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suggested by ICH in Q8 (R2) Pharmaceutical Development is an eff ective guidance, which may enable a sponsor to build quality into a product starting from the early development phases. In summary, the approach suggested consists of several distinct stages:
1. Prospective identifi cation of quantitative QTPP 2. Use of QTPP to identify Critical Quality Attributes (CQA)
3. Experimentation to identify Critical Process Parameters (CPP) and Critical Material Attributes (CMA) that impact CQA. This experimentation is performed via risk assessment tools, statistical design of experiments (DOE), and other types of experimentation
4. Establish a Design Space
A QTPP is a “prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and effi cacy of the drug product.”7 An example QTPP for the topical product in this case study is shown in Table 1, with obvious details omitted. The justifi cation and verbiage should be tailored to the precise situation for the relevant product.
Determining a list of CQAs from a QTPP is a relatively straightforward exercise. CQAs, or even potential CQAs, are identifi ed to ensure product quality, safety, purity, and effi cacy. Each CQA listed should have some relationship to one or more elements from the QTPP. An example CQA table representing the topical product in this case study is shown in Table 2. The justifi cation and verbiage should likewise be tailored to the precise situation for the product in question.
Process Risk Assessment
Once an initial QTPP has been established and CQAs have been identifi ed, a sponsor has an increased chance of identifying and understanding CPPs and CMAs, particularly as relating to impact on drug product CQAs. For this discussion, CPPs and CMAs can be
Table 1. QTPP Example: Generic Topical Semi-Solid/Liquid Product QTPP Element
Target
Active ingredient Dosage form
Dosage form appearance and characteristics Route of administration Dosage strength Container closure system
Select target required for pharmaceutical equivalence
Justifi cation
Drug Product Quality Attributes
Appearance
Dose uniformity Assay Component X Component Y Related substances Viscosity Specifi c gravity Fill weight (if applicable)
Table 2. CQA Example: Generic Topical Semi-Solid/Liquid Product Target
Critical Justifi cation of Criticality
Select target required for pharmaceutical equivalence Yes or no Justify choice of
criticality
described as factors that have an eff ect in the response of a CQA or other drug product attribute. Two methods that are eff ective for identifying and minimizing the risk a certain factor may have on a drug product attribute are risk assessment and experimentation.
Much could be said regarding risk assessment. As it pertains to this case study, the focus is a process-centric risk assessment, relating only to the unit operations directly involved with the manufacture of a topical product. Many methodologies exist for assessing risk in diverse situations. The methodology adopted in this case study was through performing an Ishikawa diagram and Failure Mode, Eff ects and Criticality Analysis.
Process Map and Preliminary Evaluation
There are several purposes for performing a high-level process map and preliminary evaluation, such as an Ishikawa diagram, when developing a topical product. First, it allows core R&D members of the project team to understand the ANDA/NDA fi ling approach, the business strategy (such as where it will be marketed), and other general aspects that are helpful to know before designing experiments. A process engineer or formulation scientist would not necessarily design an early experiment for an ANDA product considered qualitatively and quantitatively the same as an approved brand product. Once this early exercise in process mapping is complete, an appropriate risk assessment approach can then be selected and performed for relevant unit operations.
The Ishikawa diagram shown in Figure 1 represents a typical diagram for the topical product in our case study discussion.
Failure Mode, Eff ects, and Criticality Analysis
Drug product quality attributes
Physical attributes Identifi cation Assay Dose uniformity Degradation products pH
Stability
At least 24-month shelf life at 25˚C
Appropriate justifi cation
For the product in this case study, a Failure Mode, Eff ects, and Criticality Analysis (FMECA) was selected to identify potential CPPs, potential failure modes, impact of failures, cause of failures, and rating risk. Much discussion and guidance exist in the pharmaceutical industry, as well as in other industries, for FMECA and other types of risk assessment, as appropriate for diff erent situations. Usually, FMECA functions best for established processes; however, it was used in this case due to the prior knowledge and experience gained with the similar products on the same equipment with formulations containing similar material attributes and risks. It is not in the scope of this paper to educate when
18 | | January/February 2015
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