Method validation by phase of development: an acceptable analytical practice.
This article provides guidance for reasonable, minimally acceptable method validation practices and a foundation for assessing the risks and benefits associated with method validation programs, it is based on material developed from a PhRMA 2003 workshop about acceptable analytical practices. Additional articles from this workshop will cover dissolution of poorly soluble compounds, analytical method equivalency, and justification of specifications.
Validation of analytical methods is an essential but time-consuming activity for most analytical development laboratories in the pharmaceutical industry. As such, it is a topic of considerable interest in the literature and at pharmaceutical conferences (1-8). The examination of method validation practices is driven by several factors, including the desire to conduct the right science at the right time with optimal resources while maintaining the ability to rapidly implement change during the development process. Yet, many analytical scientists face a quandary: the more time is invested in a method, the more scientists are pressured to minimize changes to that method. This situation is counterproductive to the desired development process, in which one consciously and continuously adjusts to a growing technical and scientific database about the product being developed. Limiting early method validation to the essential elements helps maintain flexibility during the very fluid stages of early development.
Similar to the way scientists have various analytical methods requirements at different stages of the development lifecycle, method validation needs also adjust throughout the lifecycle. The objective during the late-development stages is to provide substantial information about whether a method can be run accurately and consistently under less-controlled circumstances (e.g., in several laboratories with a potentially wide array of instrumentation and equipment). The methods used in early development, however, generally do not face these challenges.
Requirements for method validation are clear for new drug applications (NDA) and many other worldwide marketing applications. These requirements are specified in documents from the International Conference on Harmonization (ICH) (9-10), regulatory agencies (11-12), and pharmacopeias (13-14). The validation guidelines applicable to early drug development phases, however, are not as specific. This lack of guidance, coupled with a generally conservative, risk-averse environment within the pharmaceutical industry can result in the application of more-stringent late-phase method validation requirements to products in early development.
Recognizing the dilemma many pharmaceutical companies face, the PhRMA Analytical Technical Group selected "method validation by phase of development" as a topic in need of an "acceptable analytical practice" or an industry-led guidance. The scope was limited to small-molecule drug substances and drug products in the clinical phase of development. Biopharmaceuticals, raw materials, intermediates, in-process controls, excipients, and bioanalytical and preclinical methods were excluded. A committee (which included the authors of this article) presented starting-point views on the topic at the September 2003 PhRMA workshop and the subject was debated by attendees. The group preferred a phased approach to method validation. Consensus could not be reached, however, regarding the specific details of what should be included, delayed, or eliminated when validating methods in early development.
This article provides guidance on reasonable, minimally acceptable method validation practices that are based on sound scientific principles and the experiences of the authors and workshop attendees. The article also provides some framework and foundation on which analytical scientists can assess the risks and benefits associated with their own method validation programs.
Purpose of analytical methods by phase of development
According to ICH and Food and Drug Administration guidances, the objective of method validation is to demonstrate that analytical procedures "are suitable for their intended purpose" (10-11). Therefore, to understand how a method should be validated at various phases of development, it is important to understand the analytical method's purpose at various developmental stages. The method's purpose should be linked to the clinical studies' purpose and the pharmaceutical purpose of the product being studied (see sidebar, Purpose of analytical method by phase of development").
The purposes of initial clinical trials is to determine a safe dosing range and key pharmacological data, typically in healthy human volunteers. As development continues, clinical studies are conducted on increasing numbers of patients to prove efficacy while continuing to study the drug's safety profile.
The purposes of pharmaceutical products in early phases is to deliver a known dose that is bioavailable. As product development continues, increasing emphasis is placed on identifying a stable, robust formulation from which multiple, bioequivalent lots can be manufactured and ultimately scaled-up, transferred, and controlled for commercial manufacture.
The purposes of initial analytical methods are to ensure potency, which can relate directly to the requirement of a known dose; to identify impurities (including degradation products) in the drug substance and product, which can relate to the drug's safety profile; and to help evaluate key drug characteristics such as crystal form, drug release, and drug uniformity because these properties can compromise bioavailability. As development continues, the purposes of the analytical methods mirror those of the pharmaceutical product. The methods should be stability-indicating and capable of measuring the effect of key manufacturing parameters to help ensure that the drug substance and product are consistent. Ultimately, in the subsequent development stages, the methods must be robust, cost effective, transferable, and of sufficient accuracy and precision for specification setting and stability assessment of marketed products.
Method validation plays a key role in ensuring analytical methods are suitable for these intended purposes. Validation studies conducted during early development should ensure that analytical methods are appropriately assessing the product's potency and safety. The number of validation studies required to provide this assurance vary and will be discussed in detail later in this article.
Benefits and risks of phased method validation
Although performing validation in phases has clear benefits, it also must be noted that potential risk is associated with this approach. The risk can be reduced significantly if the analytical scientist has a good understanding of the analytical methodology's limitations and a basic understanding of the chemistry or process used to produce the drug substance or product. With a strong technical base and the use of good method development practices (15), analytical scientists are much more likely to develop a suitable method for its intended purpose and limit the risk of delaying some method validation experiments. Ultimately, analytical scientists are responsible for the scientific defense of their methods; and thus, it is useful to review potential benefits and risks associated with performing method validation in phases.
Reasons for implementing a phased approach to method validation in early development include ongoing method development and optimization, a changing synthetic route for the drug substance, a changing formulation, and a high product- attrition rate. Given the desire to rapidly implement change in early development and the business driver to do more with less, a phased method validation approach can lead to benefits such as:
* fewer resources devoted to method validation;
* lower costs;
* more flexibility in early development;
* more time to focus on analytical science.
These benefits help analytical scientists focus more on the items that truly affect product quality and on the advancement of pharmaceutical medicines in general. It also is important that a phased approach to method validation not compromise product safety or increase other risks associated with the development of new drugs.
To help assess those risks, a two-step approach was taken at the September 2003 workshop. First, attendees were asked to share problems encountered later in development that could have been detected and avoided by more method validation in early development. Second, attendees were asked to numerically assess (on a 1 to 6 scale) the likelihood and the impact of the following predefined risks, using their experiences and their company practices for methods, method validation, specification setting, and/or product quality in general: