Kevin J. McGlue

International Pharmaceutical Excipients Council (IPEC) Significant Change Guide

 was first published in 2000 as an IPEC Americas guidance to help excipient manufacturers determine the significance of change and the need for customer notification. It was revised again as an IPEC Americas guide in 2009 to incorporate recommendations made at that time by FDA. Prior to its original publication, there was no guidance for excipient manufacturers on how to manage and evaluate change. As a result, changes often occurred that may have had a significant effect on the application using the material, without that user having prior knowledge. This guidance, therefore, has been invaluable to the industry in providing a framework for the management, evaluation, and notification of excipient change. It is also often used as the reference point for change clauses in excipient supply agreements and quality agreements.

	In 2013, work began with a joint IPEC Americas/IPEC Europe team to carry out a substantial revision and modernization of the guide, and at the same time, bring global applicability by incorporating the concepts of risk assessment that are the backbone of other regulatory systems. The revision team was made up of four representatives from IPEC Europe and four from IPEC Americas. This representation also covered excipient manufacturers and pharmaceutical users from both ethical and generic drug companies. This revised guide (1) was published in late 2014.

Significant change and evaluation criteria


	Significant change is defined as “Any change that has the potential to alter an excipient’s physical, chemical, or microbiological property from the norm, and/or that may alter the excipient’s performance in the dosage form.” The new guide has a substantially revised layout with reformatted sections for easier readability. The “Types of Change Categories” have been heavily revised and now define change types as follows:

		Excipient specifications and test methods

		Raw materials used for the manufacture of the excipient

	The “Evaluation Criteria” have also been heavily revised and more clearly defined. These criteria are now described as follows:

		Impact on the physical properties of the excipient

		Impact on the chemical properties of the excipient

		Impact on the microbiological properties of the excipient

		Potential for impact on the intended performance of the excipient

		Impact on the composition profile of the excipient

		Change in the origin, type, or site of manufacture of any raw materials

		Change in the distribution of the excipient

		Change in the origin and/or type of contact or barrier packaging

		Change in the regulatory status of the excipient

		Change in the compliance to a compendia or other regulation.

	More detail has been included in the guide about how to make the evaluation within each criterion and the new concepts of “historical norms” and “intended and expected ranges” have been introduced. “Historical norms” are defined as the totality of the data set for the excipient and range values that have been obtained over time. These values include, but are not limited to, comparison of chemical, physical, and microbiological properties, composition profile, stability, and functional performance. These new concepts are extremely important, as often in the past, change may have been incorrectly considered as “not significant” simply because the post-change material remained “in specification” even though some of the parameters described may have shifted significantly from their previously “normal” values. It is now clear from the use of these concepts that this would be a poor interpretation.
	
	


	In line with current regulatory thinking, a “Risk Assessment” section has been added to introduce this concept for the determination of impact of change on quality and performance, and hence, guide the determination of significance of change. This section introduces guiding principles that are described later in this article to assist the user in taking a rational and scientifically justified approach to determining significance. It describes the types of testing and statistical analysis that may be applied and gives guidance on proper documentation of the outcome. It also acts as a “catch all” to help assessment of less usual changes that may not be specifically described in the defined change types elsewhere in the guide.
	
	The most noticeable revision though is the reduction of change risk levels from three to two. In previous versions, change risk was defined as level 1: minor change, level 2: might be significant, and level 3: always significant. This version was often seen as complicated, with many people unsure of just how to define and treat a level 2 change. It was believed that a more positive approach was needed, and the new guide now defines change as simply level 1: not significant and level 2: significant. This change allows for a much clearer distinction for when customer notification is required, as opposed to the previous guide where there was often confusion. This change also meets FDA requirements of a binary position that was first outlined to
	

 in a February 2006 letter responding to the proposed 

 chapter <1195>, based on the text of the original guide and published in the July-August 2005 edition of 

, Vol. 31, No. 4. The guide defines a simple four-step approach to handling change:

		Determination of change type. The guide defines nine change types as described earlier.

		Determination of the impact of change(s) on excipient quality and performance (including risk assessment by the supplier to determine significance). The guide outlines 11 change evaluation criteria as described earlier.

		Classification of the change as level 1: not significant or level 2: significant.

		Notification to customers (if required).


	As in the previous versions of the guide, certain types of change will always be “significant.” These changes include things such as change of manufacturing site, change of scale outside historical norms or validated ranges, changes of equipment that are not “replacements in kind,” among others.

	However, for those changes that need further assessment, instead of being classified as “might be significant” as was the case in the old guide, there is now guidance for how to assess these changes to a positive “significant” or “not significant” conclusion based on the principles of “risk assessment” and “comparison to historical norms.” This guidance is described in a new section, “Determination of Significance/Risk Assessment,” which outlines and describes eight guiding principles:

		Complexity of change(s) including cumulative effects

		Level of understanding of historical norms

		Ability to fully characterize the impact of change on excipient properties and performance, and the equivalency of pre- and post-change composition profile

		Ability to assess change in a trial batch and/or model product

		Level of understanding of users’ application(s) and use of

		Potential for predictability of impact on users’ application(s)

		Content of quality/technical agreements in place

		Level of understanding of credibility/reliability of supply

		chain partners in the case of supply chain/distribution

	When determining that a change is “not significant,” there must be justification that should include a detailed rationale supported by data and a defined conclusion that the change does not pose significant risk to the user.

	As with previous versions of the guide, the new 2014 guide includes decision-tree appendices to assist in the evaluation of change types. A new inclusion is an appendix containing two worked example case studies to help explain the principles of use of the guide. The first example describes the evaluation process undertaken by a polymer manufacturer when the conditions for the polymerization are changed with the purpose of improving control of the polymerization process. It describes the items that need evaluation and the risk-assessment process that should be undertaken to do so. The second example involves the manufacture of an excipient that is a proprietary blend of ingredients prepared by a continuous process involving a high temperature step. The manufacturer is increasing the process flow rate within the defined equipment capability (overall process design space) but outside current operating ranges. The worked example describes how to use risk-assessment principles to determine if the minor resulting product changes (improvement) constitute significance or not.

IPEC Significant Change Guide for Pharmaceutical Excipients

, 2014 Revision provides scientifically based mechanisms for assessing the risk and impact of various types of excipient changes that may occur. Previous versions have already been widely used by industry and regulators, and it is expected that this new version will become the global standard for the management of excipient change.

The IPEC Significant Change Guide for Pharmaceutical Excipients

 (Third Revision, 2014), accessed Jan. 22, 2014.


	Kevin J. McGlue is director, global quality assurance, Colorco

 When referring to this article, please cite it as K. J. McGlue, “The New 2014 IPEC Significant Change Guide,” 

Articles

A revision and modernization of the IPEC Significant Change Guide incorporates concepts of risk assessment.

Significant Changes in the 2014 IPEC Significant Change Guide

This article gives an overview of the concept and contents of the revised guidance and outlines how it has changed from the previous version.