Shakin E. S., Nikityuk V. G., Ph.D., Yarnykh Т. G., Professor

National University of Pharmacy, Ukraine (sh.e.s@list.ru)

Definition of cause-and-effect relationship as element of risk-based approach during the Pharmaceutical Development by the example of solid dosage forms

According to the principles of the PQS – Pharmaceutical Quality System key factors in ensuring quality of medicinal products are Knowledge Management and Quality Risk Management (QRM). The effectiveness of these factors, as well as PQS, depends on its application at all stages of the medicinal product lifecycle.

Knowledge about the product, its quality and technology of its production, as well as risks must be managed, starting with its pharmaceutical development and technology transfer and then throughout the time of commercial production and the presence of medicinal product in the market and prior to the termination of its production and medical applications. Use of scientific approaches to the pharmaceutical development and research of the product provides access to the full knowledge of the product, understanding the technological process of its receipt, possibility of developing risk management strategies during its subsequent serial industrial production. That is why the stage of the pharmaceutical development is of paramount importance not only for building in quality, safety and efficacy into a product, but also for further ensuring its quality during routine commercial batches production.

The following algorithm was offered by us during determining the procedures (methodologies) of pharmaceutical development process for the purposes of Pharmaceutical Quality System:

• obtaining the maximum amount of knowledge about the product (including dosage form, all its components, peculiarities and characteristics of the product components, intermediates, finished dosage forms, etc.);

• performing analysis and risk assessment on the basis of the obtained knowledge about the product, identifying ways of monitoring the process in order to control identified risks that could potentially adversely affect the quality and stability of the finished product;

• systematization of knowledge about the product and results of risk assessment by their formalization and documentation (including development of relevant protocols and reports).

To ensure the combination of knowledge management and quality risk management (as components of the offered algorithm) it is crucial to identify causal relationships between established and consistent indicators of quality (according to the pharmacopoeia requirements and specifications) and changing and measured parameters of each stage (operation) of the product's technological process (taking into account the properties of the dosage form and its composition). Such cause-and-effect relationships should be set both for finished product and intermediates, and for pharmacological and technological characteristics as well, which are generally not used to assess product quality during routine production of commercial lots, but are of paramount importance for the quality of the process flow and are often used to assess the technology transfer and process validation.

The determination of cause-and-effect relationships between process parameters and quality indicators is critical for assessing processes during routine industrial production of commercial batches. It is especially important to know and understand these causal relationships and their associated risks when a qualified person (QP) performs certification of product series, during production of which deviations of process conducting parameters were recorded, as well as during adverse trending identification.

One of the most complex products, in terms of determining cause-and-effect relationships between process parameters and quality are solid dosage forms – granules, capsules, tablets and their various modifications (sublingually tablets, effervescent tablets, coated tablets and etc.). This is connected with multistage processes of their production and large variability of parameters of the most of production technology stages and complex combination of factors influencing each process' operation. For example, when receiving a mixture of dry components factors affecting the mixture quality (homogeneity) may be both characteristics of each component, their intercompatibility and the process parameters – the sequence and loaded volume of the components being mixed, modes of time, speed, characteristics of environment for mixing, etc.

Example of "cause-effect" matrix for several parameters of some technological process operations for solid dosage forms production is given below in Table 1.

Significant number of adjustable and modified parameters give rise to the risk of quality deterioration of intermediate products and finished product, maintaining the stability of its quality throughout the established expire date. Knowledge of the causality of the production process and product quality allows to analyze the risks and provide scientifically based approaches for the regulation of variables of the manufacturing process of any medicinal products. The definition of causality is one of the elements of a risk-based approach to the pharmaceutical development.

Table 1

Example of the forms of "cause-effect" Matrix of some process parameters and quality parameters for some operations of technological process of solid dosage forms production

Stage of (operation / stages) of process	Process variable parameters	Characteristics of Intermediate and/or Bulk Product				Characteristics of Finished Good Product
		Intermediate Product Quality Parameters (according to specification)		Technological Characteristics of Intermediate Product		Finished Product Quality Parameters during series certification (according to release specification)			Finished Product Quality Parameters at the end of expire date (according to specification on expire date)
		Amount of moisture	… … …	Flowability	… …	Dissolubility	… … …	Quantitative measurement