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The authors present two concepts to improve robustness and facilitate continuous improvement in analytical methods. This article contain bonus online material.
The merits of applying quality by design (QbD) to pharmaceutical products and processes is a topic of significant mutual interest to both pharmaceutical manufacturers and regulatory agencies. The pharmaceutical industry is currently embracing QbD concepts to help improve the robustness of manufacturing processes and to facilitate continuous improvement strategies to shape and enhance product quality and manufacturing productivity. As such, both industry and regulators recognize the benefits of adopting a QbD approach to drug-product development and manufacture, with key concepts described in International Conference on Harmonization (ICH) guidelines Q8(R1) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System.
This paper has been constructed to address the parallel opportunities of improving robustness and facilitation of continuous improvement within the analytical-methods environment. The authors describe two concepts intended to stimulate further discussion within the industry and regulatory arenas.
One concept is that the steps, tools, and approaches developed for application of QbD to manufacturing processes (and described in ICH Q8, Q9, and Q10) have analogous application to the development and use of analytical methods. In other words, the approaches that have been developed for defining critical quality attributes (CQAs) and process parameters for a drug product are transferable and applicable to the design, development, implementation and life-cycle management of analytical methods.
Another concept presented in the paper is the use of an Analytical Target Profile (ATP). The incorporation of this concept in the development cycle is viewed as having the potential to reduce the burdens of postapproval variations. This would be accomplished by using the ATP as a new mechanism for describing analytical methods in regulatory submissions.
The potential benefits in adopting both concepts include:
Achieving these benefits will require significant changes by industry and regulatory agencies.
The authors provide an example of how to apply QbD concepts to analytical-method design, evaluation, control strategy definition, and life-cycle management and discuss a proposal for the concept of a regulatory submission for an analytical method developed through a QbD approach. Finally, the benefits of implementing these concepts, along with the implication of changing the paradigm, will be discussed.
The ultimate goal of this position paper is to highlight that QbD concepts and terminology can be applied to analytical methods and to suggest how adoption of a QbD approach might be used to develop more robust analytical methods and effective control systems. At the same time, these efforts aim to support more advanced regulatory approaches to change management.
The ideas and concepts conveyed in this paper are the outcome of a joint effort of the Pharmaceutical Research and Manufacturers of America (PhRMA) Analytical Technical Group (ATG) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) Analytical Design Space (ADS) topic team. Although these teams acknowledge that methods developed and validated through traditional approaches are suitable for their intended use and produce reliable data, it is their strong belief that the approaches described in this paper will lead to more robust methods. In addition, by implementing these approaches, there is the potential to substantially reduce the postapproval variations burden. The content of this paper is intended to act as a stimulus for further discussion and engagement with regulatory authorities and pharmacopeial bodies worldwide regarding the concept of QbD as it applies to analytical methods.
The Analytical Target Profile
QbD, as defined in ICH Q8(R1), is a systematic approach to pharmaceutical development beginning with predefined objectives that emphasize product and process understanding as well as product and process control. Arguably, to date, industry has focused on product-development activities with little emphasis on defining tools for the analytical chemist. The development of appropriate analytical methods is, however, fundamental to establishing product and process control (in a traditional- or a QbD-development approach) and the overall control strategy (see Table I).
Table I*: Comparison of traditional and quality-by-design (QbD) approaches to a pharmaceutical process.
In many ways, the development and documentation of method requirements has not changed in decades. The EFPIA/PhRMA working group is now introducing an approach that describes a way to capture the predefined performance requirements of analytical methods—that is the ATP.
The ATP is a tool that can be used in the establishment of any analytical methodology, whether intended as a component of a QbD approach or in the development approaches that have been used historically. In either case, the ATP can be used to describe the method requirements needed to adequately measure the defined CQAs of the drug product. An ATP would be developed for each method used in the overall product control strategy; it would define what the method has to measure and to what level the measurement is required (i.e., performance level characteristics—such as precision, accuracy, working range, sensitivity—and the associated performance criteria). It is this ATP that would drive the design and development of appropriate analytical methods and it is proposed that the ATP could also form the basis of a regulatory submission.
