The International Pharmaceutical Excipients Council Federation, (IPEC Federation) announces the availability of a new guide: Incorporation of Pharmaceutical Excipients into Product Development using Quality-by-Design (QbD guide).
The primary goal of the QbD guide is to:
- introduce Quality-by-Design (QbD) and pharmaceutical formulation development concepts to excipient manufacturers and suppliers,
- explain how changes in pharmaceutical formulation practices, due to the introduction of QbD, impact excipient manufacturers and suppliers,
- help excipient manufacturers and suppliers understand what excipient users will likely require when applying QbD principles during product development, and
- explain to excipient users and regulatory agencies what may or may not be possible when considering the impact of excipient variability in the application of QbD principles during product development.
This Guide includes some recommendations related to the impact of excipient variability on drug product quality during development and how excipient variability can be managed in the control strategy. It contains useful explanations and suggestions for pharmaceutical excipient makers and users.
The Guide is applicable to excipient use throughout the pharmaceutical product development process using a Quality by Design (QbD) approach described by the International Council on Harmonization (ICH) Q8 as well as other applicable ICH Guidelines such as ICH Q9, Q10, Q11, and Q12.
Excipients are inherently variable as they are not controlled at an individual parameter level. For example, with polydispersity of particle size, molecular weight and/or chemical composition, which may be process/supplier dependent. Excipient variability may impact drug product robustness and performance, but not all causes of variability are well understood. Excipient manufacturers can control excipient variability only within the limits of their process capability and for which the processing equipment was designed and constructed. Process capability is a general statistical concept based on the ratio of the specification limits to the process variability. If the variability is the same as the specification range the process capability is one, with no room for error.
Excipients may function to aid processing, improve stability, aid in drug product administration, or influence its performance after patient administration (e.g. modified release). An excipient may perform more than one function in a formulation. Excipients may also have properties detrimental to the proper drug product performance. These potential disadvantages should be recognized (e.g. the effects of over blending magnesium stearate on dissolution and tablet hardness). Potentially detrimental effects should be part of the risk analysis performed in support of the development program.
Excipients may be offered in different grades for different routes of administration or to provide performance characteristics in the formulation. Grades are typically differentiated based on physical attributes, e.g. particle size or viscosity. However, in some cases, differentiation may be based on chemical differences, e.g. degree of substitution for hypromellose, degree of neutralization for sodium starch glycolate. Different grades may perform differently depending on application but not in all cases.
Excipient selection will be governed by route of administration, process and formulation type (from the QTPP). Excipients selected should neither adversely impact the API(s) (e.g. absence of any chemical interactions) or be adversely impacted by the process (e.g. no unacceptable degradation of the excipient due to the processing conditions). To this end, the excipient selection process should include excipient compatibility studies. A full discussion of excipient compatibility testing is beyond the scope of this Guide. However, it should be noted that excipient compatibility testing will only indicate those excipients to be avoided. Absence of problems on compatibility screening does not mean problems will not arise during drug product stability testing. Excipient incompatibilities may not be due to interaction with the labelled entity but with minor components, which might be source dependent.
Excluding too many excipients using aggressive screening conditions runs the risk of compromising finished product quality due to limited excipient choices, which are chemically compatible but are of less than optimal manufacturability. In order to avoid the time loss associated with stability failures, it is common for more than one preliminary formulation to be developed using different excipients (where possible). From knowledge of QTPP requirements and results from excipient compatibility testing, a list of potential excipients can be assembled. Final selection of preferred excipients will depend on:
- The nature of the API (dose, solubility and other physical properties), and
- The type of processing required to manufacture the dosage form.
Excipient choice will also likely be influenced by formulation scientist experience and company policies and procedures (e.g. platform formulations, preferred excipients, etc.). Even in the case of formulation development for a new drug candidate, it will be possible to leverage experience gained from other projects. Other useful excipient information sources and their application include: The Handbook of Pharmaceutical Excipients, USP-NF General Chapter <1059>, Ph. Eur. General Chapter 5.15 Functionality-related characteristics of excipients.
Once excipients are identified and preliminary formulations defined, formulation and process design can commence. Early formulation and process design objectives are two-fold:
- establish formulation composition, and
- establish processes necessary for formulation manufacture.
Once formulation and processes are defined at laboratory scale, the project can advance to achieve the enhanced understanding required of QbD development through the stages of:
- excipient risk assessment with respect to the formulation and processing,
- design of experiments (DoE),
- design space and control strategy identification, and
- scale-up.
Both excipient performance and excipient variability impact on CQAs should be a DoE output.