Life Cycle and Quality by Design for Chromatographic Methods

A recent stimulus to the review process article by the United States Pharmacopoeia (USP) expert committee proposes a major change to the way regulated laboratories develop, validate, and control analytical procedures. Is this Quality by Design (QbD) for the chromatography laboratory?

In this column I want to focus on the heart of chromatographic analysis: The analytical method or procedure. Analytical procedure development, validation, and transfer are key parts of the traditional process that starts, if you're lucky, with defining what you want the method to do and ends up with the operational use of the procedure. In the middle is the stuff that should be done properly but usually is not, as evidenced by how poorly a method operates in routine use. This is typically because the method development and validation is performed by one group and the operation of the procedure is carried out by another. In many instances the two groups rarely talk to each other except when things go wrong — and blame each other for the problems. Of course, this never happens in your organization, does it?

In the Beginning .....

Validation of analytical procedures in the pharmaceutical industry was harmonized with the agreement of the International Conference on Harmonization (ICH) quality publications Q2A and B covering the text and methodology of validation of analytical procedures (1,2) in 1994 and 1996, respectively. These two publications were merged into a single revised document ICH Q2 (R1) in 2005 without any text being amended (3).

Robustness of an analytical procedure is defined in ICH Q2(R1) as:

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.

In the methodology section there is more information on the topic of robustness:

The evaluation of robustness should be considered during the development phase and depends on the type of procedure under study. It should show the reliability of an analysis with respect to deliberate variations in method parameters. If measurements are susceptible to variations in analytical conditions, the analytical conditions should be suitably controlled or a precautionary statement should be included in the procedure. One consequence of the evaluation of robustness should be that a series of system suitability parameters (for example, resolution test) is established to ensure that the validity of the analytical procedure is maintained whenever used (3).

This is the interesting part — for a document focused on the validation of analytical procedures we have the statement that robustness is actually a job to be performed during method development. How many people actually conduct robustness studies when under time pressures? However, it does say that robustness depends on the method but then goes on to mention some variables that could be considered when looking at high performance liquid chromatography (HPLC) procedures:

In the case of liquid chromatography, examples of typical variations are:

• Influence of variations of pH in a mobile phase;

• Influence of variations in mobile phase composition;

• Different columns (different lots and/or suppliers);

• Temperature;

• Flow rate (3).

Therefore, in my view, robustness should be undertaken for chromatographic methods, especially those involved in generating data for making critical decisions.

Guidance versus Regulation

The aim of ICH Q2(R1) was to provide guidance in the validation of any analytical procedure but this document has tended to take on the role of regulation. Don't think, just do it. ICH Q2(R1) has been incorporated into the United States Pharmacopoeia (USP) <1225> Validation of analytical procedures (4), for example. Note the chapter numbering: It is an informational (strong guidance) but not a mandatory general chapter (5).

In the current version of the USP there are three general chapters involved with analytical procedures:

• USP <1224> Transfer of analytical procedures (6);

• USP <1225> Validation of analytical procedures – this is ICH Q2(R1) (4);

• USP <1226> Verification of compendial procedures (7).

Interestingly, there is no mandatory chapter on the validation of analytical procedures, only guidance. The aim of all three chapters is to allow an analytical procedure to become operational in a regulated laboratory, as shown in Figure 1. However, there is no consideration of the importance of method development except where discussed in ICH Q2(R1) (as mentioned earlier). As you can see, method development remained outside of the control of pharmacopeias — despite its importance to the operational method.

Figure 1: Current USP general chapters on analytical procedures.

ICH Q10, Q9, and Q8: Pharma is Changing

Since the publication of ICH Q2(R1), the International Conference on Harmonization has issued three key documents that impact the way that the pharmaceutical industry operates. It changes the industry from a reactive to a proactive industry — or should do if these documents are implemented correctly. The three documents are:

• ICH Q10 on Pharmaceutical Quality Systems (8): This document describes a quality management system based on ISO 9001 but adapted for the pharmaceutical industry. A key change is the introduction of continual (not continuous as pharma is a regulated industry) improvement. In response to the publication of ICH Q10, EU GMP Chapters 1 (9) and 7 (10) have been issued to incorporate this new approach.

• ICH Q9: Quality Risk Management (11): This covers an overall approach to the assessment and management of risk in the pharmaceutical industry.

• ICH Q8(R2): Pharmaceutical Development (12): This is the most important document for the remainder of our discussion as it provides the framework for the approaches that the USP have taken for analytical procedure development, validation, and application.