An ATP would be defined in the same way that the process control strategy is defined and in the same manner CQAs requiring measurement are identified. It is important that the analytical-method's performance characteristics and criteria are clearly defined in conjunction with the ATP. Currently, the method-performance characteristics requiring validation would be followed according to the guidelines described in ICH Q2(R1) Validation of Analytical Procedures: Text and Methodology. In the future, these guidelines would be considered in conjunction with the specific nature and requirements of the method as defined in the ATP. These criteria can be derived from a knowledge of how the method will be used—over what range of analyte concentrations it will be used, what precision is required to ensure the analyst can confidently determine whether a material meets specification, and so forth. It is clear that some methods (e.g., continuous on-line quantitative spectroscopic methods) will not be amenable to validation approaches strictly adhering to the current ICH Q2(R1) guideline. As such approaches evolve, the methodology to assess suitability for intended use will need to be developed.
Applying QbD to analytical methods
Having defined the ATP, the principles of QbD can be used during method development and evaluation to ensure that an appropriate analytical-measurement technology is selected and that the analytical method is designed to meet its intended performance requirements. In addition, the assessment of the methodology will need to evolve as the program develops.
There are, of course, different approaches companies may wish to adopt in ensuring the analytical method is developed to meet its intended performance requirements (defined by the ATP), including the traditional approach followed by the industry today. An alternative approach might be more structured and fully embrace the concepts of QbD. For example, ICH Q8(R), Step 2, defines "a systematic approach to development that begins with predefined objectives [in this case the ATP] and emphasizes product and process understanding and process control, based on sound science and quality risk management."
The establishment of an ATP is in complete alignment with ICH Q10, that is, the application of a holistic quality-management system. Although additional information is gained when using an ATP combined with a QbD approach, the ATP can also facilitate the establishment of some of the recommendations of ICH Q10 when used with a traditional approach. The application of the ATP provides confidence that future method changes and improvements may be introduced with the full knowledge of their likely effect on the product (see Figure 1).
Figure 1: Components of application of quality by design (QbD) to analytical methods (Courtesy of Authors).
The following case study illustrates how the ATP concept affords the opportunity for continuous improvements in analytical methods and technologies without the need for prior regulatory approval. In addition, the case study demonstrates the potential impact on different testing sites and how they can benefit from a QbD approach by being flexible enough to accommodate site-specific business and operational preferences with respect to adopted measurement technology.
Hypothetical ATP case study
In this example, a specific impurity "X" has been identified as a critical material attribute (CMA) of a drug substance (input variable) that must be controlled to a level of not more than 1.0% as part of the definition of the design space for the drug product. Through knowledge gained during the design and development phases, it has been determined that it is useful for the process chemists to be able to accurately measure the level of this specific impurity down to a level of 0.1% with a relative standard deviation (RSD) of not more than 10% across the range of measurements. This information essentially forms the ATP.
By sharing this knowledge with the process-development and analytical scientists during the initial phases of development, a classical high-performance liquid chromatography (HPLC) method (Method 1) was developed, optimized, and validated to measure the level of Impurity X in the drug substance. Method 1 was used to support registration-stability studies and was successfully transferred under appropriate quality oversight and change-management systems to the quality-control laboratories that support commercial manufacturing of the drug substance and drug product.
An improved method. During the knowledge-transfer phase of the process, an opportunity for improved control of Impurity X was identified at the drug-substance manufacturing site (Site A) and the technical-services scientists requested a shorter turnaround time for the analytical results. Analytical scientists took this request for improvement into consideration and were able to design and develop a fast-LC (liquid chromatography) method using recent improvements in efficiencies of chromatographic systems. Method 2 was then designed, developed, and validated to meet the original ATP as stated in the regulatory submission and met the reduced cycle-time requirements of the process engineers and chemists. The new method would allow for improvement in the control of the manufacturing process as well. As with Method 1, Method 2 was implemented with the appropriate quality oversight under change management at Site A.
In addition, Method 2 was successfully transferred to Site B, where the newer technology equipment and chromatographic columns were readily available. Unlike Site A, the drug-product testing laboratory at Site B was not required to meet a faster cycle time. The reduction in assay time, however, freed up analyst and instrument time. Also, the use of higher efficiency LC systems resulted in less solvent consumption and less waste.
A "real-time" method. There is continued emphasis on process improvement in the typical life cycle of a drug substance. Improvements in process control can often be achieved by using on-line or at-line technologies, also known as process analytical technology (PAT). Site A was interested in pursuing this opportunity for the real-time measurement of Impurity X.
