination
posed by the buildings and facilities. This assessment is to consider the intended use of the excipient (i.e., oral, parenteral,
topical applications, etc.). The five aspects presented for consideration are discussed in the IPEC–PQG guide (2). The provision
to perform the risk assessment relative to the marketed intended use of the excipient links how the excipient is marketed
to the tolerance for risk of contamination from the manufacturing facility.
- Clause 6.3.3 (Utilities) stipulates evaluation of contamination risk from utilities but does not require linkage to the intended
use of the excipient.
- Section 6.4 on Work Environment requires the assessment of contamination risk from exposure to the work environment. This
risk assessment is linked to customer requirements and marketed use. The standard notes five control measures that are to
be considered when conducting this assessment for risk. The clauses under 6.4 require documentation of conformance to the
control measures implemented to address the risk to excipient quality noted in the assessment. However, Clause 6.4.4 (Pest
Control) provides for a risk assessment to identify the elements needed in a pest control program.
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