Abstract
Abstract
Question-based Review (QbR) is a format proposed by United States Food and Drug Administration (US FDA) enhancing the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use's Common Technical Document (ICH CTD) format to streamline the submission process. It is a question–answer format applied to Quality Overall Summary section of the submission. The format includes putting up questions under every section, so the applicant can submit precise and accurate data for approval of the respective application. The QbR format can be applied to NDA, ANDA, and Type II DMF applications. The companion document available with Manual of Policy and Procedures 5015.10 (MaPP 5015.10) allows the reviewer to inspect the critical information in the data provided. It encourages applicants to encompass Quality by Design (QbD) in their development process. QbR gives a structure through which the data collected by applying QbD can be presented. For effective application of QbR format, the submission should be backed with thorough scientific knowledge, risk assessment data, and data integrity. The questions asked compel the applicant to provide justification for the various decisions made in the development phase. Also, questions regarding quality target product profile, critical quality attributes, critical material attributes, critical process parameters and design of experiment are covered under the QbR format. MaPP 5015.10 finalized by US FDA in 2014 clarifies the concept of QbR. There is MicroQbR available which includes questions confirming the sterility of the product. QbR is a step towards speeding up the review process with an intention to motivate the applicants to implement QbD to the project.
Introduction
Question-based Review (QbR) is a question–answer format intended to be incorporated in the Quality Overall Summary (QOS) section of Common Technical Document (CTD) which includes the summary of data submitted to get the new drug approval. QbR is a framework proposed by the Office of Generic Drugs (OGD) that focuses primarily on critical pharmaceutical quality attributes. QbR is a podium for application of Center for Drug Evaluation and Research’s (CDER’s) Pharmaceutical current Good Manufacturing Practices (cGMPs) for the 21st century: A risk-based approach and an initiative to include Quality by Design (QbD) studies and process understanding in the drug approval applications. 1 QbR contains important scientific and regulatory review questions related to product and process design and understanding, product performance, analytical method validation, stability study, control strategy, etc. The current framework addressed in Manual of Policy and Procedures 5015.10 (MaPP 5015.10) can be used to review New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), or Type II Drug Master File (DMFs) submissions. On the other hand, recently, obstetrician topics also executed QbR successfully in clinical data handling in favour of branch of multiple choice question of respective category, viz. anaemia in pregnancy, screening of fatal chromosomal abnormality and vaginal birth after previous caesarean delivery. 2
QbR is also regarded as product development cross-road promoting inclusion of Pharmaceutical Development Report (PDR).
Quality by Design (QbD) is an approach to incorporate quality in the product process from the very first. It stresses majorly on product and process understanding and Quality Risk Management. Approval of QbD design reduces the number of supplements, usually, required to be filed post approval.
There are QbR templates available for extended release capsule and immediate release tablets. QbR framework is also available for Labeling Requirements for various dosage forms 3 and Chemistry, manufacturing and control (CMC) Technical Section of Animal Drug Application.
With the augmenting number of applications filed every year and a subtle increase in the number of reviewers, there stood a necessity to undertake steps to streamline the review process. One such step was implementation of QbR to QOS in the applications filed for approval to FDA. This article gives a basic overview on QbR and its emergence. It points out how QbR benefits applicants and reviewers. An attempt is made to tailor a questionnaire which could be used for QbR of an Analytical Method Development.
Emergence of QbR
The introduction of QbD required a platform to execute the same; QbR-QOS is the platform (Figure 1). It encourages the implementation of QbD. It makes the review process more efficient. Also the bottlenecks with previous review system necessitated the implementation of QbR. It uses QbR experiences from other CDER components (e.g. CDER MaPP 4000.4 Clinical Pharmacology and Biopharmaceutics Review Template), as well as other regulatory authorities (e.g. Health Canada) that use the QOS as a foundation for the primary chemistry review document.
Before the introduction of CTD format, the applicants would submit an Expert Report produced by an expert in the field, giving a summary of the documents. Later, with the introduction of CTD, QOS was submitted by applicants. Further, to streamline the application-review process, US FDA introduced QbR-QOS. A timeline depicting development of QbR-QOS is given in Figure 2.
Evolution of QbR-QOS.
Chronological evaluation of QbR system.
Hypothetical schematic case study (analytical method development) on QbR-QbD environment.
Why is QbR necessary?
The bottlenecks of previous review system were: (a) quality by end product testing, (b) little or no scrutiny on product and process design, (c) little or no mechanistic understanding, (d) overly conservative specifications, (e) does not adjust review to the level of scientific understanding. 4
Benefits of QbR 5
The QbR format benefits applicants in the following ways: (a) helps execute QbD, (b) better inter departmental communication, (c) reveals what information FDA considers critical, (d) reduced supplements.
The QbR has come handy to reviewers as it has encouraged: (a) consistent evaluation, (b) assess critical information, (c) reduced supplements, (d) concise data, (e) smooth preparation of primary review report.
Micro QbR 6
The QbR framed for terminal sterilization and/or aseptic processing cover the following aspects:
Overall manufacturing operation Microbiological monitoring of the environment Container closure integrity Sterilization/depyrogenation processes Specifications for product release and product stability.
