INTRODUCTION

The Food and Drug Administration (FDA) has developed a question-based review (QbR) for its Chemistry, Manufacturing, and Controls (CMC) evaluation of abbreviated new drug applications (ANDAs). QbR is a new quality assessment system that is focused on critical pharmaceutical quality attributes. It is a concrete and practical implementation of the underlying concepts and principles outlined by the FDA's Pharmaceutical current good manufacturing practices (CGMPs) for the 21st century and Quality by Design (QbD) initiatives.¹ The QbR was partially implemented in 2006 and is being fully implemented in 2007. This paper discusses (1) why QbR is necessary, (2) what QbR is, (3) what the impact of QbR is on ANDAs and their review, and (4) what the benefits of QbR are.

WHY IS QbR NEEDED?

The FDA Pharmaceutical CGMPs for the 21st Century initiative is meant to enhance and modernise the regulation of pharmaceutical manufacturing and product quality — to bring a 21st century focus to this critical FDA responsibility. The first impetus for developing QbR was the discrepancy between the objectives of FDA's Pharmaceutical CGMPs for the 21st Century and QbD initiatives, and old CMC review practices for ANDAs. The CGMP initiative¹ described a 'desired state' for pharmaceutical quality in which:

• product quality and performance are achieved and assured by design of effective and efficient manufacturing processes;
• product specifications are based on mechanistic understanding of how formulation and process factors impact product performance;
• manufacturers have the ability to affect continuous improvement and continuous 'real time' assurance of quality;
• regulatory policies and procedures are tailored to recognise the level of scientific knowledge supporting product applications, process validation, and process capability;
• risk-based regulations are commensurate with the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance, and the capability of process control strategies to prevent or mitigate the risk of producing a poor quality product.

Woodcock² proposed that in this desired state, manufacturers and the FDA would work together in the following manner to ensure quality:

• Manufacturers would have extensive knowledge about critical product and process parameters and quality attributes.
• Manufacturers would strive for continuous improvement.
• FDA would initially verify and subsequently audit drug products to ensure their quality.
• No manufacturing supplements would be needed (outside of formulation changes).

The main philosophy conveyed in the pharmaceutical CGMP regulations and in the modern quality system is 'quality should be built into the product, and testing alone cannot be relied on to ensure product quality.' Although the pharmaceutical quality in the old system is high, when one compares these goals of CGMP and QbD initiatives to the old CMC review practice, it becomes apparent that in the old CMC review system:

• Product quality and performance are predominantly ascertained by end product testing. The present review system places little or no scrutiny on how the design of an effective and efficient manufacturing process can ensure product quality. This also has the effect of not recognising the many complexities of process scale-up, particularly for complex dosage forms.
• Product specifications are derived empirically based on test data from one batch, which is often not at production scale. Mechanistic understanding also does not play a significant role in this process. This practice often has the effect of leading to 'overly conservative and often irrelevant specifications.'²
• The burdensome regulatory requirement of supplements imposed on applicants for executing minor and incremental changes to manufacturing processes and controls stifles the implementation of continuous improvement of manufacturing processes and strategies for the implementation of continuous 'real time' assurance of quality.
• All products are treated equally without regard to the risk to the consumer. This has the effect of placing too much review time on low-risk products and more importantly, takes away needed resources from the review of high-risk products. Hence, CMC review assessments of complex dosage forms (modified release products, topicals, and transdermals) as well as narrow therapeutic index (NTI) drugs differ only marginally from those of simple dosage forms (many immediate release solid oral products).

The second impetus for developing QbR was the ever increasing FDA Office of Generic Drugs (OGD) review workload. In the year 2002, OGD received a total of 361 ANDAs. This number increased to 449 in 2003, 563 in 2004, 781 in 2005, and 793 in 2006. For 2007, over 800 ANDAs are expected. As shown in Figure 1, the rate of increase in ANDA submissions has outpaced the rate of growth of the review resources. The increase in ANDA submissions will result in a concurrent increase in CMC supplements that are used for requests of post-approval changes. Extrapolation of current trends in the number of supplements indicates that, in the future, review of supplements could consume all FDA OGD resources. Therefore, it is essential to change our CMC review system to one that can more effectively utilise review resources.

