Quality Issues for Multiregional Clinical-Trial Materials - Pharmaceutical Technology

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Quality Issues for Multiregional Clinical-Trial Materials
The authors examine risk management relating to the quality issues of clinical-trial materials and discuss areas that would benefit from additional consideration and harmonization.


Pharmaceutical Technology
Volume 35, Issue 10, pp. 124-132

Establishing specifications

The quality of a commercial pharmaceutical product is set by a well-designed, understood, and executed manufacturing process using high quality raw materials. This built-in quality is verified at release and on stability by random sampling and testing of critical product characteristics against established specifications containing specific acceptance criteria per characteristic. A natural aim is to control the quality of an investigational pharmaceutical product in a corresponding way, but this quality control is more challenging for several reasons.

In-vivo/in-vitro correlation . Ideally, one would like to know how a change in an in vitro characteristic influences a desirable or undesirable response in vivo. Using such knowledge, together with clinical judgment about where to draw the line between acceptable and unacceptable in vivo responses, it is fairly straightforward to develop appropriate control limits for in vitro characteristics. Unfortunately, these relations often are not fully understood even for products on the market, and the likelihood of being able to develop specifications using this approach is even more unlikely earlier in development.

Lack of information. For a product that is close to registration, several batches already have been studied in Phase I-III development. The recorded release and stability in vitro characteristics of successful earlier clinical batches, together with batches manufactured under similar conditions as the clinical batches, can be used as a basis for statistically established limits for different critical quality attributes (CQAs). However, the earlier in the development process, the more limited this pool of historical knowledge becomes, including that some of the CQAs might not have been recorded for early batches. This problem can happen by not realizing that an attribute was critical or by not having appropriate analytical methodology to make that evaluation.

Change to product. A basis for developing specifications based on previous knowledge is that earlier batches are representative of recently manufactured batches or at a minimum, it is understood how these batches relate to each other. During development, changes to raw materials, excipients, scale, packaging, and formulation occur frequently. Some data from previous batches, therefore, may be irrelevant and difficult to interpret.

Method development . Characterizing a batch of product requires sophisticated analytical methods, and as such, takes time to develop, optimize, and validate. Batches used during development often are characterized using different methods of increasing complexity and performance. Moreover, characterization of development batches and clinical-trial material may be done using different equipment in different laboratories. In vitro data for earlier batches may not be fully comparable to the corresponding data for later batches.

Subjectivity of regulatory authorities in different regions . Considering all issues associated in developing specifications during the early stages of development, it often comes down to collecting all data and scientific information available, judging the value of different pieces against each other, and making the best overall subjective judgment, taking all relevant regulatory guidance into account. The fact that a subjective element is involved can cause issues for releasing clinical-trial material in different regions as the guidelines and regulators' judgment may differ from the sponsor's. As a consequence, the tightest release specification over all regions often must be used. This need to simultaneously satisfy requirements in several regions in some cases lead to unreasonable situations, especially when the requirements are incompatible.


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