To understand the approach taken in ICH Q8(R2) we have to step back in time and outside the pharmaceutical industry.

Quality by Design

A catchy phrase is it not? However, this is key to understanding the overall approach proposed by the USP paper. We need to consider what is Quality by Design (QbD)? It is a concept that was outlined first by Joseph Juran, a well-known expert and consultant in quality, who stated that "product features and failure rates are largely determined in planning for quality" (13). Put simply, quality must be designed into a product or a process but quality cannot be tested into it, that is, the analytical procedure. Therefore without adequate quality designed into the procedure during the development phase, there is not much point putting it into operation because it would not be very effective. This ineffectiveness would be typically evidenced in the operational use of the method with more out of specification (OOS) results when compared with a similar procedure where time and effort has been taken to understand how the chromatographic method works.

Back to the Future

Some of the key terms and definitions from ICH Q8(R2) are presented in Table 1. Although ICH Q8 is focused on the development of a pharmaceutical product, there are several topics that are pertinent to the development, validation, and operation of an analytical method such as the life cycle, design of experiments, or the robustness that form the basis of the USP proposed approach, which is why it is important to understand the role and terminology of ICH Q8. We will meet the modified versions of these terms as we look at the new USP approach.

Table 1: ICH Q8 key terms and definitions.

USP Stimulus Paper

In September's issue of Pharmacopoeial Forum (14), a USP expert committee published a stimulus to the revision process paper entitled: Lifecycle Management of Analytical Procedures: Method Development, Procedure Performance Qualification, and Procedure Performance Verification. This paper proposes a QbD approach to method development, validation, and operational use using a life cycle concept. The importance of this stimulus paper is that for the first time there would be a formal link between method development and method validation within a Pharmacopoeia. Just from the title of the paper we can see the adaption of two ICH Q8 terms: Life cycle management (Q8: Life cycle) and procedure performance verification (Q8: Continuous process verification). However, there are other terms that are a little strange such as procedure performance qualification, and just where is method validation in the title?

Rewriting USP General Chapters: In the stimulus to the revision process paper it is proposed that the three existing USP general chapters dealing with analytical procedure validation, verification, and transfer will be replaced by two general chapters. There will be a mandatory general chapter, <220>, dealing with the minimum requirements for method validation and an informational general chapter, <1220>, covering the whole life cycle of analytical procedure development, validation, use, and modification best practices.

Overview of the Analytical Procedure Life Cycle: Following on from the principle of ICH Q8, analytical procedure development, validation, use, and modification is a life cycle process with defined activities and deliverables. The outline of the three stage process is shown in Figure 2.

Figure 2: Proposed stages in the analytical procedure life cycle (14).

The first stage of the process is method development and understanding. The last word is important! This goes back to Juran: Quality is designed into an analytical procedure during the method development stage and not tested during the validation part of the life cycle. You need to therefore understand how the method works by knowing the key variables and how these influence the analysis. The KISS principle applies here. KISS? Keep it simple, stupid. Don't make an analysis more complex than it needs to be.

The second stage is procedure performance qualification — what? This is method validation under another name and has been taken from the US Food and Drug Administration's (FDA) updated guidance for industry on process validation (15). In essence, this stage demonstrates that the procedure or updated procedure is fit for the intended purpose of the assay.

The third stage is the procedure performance verification which checks how the method operates in actual use and remains under control. This can be achieved through routine monitoring and by charting performance using either Shewart or Cusum plots and reviewing variations in the performance of the procedure. If data indicate that the method is not functioning as expected, it should be investigated to see the cause of the variation. Outcomes of an investigation may be a change to the method which we will discuss later.

Method Development Stage in More Detail

As the aim of this column is to discuss quality by design, I want to look in more detail at the proposals for the method development stage. Within this stage there are a number of activities, as outlined in the USP stimulus paper (14).

Define the Analytical Target Profile (ATP) for the Procedure: The ATP is the interpretation of the Quality Target Product Profile under ICH Q8 for quality control and analytical development laboratories. An example of an ATP may be measuring analyte X in a specified matrix over the concentration range between A% and B% with a pre-defined uncertainty for the reportable result. The ATP may also define the matrix of the sample or any limits of detection if measuring impurities and in the presence of any potentially interfering compounds. In a move away from the typical ICH Q2 definitions, the USP stimulus paper talks about uncertainties, not precision and accuracy, therefore bringing the pharmaceutical industry into the ISO world. Defining the ATP is an important first step because it is the specification for the method against which the procedure will be validated. The first stage of quality by design is therefore to put a marker in the sand with the specification for the analytical procedure.