Figure 1.

The numbers of ANDAs and FDA OGD employees from 2001 to 2006

Full figure and legend (34K)

WHAT IS QbR?

The goal of the CMC review of ANDAs is to ensure that the generic product is appropriately designed and pharmaceutically equivalent³ to the reference listed drug (RLD), and that applicants have methods and controls in place for the manufacture, processing, and packaging of a drug product that are adequate for assuring and preserving its identity, strength, quality, and purity. In this context, a high quality drug product is defined as a product free of contamination that reproducibly delivers the therapeutic benefit promised in the label to the consumer.⁴

The QbR has a series of questions for ANDA applicants that provide a general framework for a science and risk-based assessment of product quality. It contains the important scientific and regulatory review questions that will:

• guide FDA CMC reviewers to assess critical quality attributes, formulation, manufacturing process parameters and controls, to establish regulatory specifications relevant to product performance, and to prepare a consistent and comprehensive evaluation of the ANDA;
• help generic drug applicants to recognise issues FDA generally considers critical and direct them toward QbD;
• inform readers of the regulatory review how QbD was used in the ANDA and determine the level of risk associated with drug product and process design and understanding.

Appendix A lists all the FDA QbR questions for ANDAs.

WHAT IS THE IMPACT OF QbR ON ANDAs AND THEIR REVIEW?

The QbR development followed four underlying principles:

• quality built in by design, development, and manufacture; and confirmed by testing;
• risk-based approach to maximise economy of time, effort, and resources;
• preservation of the best practices of the OGD review system and organisation;
• best available science and open communication with stakeholders.

The QbR development process began with the identification of the essential aspects of the old review process. A comparison of the goals of the CGMP and QbD initiatives to the old review process revealed those key scientific areas for which a risk-based approach could be used. Questions were then developed that would appropriately assess the quality characteristics to ensure the required levels of safety and effectiveness. Table 1 highlights OGD's major activities in developing QbR and the communications we have had with our stakeholders, including the Generic Pharmaceutical Association (GPhA). Through this process, the questions in the QbR were refined and focused.

Table 1 - FDA QbR development and major communications with stakeholders.

Full table

There are two fundamental changes that impact all ANDAs and their reviews. The first of these changes recommends that all the QbR ANDAs include a QbD section as outlined in the International Conference on Harmonisation (ICH) Q8.⁵ Here QbD means designing and developing formulations and manufacturing processes to ensure predefined product quality objectives.⁶ QbD identifies characteristics that are critical to quality from a safety and efficacy perspective, translates them into the attributes that the drug product should possess, and establishes how the critical process parameters can be varied and controlled to consistently produce a drug product with the desired attributes. This is achieved by establishing a relationship between formulation and manufacturing process variables (including drug substance and excipient attributes and process parameters) and product quality, and identifying the sources of product variability. This knowledge is then used to implement flexible and robust manufacturing processes that can be adapted to produce a consistent product over time. Thus, QbD consists of the following elements:

• define target product quality profile;
• design and develop product and manufacturing processes;
• identify critical quality attributes, process parameters, and sources of variability;
• control manufacturing processes to produce consistent quality over time.

The second change recommends that, under the QbR system, all ANDAs be submitted in Common Technical Document (CTD) format⁷ and preferably in electronic CTD. Significantly, as required by the CTD, ANDAs should include a Quality Overall Summary (QOS) that addresses all the important scientific and regulatory QbR questions. The QOS should provide a consistently organised synopsis of the critical quality information for the drug product. FDA OGD has prepared QOS models for an immediate release and an extended release dosage form that are posted on the FDA OGD website.⁸ These models are illustrative examples of the types of information expected within an ANDA submission in the context of the QbD paradigm.