Once again, process engineers and chemists worked together with the analytical scientists, this time to investigate the use of Raman spectroscopy for the measurement of Impurity X in the drug substance as it was off-loaded from the dryer. Raman spectroscopy has been shown to be amenable to measurement of analytes "in" or "at" the processing line so further efforts were pursued to determine feasibility.
Site A was able to implement Method 3, an at-line Raman method, after completion of appropriate method development, validation, and change-management processes and procedures. An at-line Raman method could now be used to measure the level of Impurity X in the drug substance at Site A. Meanwhile Site B used the fast-LC Method 2 to confirm the level of Impurity X in the drug substance before manufacturing the final drug product.
Three very different analytical methods were shown to be capable of meeting the ATP set forth in the regulatory submission document, each one with the added benefit of meeting the very specific needs of the particular business unit being supported by the testing site.
A company similar to the one in the case study presented above that operates a pharmaceutical quality system in line with ICH Q10 and adopts a structured risk-assessment process to ensure any new method's suitability for use, should not be required to seek prior regulatory approval before implementing any of the three methods described because there was no change to the ATP contained in the regulatory submission. However, a change to the ATP could be handled in an annual product update or similar communication mechanism to the competent authority. All three methods (1—classical HPLC, 2—fast LC, 3—Raman) would have appropriate documentation in place to be reviewed upon preapproval or routine inspections and all three were designed, developed, validated, and implemented under well-founded quality and change-management systems. In addition, documentation would be available to share with a regulatory agency's laboratories if needed. The methods would be appropriate for use as an example in their laboratories for measurement of Impurity X in the drug substance.
Implications and benefits
From an industry perspective, development of analytical methodology aligned with an ATP approach will require changes, including the way enhanced knowledge and understanding of the methods and their linkage to CQAs and CMAs are captured. The ATP approach described above will also require adjustment to the manner in which analytical methods and their assessment are presented in regulatory filings.
Traditional views on analytical-method validation and analytical method transfer may also need to be adjusted or supplemented with more focus on variation management and continuous verification throughout the method life cycle. A summary of the key changes required to support a QbD approach to analytical- method development, evaluation and improvement is provided in Table I.
In the desired future state for a QbD-approach based submission, the focus of the analytical-measurement portion of the submission will be to demonstrate a thorough understanding of the requirements for measuring the drug substance/product and process CQAs used to define the design space of the process and describe how this understanding is translated into an ATP. The commitment the company makes will be to ensure that any method used to measure CQAs and quality assurance meets the registered ATP, but there shall be no commitment to follow the detailed analytical methodology provided as an example.
All analytical methods used will be available for regulatory review during preapproval and routine inspections. Indeed, inspectable documentation could include the detailed analytical-methodology design, evaluation, and control strategy as an example method that can be used to meet the ATP and the approach the company takes to demonstrate the suitability of the method. Further, the example method could be used by the authority's testing laboratories to confirm that a drug product meets a particular CQA, as specified in the regulatory submission, or to ensure authentication of a suspected counterfeit drug product.
As the ATP approach evolves, additional focus will be required to define the evaluation/assessment (validation) of the analytical methods developed. Many of the methods developed may be aligned with ICH Q2(R1). Other methods, however, may require new approaches to ensure suitability. In addition, as multiple methods (alternative methods) may be in use and may be available for regulatory authorities, tools to compare the performance of these alternative methods with others and ensure equivalency will need to be established.
The investments required are significant on the part of industry and regulatory agencies. However, the potential returns from adopting an analytical QbD paradigm, as described, are even more significant.
The current situation
The barriers to successful implementation of an analytical QbD approach are no different than those facing other QbD initiatives. The authors have discussed the need to shift the paradigm of regulatory submissions away from traditional information-rich documents, to scientifically-sound, knowledge-rich documents that clearly and concisely define the product and process design space as well as the CQAs of the drug product. Common terminology and concepts will need to be agreed upon and adopted on a global basis, and training and education of resources in industry and within regulatory agencies may be needed to ensure success. In addition, although the examples discussed in this paper have focused on methods for new products and processes, the concepts and benefits are equally applicable to existing marketed products.
