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Analytical Validation within the Pharmaceutical Lifecycle

Phil Nethercote and Joachim Ermer

1.1 Development of Process and Analytical Validation Concepts

The concept of validation in the pharmaceutical industry was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers, and Bud Loftus, in the mid 1970s in order to improve the quality of pharmaceutical products [1]. Validation of processes is now a regulatory requirement and is described in general and specific terms in the FDA's Code of Federal Regulations - CFR21 parts 210 and 211 as well as in the EMA's Good Manufacturing Practices (GMP) Guide Annex 15. The 1987 FDA guide to process validation [2] defined validation as Establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes. While the first validation activities were focused on the processes involved in making pharmaceutical products, the concept of validation quickly spread to associated processes including the analytical methods used to test the products.

Regulatory guidance on how analytical methods should be validated has also existed for some time [3], however, it was not until the establishment of the International Conference on the Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) in 1990 that there was a forum for dialogue between regulatory authorities and industry and one of the first topics within the Quality section was analytical procedure validation. The ICH was very helpful in harmonizing terms and definitions [4a] as well as determining the basic requirements [4b]. Of course, due to the nature of the harmonization process, there were some compromises and inconsistencies.

Table 1.1 shows the ICH view on the required validation characteristics for the various types of analytical procedures.

Table 1.1 Validation characteristics normally evaluated for the different types of test procedures [4a] and the minimum number of determinations recommended [4b]

Yes/no, normally evaluated/not evaluated.

a Including dissolution, content/potency.

b Lack of specificity of one analytical procedure could be compensated by other supporting analytical procedure(s).

c Reproducibility not needed for submission.

d No number given in [1], logical conclusion.

e May be needed in some cases.

The recognition that the current pharmaceutical industry's manufacturing performance was not as state of the art as other industries [5-7] has resulted in unprecedented efforts over the last 15 years to modernize pharmaceutical development and manufacturing. In August 2002, the FDA announced a significant new initiative to enhance and modernize the regulation of pharmaceutical manufacturing and product quality, which resulted in the issue of a report in September 2004 entitled Pharmaceutical cGMPs for the 21st Century - A Risk Based Approach [8]. The aims of the initiative included encouraging industry to adopt modern quality management techniques and to implement risk-based approaches that focused both industry and regulatory attention on critical areas. The need to modernize the approach to quality management was also recognized by the ICH and resulted in a series of new ICH guidelines being produced. In November 2005, ICH Q8 [9] and Q9 [10] were issued to provide guidance on best practice in pharmaceutical development and risk management. These guidelines were followed by ICH Q10 [11] in June 2008, which described the key aspects of a modern pharmaceutical quality system and by ICH Q11 [12] in May 2012, which gave guidance on the development and manufacture of drug substances. In November 2008, an updated version of ICH Q8 was issued [13], which included an Annex that described the concept of quality by design (QbD), which was defined as A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.

In November 2007, Borman et al. [14] published a paper that recognized that the concepts of QbD that had been developed with an aim of enhancing the robustness of manufacturing processes could also have applicability to analytical procedures. The authors noted that the existing guidance on method validation as described by ICH Q2(R1) would need to be substantially rewritten to take account of the QbD risk-based approaches.

The FDA had also recognized that existing guidance on manufacturing process validation would need to be revised to better align with modern quality assurance concepts and the report Pharmaceutical cGMPs for the 21st Century - A Risk Based Approach included recommendations that the 1987 industry guideline on process validation be revised to include twenty-first century concepts, including risk management and adoption of a life-cycle approach. In January 2011, the FDA issued a new guidance for industry document entitled Process Validation: General Principles and Practices [15]. This guidance aligns process validation activities with a product life-cycle concept and with the ICH Q8, 9, and 10 guidelines. The life-cycle concept links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production. The FDA guidance revised the definition of process validation to the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product and recognized that process validation involves a series of activities taking place over the life cycle of the product and process. The guidance describes process validation activities in three stages:

1. Stage 1 - Process design: The commercial manufacturing process is defined during this stage on the basis of knowledge gained through development and scale-up activities.
2. Stage 2 - Process qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
3. Stage 3 - Continued process verification: Ongoing assurance is gained during routine production that the process remains in a state of control.

The guideline emphasized that understanding and controlling variation was key to ensuring that a process delivered a fit-for-purpose product. It suggested that manufacturers should

• Understand the sources of variation
• Detect the presence and degree of variation
• Understand the impact of variation on the process and ultimately on product attributes
• Control the variation in a manner commensurate with the risk it represents to the process and product.

and recognized that focusing exclusively on qualification efforts without also understanding the manufacturing process and associated variation may not lead to adequate assurance of quality. It also acknowledged that after establishing and confirming the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change.

1.2 Alignment between Process and Analytics: Three-Stage Approach

In 2010, Nethercote et al. [16] suggested that, just as process validation can benefit from a product life-cycle approach so also can analytical method validation. They suggested that there were a number of key factors that are important in a QbD/life-cycle approach. These include

• the importance of having predefined objectives;
• the need to understand the method, i.e. being able to explain the method performance as a function of the method input variables;
• the need to ensure that controls on method inputs are designed such that the method will deliver quality data consistently in all the intended environments in which it is used;
• the need to evaluate method performance from the method design stage throughout its life...