Figure 2 illustrates similarities and differences between the old and new QbR quality assessment systems. The most significant difference between the two systems is that in the old ANDA review system, little if any QbD information was submitted for evaluation by FDA quality reviewers while in the new QbR review system this information is a critical element of the overall quality assessment. Another important difference is that in the old review system, reviewers spent a considerable amount of time summarising the CMC information in the application, as a basis for providing a brief assessment of the quality information. In the new QbR ANDA system, quality reviewers use the applicant's QOS and adapt it for their review document. The use of the QbR-based QOS shifts the focus from extensive documentation to QbD-driven quality assessment.

Figure 2.

Similarities and differences between the old and new QbR quality assessment systems

Full figure and legend (43K)

WHAT ARE THE BENEFITS OF QbR?

FDA OGD's QbR framework provides a concrete implementation of FDA's Pharmaceutical CGMPs for the 21st Century and QbD initiatives and aids in the effective allocation of limited review resources. We identify four benefits of the new QbR quality assessment system:

QbD and performance-based specifications assure product quality

QbR enables two new review practices to ensure more relevant performance-based specifications. The first new practice is the product development presented in the QbD section of the application from which reviewers will learn how drug substance and formulation variables affect the performance and stability of the drug product. In early experience with QbR submissions, the reviewers have found that a better understanding of applicants' rationale for decisions reduces misunderstandings and the need to write deficiencies to obtain additional information. The second new practice is a critical comparison of the proposed generic drug product and RLD formulations. For complex dosage forms, this will ensure the approval of therapeutically equivalent products through a justification of the design of the proposed generic product. These new practices will contribute to the goal of establishing product specifications based on a mechanistic understanding of how formulation factors affect product performance.

With respect to manufacturing, the QbR includes a consideration of the process development report. From the process development report, reviewers learn how the applicant identifies the critical steps, determines critical process parameters, and establishes appropriate controls to the process, particularly for complex dosage forms. This process knowledge helps ensure that after process scale-up, the commercial manufacturing process will reliably produce a product that retains its critical quality attributes. Incorporating process development information into the QbR review will help OGD realise the goal that product quality and performance are achieved and assured by the design of effective and efficient manufacturing processes.

Risk-based assessment facilitates continuous improvement and reduces supplements

Based on the applicant's answers to the QbR questions on QbD, OGD reviewers perform a risk assessment that can potentially eliminate/downgrade the majority of CMC supplements. Products classified as low risk will be granted relaxed post-approval CMC supplement classifications. This will provide appropriate regulatory relief for supplements of minor and incremental changes to well understood manufacturing processes and in-process controls. Removing these burdensome regulatory requirements facilitates continuous improvement of manufacturing processes and encourages the use of innovative strategies for the implementation of continuous 'real time' assurance of quality. Supplement reduction is contingent upon the submission of a QbD report that demonstrates the applicant's product and process understanding. Such an approach takes into consideration the applicant's level of mechanistic understanding and introduces regulatory policies and procedures tailored to recognise the product and process knowledge.

Standardised review questions enhance the quality of CMC evaluation

The QbR identifies and incorporates the best practices of the current CMC review system and makes these practices common for the entire FDA OGD. As such, the new QbR questions will provide a standardised method of delivering a comprehensive CMC review. Many of the questions require critical analysis by reviewers and will encourage reviewers to link deficiencies sent to the applicant to scientifically justified quality concerns. QbR ensures that FDA quality reviewers are asking the right questions at the right time and in the most efficient manner.

The QbR also provides for an efficient review of low-risk products and an in-depth review of complex dosage forms and NTI drugs. The design of the questions allows for efficient answers in common cases, thereby enabling reviewers to spend little effort on low-risk elements of the review. Conversely, in the case of complex dosage forms and NTI drugs, the questions will encourage critical thinking and promote a mechanistic understanding of how formulation and manufacturing process variables affect pharmaceutical quality. This approach, which utilises the QbD report, implements the concept of risk-based regulatory scrutiny that considers both the degree of dosage form complexity and therapeutic index, and the level of scientific understanding of how formulation and manufacturing process factors affect product quality.

QbR-based QOS assists CMC review and reduces review time

The formalised QbR questions transparently expose the logic used in drug product quality assessment. This benefits applicants with clear directions to improve the quality of their submissions. Such transparency should result in more first-cycle approvals and minimise the inefficient and time-consuming process associated with multiple-cycle approvals, particularly in the case of simple drug products.