Select the Analytical Technique: Typically, an ATP would not define the analytical technique used but as this column is published in a chromatographic magazine it will be safe to assume that we're looking at a separation method of analysis, typically gas chromatography (GC) or HPLC. However, the responsible analyst should select an appropriate technique that is able to meet the ATP, and in doing so the ATP will be broken down into more detailed critical performance characteristics. Keep in mind that although I'm putting the emphasis on the chromatographic technique, there is also a sample preparation element of any analysis as the samples may be liquid, semi-solid, or solid.

Assessment and Management of Risk: Once the ATP has been defined and the analytical technique selected, the potential method can be designed in outline. To ensure that the method is reliable and meets the requirements in the ATP, a risk assessment should be undertaken — including of the overall procedure. The stimulus paper recommends the use of process mapping the stages of the procedure (as the method is equated to a process) or Ishikawa (fishbone) diagrams to identify potential variables that could impact on determining a reliable reportable result. One way of ranking these variables is a technique known as CNX (Control, Noise, Experimental). Each variable is ranked as a factor to be controlled (C), those that are noise (N), and the ones that need to examined experimentally (X). Naturally, for a regulated industry all these classifications should be justified and documented. Further risk analysis tools can be used to screen variables and reduce the number of experiments.

Design of Experiments (DoE) and Robustness Studies: Ideally, this part of the process will be automated using a software application that can control the chromatograph, acquire and process data, and then refine the experiment. In this phase of the work, variables that could have an impact on the procedure are identified and examined in detail to determine the design space of the method. Space does not permit me to go into detail on design of experiments but there are several papers published on the subject, for example, Nethercote and Ermer (16), Kormany et al. (17), and Rozet et al. (18).

Analytical Control Strategy: The strategy and justification for the approach to control the variables that influence the generation of reliable results and to reduce the overall uncertainty of the procedure are developed at this stage, such as:

• Size of sample to be taken from production;

• Size and number of aliquots for the procedure;

• Number of replicate determinations (for example, multiple preparations or multiple injections) and how these will be treated to calculate the reportable value;

• Impact of different chromatographic columns on selectivity and performance of the separation;

• Control of the pH value of mobile phase buffers;

• Should LC mobile phases be made up volumetrically or gravimetrically (especially if the percentage organic component of the mobile phase is a key variable)?

• Development of the system suitability test acceptance criteria to determine that the procedure is fit for purpose on the day of analysis.

The analytical control strategy can be updated with results from the other two stages of the procedure life cycle (stages 2 and 3 in Figure 2).

Knowledge Management: Throughout the method development process, data is generated and turned into information which is then transformed into knowledge about how the method operates and which are the key variables. This part of the process enables the understanding of the procedure and is vital to understanding why decisions were taken on the development.

The key message in the method development and understanding stage of the life cycle is to think before you act: Define what the procedure is required to measure and the matrix in which the determination is to be made. Then spend time looking at the design of the analytical method and conducting experiments to understand and control the key variables.

Documenting the Analytical Procedure: From all this work, the written description of the analytical procedure will be documented and authorized. It needs to have sufficient detail and rationale for the approach to allow a chromatographer unfamiliar with the development to set up and run the method. In light of the procedure performance qualification results, there may need to be an update of this document.

Procedure Performance Qualification

This is the verification of the performance of the analytical procedure (either a new one or a revised procedure) against the requirements of the ATP. This requires a pre-defined plan or protocol that outlines the work to be done to demonstrate that the method is fit for its intended use. One aspect of the protocol is how the data will be acquired, interpreted, and compared with pre-determined acceptance criteria explicitly stated in the ATP. The key elements from the previous stage's work are the control of key variables, understanding of the way the procedure works (derived from the design of experiments), the robustness of the method, and overall knowledge and understanding of the method.

The work should be performed by a user laboratory under actual conditions of use to comply with existing GMP regulations (19). If the method development stage has been performed well then this work should merely be a confirmation of that. However, there may be cases where further controls need to be put in place to ensure that reliable reportable results will be obtained, in which case the analytical control strategy will be updated.

When completed, the work will be documented in a report. This report will also outline the work to be done when establishing the procedure in another laboratory, called the local analytical control strategy (14).

Procedure Verification

To ensure that the analytical procedure remains in control during operational use in a laboratory, the main performance indicators should be trended routinely to allow proactive intervention when there is an unexpected trend or specification result. Some unexpected results may result from a variable that was not identified or studied adequately during the method development stage of the life cycle. Investigation of the problem should identify the root cause of the issue and corrective and preventative action plans developed to stop this occurring again.