Methodology for applying QbR approach adjoined with QbD
QbR incorporates a list of questions which intend to cover the multiple sections under QOS with a focus on implication of QbD and risk-based knowledge. The various questions addressing the elements of QbD are categorised in this review article. Quality by Design (QbD) is an approach to incorporate quality in the product process from the very first. It stresses majorly on product and process understanding and Quality Risk Management. Approval of QbD design reduces the number of supplements, usually, required to be filed post approval. Hence, an updated and thorough review summarizing the QbR for application of the adjoining QbD in regulatory window in detail presented here. 7
Step 1: Quality target product profile
What is the quality target product profile (QTPP) of the finished product based on the proposed indication and patient population? How is the QTPP justified? What are the quality attributes of the finished product?
Step 2: Critical quality attributes
What are the quality attributes of the finished product? Which quality attributes are considered critical quality attributes (CQAs)? For each CQA, what is the target and how is it justified? What is the approach for meeting the CQAs related to clinical performance? If applicable, what in vitro bio-performance evaluations (i.e. dissolution method, flux assay, etc.) were used during pharmaceutical development to ensure clinical performance?
Step 3: Identification of critical material attributes and critical process parameters
What attributes of the drug substance, excipients and in-process materials were identified as critical and how do they impact the drug product CQAs? What input material attributes and process parameters were selected for study and what are the justifications for the selection? What process parameters and material attributes were identified as critical and how do they impact the drug product CQAs?
Step 4: Understanding of the development process
What formulation development studies were conducted? What biopharmaceutics evaluations (comparative dissolution, bioequivalence studies, biowaivers, etc.) support the formulation changes and link the development formulations to the proposed commercial formulation? What process development studies were conducted? Provide a summary table listing batch size, process parameter ranges, equipment type and estimated use of capacity
Step 5: Control strategy including justifications
For 505(b) (1) applications, what is the rationale for selecting the proposed dosage form for the drug product? What is the rationale for the excipient selections? What is the rationale for selecting this manufacturing process for the drug product? How were the process parameters adjusted across lab, pilot/registration and commercial scale? What are the justifications for any changes? If applicable, what online/at-line/in-line monitoring technologies are proposed for routine commercial production that allows for real-time process monitoring and control? Provide a summary of how each technology was developed. If applicable, what supportive data demonstrate the compatibility of the drug product with the means of administration (e.g. additives and/or diluents, other co-administered drugs, dosing device)? What is the commercial batch formula and how does it differ from the registration batch formula? Provide justifications for any differences? What is the flow diagram of the manufacturing process that shows all incoming materials, processing steps/unit operations and in-process controls? What are the in-process test results for each process step of the registration batch(es)? What are the differences, if any, in the in-process controls for the registration batch(es) and the intended commercial batches? What are the justifications for these differences?
Step 6: Design space
What evidence supports excipient–drug substance compatibility and if applicable, excipient–excipient compatibility? What are the excipient specifications and how are they justified? How do the proposed acceptance criteria for the material attributes of the excipients ensure the quality of the final drug product?
Step 7: Risk evaluation
What aspects of the formulation were identified as potentially high risk to the drug product performance? What is the potential risk of each process step to impact the drug product CQAs and how is the risk level justified? What are the residual risks upon implementation of the control strategy at commercial scale? Hypothetical experimetal protocol of analytical method development on HPLC-PDA with QbR-QbD are shown in Figure 3.
Literature on QbR using QbD approach in Pharmaceutical field
In the current picture, regulatory bodies are focusing more on implementation of QbR-based QbD approach for method development, quality assessment, product improvement for the period of production, product quality control, PAT application, control strategy, risk evaluation, etc. Several reports have been in print on QbR-QbD approach, as detailed in Table 1. Manzural et al.8 reported a road map in the context of generic solid dosage formulation with three important categories, i.e. product, process understanding and control strategy along with critical attributes, respectively, with regard to the QbR-QbD approach. They also briefly explained to control the risk of bioequivalence study, scale up, validation and stability studies. Yu et al.9 well explained the US FDA QbR system for quality assessment of generic drugs and covered up to promote QbR four important beneficial points, viz. assure product quality through design and performance-based specification, continuous improvement along with reduced CMC supplement through risk assessment, quality of review on behalf of standardized review question and reduced CMC review time by submitting QOS followed by QbR. Jinag et al. reported in context QbR on behalf of modern pharmaceutical quality regulations. They incorporated QbD (various Design of Experiments selecting process variable) to influence the product quality by process performance except the previously taken documentation in mechanistic way, viz. manufacturing process, testing result of raw materials, in-process and finished product.
Review of literature on various discipline using the QbR-QbD approach.
QbR: Question-based Review; FDA: Food and Drug Administration.
Conclusion
This review article illustrates the concept of QbR-QOS and its execution in generic drug development along with QbD, offer better knowledge presentation of raw materials, manufacturing parameter (with critical quality attributes) impact on finished product quality. This will result in more robust process for US-FDA review system in various complicated situation (production, manufacturing, quality control, pharmacovigilance) form of QbR advance scheme. Therefore, we conclude that QbR-QOS is a dynamic model that will give better prospect for ANDA sponsors to make generic drugs available to the market faster and also be helpful in maintaining quality of drug product through relevant document submission in regulatory compliances.
Footnotes
Acknowledgements
The author wishes to acknowledge Jayanta Kr Maji, Research Fellowship, Institute of Pharmacy, Nirma University; Dr. Priti J. Mehta, Professor IP-NU, Pharmaceutical Analysis and Dr. Kanhoba Walavalkar, Associate Vice President, Regulatory Affairs (API), Sun Pharmaceutical Industries Ltd, for their encouragement and invaluable insight.
Disclaimer
The views and opinions expressed in this article are only those of the authors and do not necessarily reflect the views or policies of FDA.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.