The QbR questions and expected format guide the preparation of the QOS part of the ICH CTD ANDAs. When applicants provide a QOS that directly provides answers to the QbR questions and is prepared in OGD's recommended format, this eliminates recopying information such as composition and specification tables, and reduces review time. This is a benefit for applicants, OGD, and the public.

CONCLUSION

The FDA OGD QbR is a concrete and practical implementation of the concepts and principles in the Pharmaceutical CGMPs for the 21st Century and QbD initiatives that enhances the evaluation of pharmaceutical quality for generic drug products in three respects:

1. By guiding reviewers to address the right questions, it enhances their critical analyses with a specific emphasis on QbD, and thus better enables them to recognise only those deficiencies in CMC information that affect product quality.
2. By encouraging applicants to implement QbD and share their pharmaceutical development knowledge, it promotes a mechanistic understanding of how formulation and manufacturing process factors affect pharmaceutical quality, and hence leads to more relevant specifications and manufacturing controls.
3. By containing a risk assessment section, it relates regulatory scrutiny to the level of scientific understanding and dosage form complexity, supporting innovation and continuous improvement. It is anticipated that this will significantly eliminate/downgrade⁹ CMC supplements, and thus free up scarce resources.

In conclusion, the QbR system focuses on important attributes of drug product quality, encourages regulatory reviewers to identify which key specifications and manufacturing controls are necessary to ensure product quality, and includes a risk assessment for the product. Under QbR, the CMC review provides more information about how the specifications connect to product quality, the risks associated with the manufacture and formulation of the product, and why FDA believes the product can be manufactured consistently.

Conflict of interest: The opinions expressed in this report by the authors do not necessarily reflect the views or policies of the Food and Drug Administration (FDA).

This article is a 'United States Government Work' paper as defined by the US Copyright Act.

References

References and Notes

1. U.S. Food and Drug Administration (2003) Final Report on Pharmaceutical cGMPs for the 21st Century — A Risk-Based Approach. U.S. Food and Drug Administration. http://www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.htm, accessed 6th April, 2005.
2. Woodcock, J. (2005). Pharmaceutical quality in the 21st century — An integrated systems approach. AAPS Workshop on Pharmaceutical Quality Assessment — A Science and Risk-Based CMC Approach in the 21st Century, 5–7 October.
3. Pharmaceutical equivalence requires that the generic drug product contain the 'same' active ingredient(s) as the RLD, that it be identical in strength, dosage form, route of administration, and that it meet compendial or other applicable standards of strength, quality, purity, and identity.
4. Woodcock, J. (2004). The concept of pharmaceutical quality. Am. Pharm. Rev. 7 (6), 10–15.
5. U.S. Food and Drug Administration (2006). Guidance for Industry, Q8 Pharmaceutical Development. Available from http://www.fda.gov/cber/gdlns/ichq8pharm.pdf.
6. Yu, L. X. (2006). Implementation of quality by design: question-based review. DIA Annual Meeting, Philadelphia, 18th–22nd June, 2006.
7. U.S. Food and Drug Administration (2001). Guidance for Industry, M4Q: The CTD — Quality. Available from http://www.fda.gov/Cder/guidance/4539q.pdf.
8. FDA Office of Generic Drugs (2006): www.fda.gov/cder/ogd/OGD_Model_Quality_Overall_Summary.pdf and www.fda.gov/cder/ogd/OGD_Model_QOS_IR_Product.pdf, accessed 15th January, 2007.
9. Downgrade means that the regulatory burden for implementing the proposed change will be reduced.

Appendices

Appendix A

QUESTIONS TO BE ANSWERED BY APPLICANTS FOR THE PREPARATION OF A QOS

Pharmaceutical Product Quality: Question-based Review for ANDAs

Definition: Simple Dosage Form — Either a solution or an IR solid oral dosage form

2.3 INTRODUCTION TO THE QUALITY OVERALL SUMMARY

Proprietary Name of Drug Product

Non-Proprietary Name of Drug Product

Non-Proprietary Name of Drug Substance

Company Name

Dosage Form

Strength(s)

Route of Administration

Proposed Indication(s)

2.3.S DRUG SUBSTANCE

2.3.S.1 General Information

What are the nomenclature, molecular structure, molecular formula, and molecular weight?

