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Standardized Excipient GMP
The need for risk assessment
Documenting a risk assessment
Risk assessment consists of risk identification, risk analysis, and risk evaluation with the output forming the basis for
determining appropriate risk control. The sections of NSF 363 requiring risk assessment preload the process by defining the
scope or risk question, providing the nature of hazards to be considered, and pointing to risk controls that should be implemented.
The documentation necessary to demonstrate conformance to the standard should facilitate assessment of the results in terms
of the risks to be controlled, the reasoning and facts leading to the conclusions, understanding the risks that were considered,
and provides evidence that competent people equipped with adequate information followed a process that ensured a complete
assessment. The actual process for conducting a risk assessment may vary depending on the scope of the exercise but the documentation,
except where risk are either obvious or cannot possibly exist, should include (4):
As with all records, this documentation should be maintained and be available for audit as well as for use in periodic review of the assessment to ensure its continuing validity and suitability in the presence of new information. Including a summary and reference to the risk assessment reports in the quality manual helps describe the quality management system and aids in understanding the basis for controls included as part of the GMPs. To prevent the loss of a company's knowledge base, training and familiarization with the content of the risk-assessment documents should be included as part of succession planning, personnel development or job descriptions for key positions where appropriate.
Conducting a risk assessment
Conducting and documenting a risk assessment of the manufacturing process as directed in the NSF 363 Section 6 6.2.3 on Hygienic
Practices, 6.3.1 on Buildings and Facilities, 6.3.3 on Utilities, and 6.4 on Work Environment can be combined into a common
exercise and risk-assessment report. The report may begin with a summary of the risk-assessment results and supporting arguments.
The common supporting documentation would be included in the body or an appendix. Supporting documentation includes items
such as a description of the product with background information such as:
A clear statement supporting the excipients unique chemical and physical characteristics and any unique processing conditions or equipment will help justify the exclusion or inclusion of potential hazards. For example, a low pH can be used to justify the absence for specific controls to prevent microbiological contamination.
Documentation should demonstrate that the risk assessments required in NSF 363 Section 6 were performed for all unit operations. A matrix table can be included documenting the process flow, unit operations, and production and storage areas in rows with columns listing potential hazards and the justification for suitable controls (or controls being unnecessary) to protect against such risks as: contamination from personnel and/or their activities; contamination or mix-ups due to deficiencies in buildings or facilities; deterioration of excipient quality from contact with utilities; and contamination from exposure to the work environment. Reference to the supporting documentation (including a statement of how the process flow was verified for accuracy and inclusion of all operations) should accompany the table.
The risk-assessment process for determining significant change as a part of change control is discussed in the IPEC–Americas Significant Change Guide (5). A key point from this guide is that, "Any change by the manufacturer of an excipient that [may] alter an excipient physical or chemical property outside the limits of normal variability, or that is likely to alter the excipient performance in the dosage form is considered significant." The level of significance depends on the type of change and is evaluated according to seven criteria:
1. Will there be a change in the chemical properties of the excipient as a result of the change?
2. Will there be a change in the physical properties of the excipient as a result of the change?
3. Will there be a change in the impurity (composition) profile for the excipient as a result of the change?
4. Will there be a change in the functionality of the excipient as a result of the change?
5. Where applicable, will the moisture level changed?
6. Where applicable, will the bioburden changed?
7. Will there be a change in the origin of any raw materials or contact packaging?
These criteria can be used in a change-control program and should be referenced in the documentation to comply with NSF 363 Section 4.3 on Change Control.
The requirements to perform documented risk assessments in support of GMP controls are not entirely new. Section 8.3.2 of the IPEC–PQG GMP guide states (2): "An activity that is not a normal part of the manufacturing process (reworking) should only be conducted following a documented review of risk to excipient quality and approval by the quality unit. As appropriate, when performing the risk assessment, consideration should be given to....."
The procedures and controls associated with the IPEC–PQG GMPs have always been the output of risk- assessment exercises. NSF 363 takes this concept further to justify the thought process used to support and document controls are. Such documentation facilitates better understanding of GMP controls across excipient manufacture.
Dale Carter is chair of the International Pharmaceutical Excipient Council of the Americas (IPEC–Americas).
1. NSF Joint Committee, Draft Good Manufacturing Practices (GMP) for Pharmaceutical Excipients (2012).
2. IPEC–PQG, Joint IPEC–QG Good Manufacturing Practices Guide for Pharmaceutical Excipients (2006).
3. ICH, Q9 Quality Risk Management (2006).
4. IEC/ISO 31010, Section 5.5, Risk Management–Risk Assessment Techniques, 1.0 (2009-2011).
5. IPEC–Americas, Significant Change Guide for Bulk Pharmaceutical Excipients (2009).