In addition, there may be time when the analytical procedure can be changed to improve the overall performance of the method. In these cases the nature of the change indicates what actions should be taken. The stimulus paper defines five types of change:

• Change Type 1: Changes within the existing design space of the procedure are considered adjustments and no revalidation is required.

• Change Type 2: Changes outside of the proven range(s) require confirmation that the method works according to the ATP but that full redevelopment of the procedure is not required.

• Change Type 3: If the procedure is to be used in a different environment and are typically treated as a procedure transfer.

• Change Type 4: A change requiring a new procedure but the ATP remains the same. In these instances the method development stage is repeated.

• Change Type 5: Changes where the ATP is redefined require a full redevelopment and procedure performance qualification.

Now you can also see the importance of the method development stage of the life cycle and knowledge of the design space: you can reduce the amount of revalidation work when the procedure is used operationally.

Pros and Cons of Quality by Design

The aim of this USP stimulus paper (14) is to ensure that analytical procedures become more robust and this should result in fewer resources spent investigating OOS results and greater confidence in the reportable results generated. This approach should also result in quicker procedure performance qualification and procedure transfers, which in turn should allow the resources to be reinvested into the method development stage of the life cycle to ensure that procedures are truly robust. BUT.....

This approach requires that companies change their current approach and it requires an understanding in experimental design techniques, and also an investment in software and instrumentation (if not already available) to design and perform the experiments. However, this will be offset by using more robust methods with a known design space and with fewer OOS results to investigate.

Conclusions

In this column I have presented an overview of the USP stimulus to the revision process paper for life cycle management of analytical procedures (14). As I can only provide an overview of the approach, please read the original paper to understand all the specific detail and nuances.

An Anniversary

This column marks the 20th anniversary of Questions of Quality for LC•GC Europe. This column originally started when I was asked to write a series of four or five articles on data integrity. This rapidly developed into a regular column for the magazine, so much so that I never finished the original series on data integrity!

"Questions of Quality" editor Bob McDowall is Principal at McDowall Consulting, Bromley, Kent, UK. He is also a member of LC•GC Europe's Editorial Advisory Board. Direct correspondence about this column should be addressed to "Questions of Quality", LC•GC Europe, 4A Bridgegate Pavilion, Chester Business Park, Wrexham Road, Chester, CH4 9QH, UK, or e-mail the editor-in-chief, Alasdair Matheson, at amatheson@advanstar.com

References

(1) International Conference on Harmonization (ICH) Q2A Text on Validation of Analytical Procedures, (1994).

(2) International Conference on Harmonization (ICH) Q2A Guideline on Validation of Analytical Procedures: Methodology, (1996).

(3) International Conference on Harmonization (ICH) Q2(R1) Validation of Analytical Procedures: Text and Methodology, (2005).

(4) United States Pharmacopoeia, <1225> Validation of Analytical Procedures.

(5) United States Pharmacopoeia, General Notices.

(6) United States Pharmacopoeia, <1224> Transfer of Analytical Procedures.

(7) United States Pharmacopoeia, <1226> Verification of Compendial Procedures.

(8) International Conference on Harmonization (ICH) Q10 Pharmaceutical Quality Systems, (2008).

(9) EU Good Manufacturing Practice, Chapter 1 Pharmaceutical Quality System (2013).

(10) EU Good Manufacturing Practice, Chapter 7 Outsourcing (2013).

(11) International Conference on Harmonization (ICH) Q9 Quality Risk Management.

(12) International Conference on Harmonization (ICH) Q8 Pharmaceutical Development.

(13) J.M. Juran, Juran on Quality by Design: The New Steps for Planning Quality into Goods and Services (Free Press, New York, USA, 1992).

(14) G.P. Martin et al., Pharmacopoeial Forum39(5) (September–October 2013) (Available on-line at www.usp.org)

(15) FDA Guidance for Industry, Process Validation.

(16) P. Nethercote and J. Ermer, Pharmaceutical Technology36(10), 74–79 (2012).

(17) R. Kormany, H-J Reiger, and I. Molnar, LC•GC Europe Supplement10, 14–19 (2013).

(18) E. Rozet, P. Lebrun, B. Debrus, B. Boulanger, and P. Hubert, Trends in Analytical Chemistry42, 157–167 (2013).

(19) Current Good Manufacturing Practice for Finished Pharmaceutical Goods, 21 CFR clauses 211.194(a)(2) and 211.194(b).