The foundation to overcome these barriers has been established. Regulatory agency and industry representatives around the globe are currently engaged in productive dialogue regarding QbD approaches for pharmaceutical processes and products. In fact, external authorities in the industry are already considering evidence of QbD approaches applied to analytical methodology. See, for example, the 2008 Stimuli article from the USP Ad Hoc Advisory Panel on Inorganic Impurities and Heavy Metals and USP Staff on the proposal of a new USP General Chapter for the control of inorganic impurities in drug and dietary supplement articles intended for use in humans (2). In this proposed General Chapter, a performance-based approach has been introduced for selection of appropriate analytical technology that would essentially provide flexibility in choice of technology so long as the technique can meet the requisite accuracy (trueness and uncertainty) and established sensitivity and specificity.
It would, therefore, be short-sighted to overlook the opportunity to further expand the application of these concepts to analytical measurements and methods. There is too much to be gained from the application of these concepts for all parties involved—the patient, the pharmaceutical manufacturer, and the regulatory agency.
As noted, this position paper is intended to act as a stimulus for further discussion and engagement regarding the application of the QbD concept to analytical methods. Several steps are proposed to support further clarification and adoption of these concepts. These include:
1. P. Borman et al., Pharm. Technol., 31 (12), 142–152 (2007).
2. USP Ad Hoc Advisory Panel on Inorganic Impurities and Heavy Metals, Stimuli paper (2008), www.usp.org/pdf/EN/USPNF/2008-04-0InorganicImpuritiesStim.pdf.
Moving from the Analytical Target Profile (ATP) to robust and rugged analytical measurements.
An example of an approach to method development and evaluation that aligns with the concepts proposed in Figure 1 of this paper is described below.
Method design: Once the method requirements are thoroughly understood and the ATP is defined, an appropriate analytical method can be designed to achieve the desired measurement of the material, process, or product attribute. Information to be considered during the analytical-method design phase might include: prior experience with similar measurements or matrices, regional or geographic limitations and/or availability of reagents, supplies, or specific technologies in laboratories that will be conducting the testing and cycle-time requirements to support process operations.
Having identified a suitable analytical method, the factors that can influence the performance of an analytical method can be mapped against the unit operations within the method. The method design phase then continues by systematically evaluating the impact of each factor. This assessment can be performed either through the utilization of appropriate risk assessment tools or based on experience (prior knowledge) or a combination of both.
Method evaluation: The next step is the method evaluation phase where the factors that have been identified as having a potential impact on method performance are evaluated (e.g., through structured multivariate design-of-experiment investigations or appropriate screening experiments). A preliminary assessment of the potential impact of the factors may also be explored using a robustness screening design (e.g., a Plackett-Burman fractional factorial experiment).
Method control strategy: The outcome of the method evaluation phase leads to the final definition of the operating parameters and parameter ranges required to ensure performance of the analytical method. These set points and operating ranges are specified and a change-control process is implemented to ensure control of the established method parameters. A diagram proposing how analytical method factors might be evaluated and their relationship to ruggedness and robustness testing is shown in Figure 2.
Figure 2: Diagram proposing how analytical method factors might be evaluated and their relationship to robustness and ruggedness testing. Adapted from Borman et al (1).
Continuous improvement/life-cycle knowledge management: To get the most out of a QbD method-development process, it is important to consider how the information generated (e.g., factors considered, risk-assessment tools used to select variables for experimental study, and outcomes from each study) will be captured in an appropriate knowledge repository. Once this repository is established, the impact of any proposed future changes to the analytical method may be assessed. In this assessment, the prior knowledge gained during development is evaluated relative to the proposed changes to the method, forming a basis for a follow-on risk assessment to determine whether the changes are justified and within the control strategy established for the product. The critical assessment is whether or not the proposed change still meets the requirements established in the ATP. Additionally, as appropriate, method equivalency experiments may be included to further justify the proposed changes.
The combination of a structured, rigorous scientific and statistically sound approach to method development and evaluation, combined with a robust quality management system based on ICH Q10 Pharmaceutical Quality System, ensures that changes to methods are appropriately evaluated before implementation and can provide the basis for enhanced flexibility to introduce change without excessive regulatory oversight.