What are the physicochemical properties including physical description, pKa, polymorphism, aqueous solubility (as a function of pH), hygroscopicity, melting points, and partition coefficient?

2.3.S.2 Manufacture

Who manufactures the drug substance?

How do the manufacturing processes and controls ensure consistent production of drug substance?

2.3.S.3 Characterisation

How was the drug substance structure elucidated and characterised?

How were potential impurities identified and characterised?

2.3.S.4 Control of Drug Substance

What is the drug substance specification? Does it include all the critical drug substance attributes that affect the manufacturing and quality of the drug product?

For each test in the specification, is the analytical method(s) suitable for its intended use and, if necessary, validated? What is the justification for the acceptance criterion?

2.3.S.5 Reference Standards

How were the primary reference standards certified?

2.3.S.6 Container Closure System

What container closure system is used for packaging and storage of the drug substance?

2.3.S.7 Stability

What drug substance stability studies support the retest or expiration date and storage conditions for the drug substance?

2.3.P DRUG PRODUCT

2.3.P.1 Description and Composition

What are the components and composition of the final product? What is the function(s) of each excipient?

Does any excipient exceed the IIG limit for this route of administration?

Do the differences between this formulation and the RLD present potential concerns with respect to therapeutic equivalence?

2.3.P.2 Pharmaceutical Development

2.3.P.2.1 Components of the Product

2.3.P.2.1.1 Drug Substance
Which properties or physical chemical characteristics of the drug substance affect drug product development, manufacture, or performance?

2.3.P.2.1.2 Excipients
What evidence supports compatibility between the excipients and the drug substance?

2.3.P.2.2 Drug Product

What attributes should the drug product possess?

How was the drug product designed to have these attributes?

Were alternative formulations or mechanisms investigated?

How were the excipients and their grades selected?

How was the final formulation optimised?

2.3.P.2.3 Manufacturing Process Development

Why was the manufacturing process described in 2.3.P.3 selected for this drug product?

How are the manufacturing steps (unit operations) related to the drug product quality?

How were the critical process parameters identified, monitored, and/or controlled?

What is the scale-up experience with the unit operations in this process?

2.3.P.2.4 Container Closure System

What specific container closure attributes are necessary to ensure product performance?

2.3.P.3 Manufacture

(For All Products)

Who manufactures the drug product?

What are the unit operations in the drug product manufacturing process?

What is the reconciliation of the exhibit batch?

Does the batch formula accurately reflect the drug product composition? If not, what are the differences and the justifications?

What are the in-process tests and controls that ensure each step is successful?

(If Product is Not a Solution)

What is the difference in size between commercial scale and exhibit batch? Does the equipment use the same design and operating principles?

(If the Product is a NTI Drug or a Non-Simple Dosage Form)

In the proposed scale-up plan, what operating parameters will be adjusted to ensure the product meets all in-process and final product specifications?

What evidence supports the plan to scale up the process to commercial scale?

2.3.P.4 Control of Excipients

What are the specifications for the inactive ingredients and are they suitable for their intended function?

2.3.P.5 Control of Drug Product

What is the drug product specification? Does it include all the critical drug product attributes?

For each test in the specification, is the analytical method(s) suitable for its intended use and, if necessary, validated? What is the justification for the acceptance criterion?

2.3.P.6 Reference Standards and Materials

How were the primary reference standards certified?

2.3.P.7 Container Closure System

What container closure system(s) is proposed for packaging and storage of the drug product? Has the container closure system been qualified as safe for use with this dosage form?

2.3.P.8 Stability

What are the specifications for stability studies, including justification of acceptance criteria that differ from the drug product release specifications?

What drug product stability studies support the proposed shelf life and storage conditions?

What is the post-approval stability protocol?