Appendix II: Glossary of terms and definitions
Analytical Target Profile (ATP): The combination of all method performance criteria that direct the method development process. An ATP would be developed for each of the attributes defined in the control strategy and defines what the method has to measure (i.e., acceptance criteria) and to what level the measurement is required (i.e. performance level characteristics: e.g. precision, accuracy, working range, sensitivity and the associated performance criterion). For example, the ATP for a specific method might be that it is specific for impurity X, can quantify X at levels of 0.05% or above with a precision of 1.0% relative standard deviation (RSD) or better, and an accuracy of not more than 2.0 % bias.
Method control strategy: The controls on analytical factors and parameters, and monitors (e.g., system suitability checks) that ensure analytical method performance criteria are met.
Analytical method performance characteristics: The elements of method performance that must be measured to assess whether a method is capable of producing data that is suitable for its intended purpose (e.g., selectivity, precision, accuracy, limit of quantification_.
Analytical method performance criteria: The targets for each analytical method performance characteristic that must be met if the method is to be considered to be capable of producing data that is suitable for its intended purpose. For example: an RSD of no more than 1.0%, a bias of not more than 2.0%, and a limit of quantitation of no less than 0.05%.
Method factor: Any factor that forms part of the method definition.
Noise factor: Any factor that cannot be controlled or that is allowed to vary randomly from a specified population (e.g., operator, reagent supplier).
Method parameter: Any factor that can be varied continuously or can be specified at controllable unique levels. For example: A flow rate would be an example of a factor that can be varied continuously whereas GC liner type or column type would be examples of parameters that can be specified at controllable unique levels.
Critical quality attribute: A quality attribute for which there is a substantial risk of impacting the safety or efficacy of a product. The safety and efficacy can be achieved by demonstrating measurable control of the quality attribute (i.e., product specification, intermediate specification, in-process tests or process controls).
Method robustness: The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage (ICH Q2 Validation of Analytical Procedures: Text and Methodology). The definition of robustness using a QbD approach adapted from the guideline would be: The robustness of an analytical method is defined as the capacity of its analytical method performance characteristics to remain unaffected by small variations in analytical method parameters that the method is likely to encounter under normal conditions of use.
Method ruggedness: The ruggedness of an analytical method is the degree of reproducibility of test results obtained by the analysis of the same sample under a variety of normal test conditions such as different laboratories, different analysts, different instruments, different lots of reagents, different elapsed assay times, different assay temperatures, different days, and so forth (i.e, US Pharmacopeia). The definition of ruggedness using a QbD approach would then be: The ruggedness of an analytical method is defined as the capacity of a method to remain unaffected by variations due to noise factors that the method is likely to encounter under normal conditions. Ruggedness may be assessed through structured experimentation such as intermediate precision studies.
Measurement systems analysis: A specially designed experiment that seeks to identify the components of variation in the measurement.
Quality attribute: A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.
The authors would like to acknowledge the EFPIA ADS topic team, the PhRMA ATG—and extended team members, the International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS)—for their sharing and consultation on concepts, and EFPIA's Product Development and CMC (EFPIA PDC) ad hoc group for its sharing and consultation on concepts.
Mark Schweitzer* is global director of global analytical R&D at Abbott Laboratories in Abbott Park, IL, and a member of the Pharmaceutical Research and Manufacturers of America (PhRMA) Analytical Technical Group (ATG). Matthias Pohl is head of TechOps QA at Novartis in Basel, Switzerland, and a member of the European Federation of Pharmaceutical Industries and Associations (EFPIA) Analytical Design Space (ADS) topic team. Melissa Hanna-Brown is with Pfizer. Phil Nethercote and Phil Borman are with GlaxoSmithKline. Gordon Hansen is with Boehringer-Ingelheim. Kevin Smith is with Cephalon, and Jaqueline Larew is with Eli Lilly. Additional contributors to the article include John Carolan (Merck, Sharp & Dohme), Joachim Ermer (sanofi-aventis), Pat Faulkner (Pfizer), Christof Finkler (Roche), Imogen Gill (Pfizer), Oliver Grosche (Novartis), Jörg Hoffmann (Merck KGaA), Alexander Lenhart (Abbott Laboratories), Andy Rignall (AstraZeneca), Torsten Sokoliess (Boehringer Ingelheim), and Guido Wegener (Bayer Healthcare).
This paper is coauthored by members of the PhRMA ATG and the EFPIA ADS topic team. This paper is not officially sponsored or endordsed by PhRMA or EFPIA. *Correspondence can be addressed to Mark Schweitzer at firstname.lastname@example.org