Global Regulatory Perspectives on Quality by Design in Pharma Manufacturing

CHAPTER 2

Global Regulatory Perspectives on Quality by Design in Pharma Manufacturing Buket Aksu, Gizem Yeğen Altınbaş University, School of Pharmacy, Department of Pharmaceutical Technology, Istanbul, Turkey

1 INTRODUCTION Pharmaceutical manufacturing process involves processes requiring high costs. The research and testing work that needs to be done to deliver a new drug to patients takes 10–15 years on average and requires a budget of over 800 million dollar. As the drug must be manufactured on a large scale, safely, and in accordance with appropriate specifications, its development may fail after its discovery. Consequently, only 20% of the drugs involved in clinical trials are approved by the authorities. The legislations have almost frozen the processes used in pharma manufacturing overtime. Even after the receipt of drugs’ permits/certificates, even a small change in the method of manufacturing of medicines requires examination and approval of authority, resulting in time and paperwork. This prevents update by companies that are worried about production delays and thus a heavy financial burden for them. The Food and Drug Administration (FDA) is at the forefront of work in the field of “Quality by Design (QbD),” which implements regulatory intelligence to modernize the understanding and control of pharma manufacturing processes. In terms of authority and industry relations, it has been thought that until recently these regulatory processes and requirements have hindered the development and innovations in manufacturing. Developments in the registration field will not only ensure better quality, but also will make it possible to reduce development and manufacturing costs. Research areas supported by the FDA include: continuous processing in which materials constantly enter and exit equipment and reduce overall production time and cost; rather than just the use of test products, use of process analytical technology (PAT) to monitor and control the manufacturing processes, and use of new statistical approaches to determine the changes in the Pharmaceutical Quality by Design https://doi.org/10.1016/B978-0-12-815799-2.00002-2

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process or product quality. With the introduction of current Good Manufacturing Practices (cGMP) applications in 2002 and the publication of the PAT Guide by the FDA in 2004, the pharmaceutical industry has begun to modernize. In this guide, while we focus more on PAT, we have also examined several principles of the QbD approach.1 It is important to understand the fundamental differences between the European Medicines Agency (EMA) and the FDA in the United States, because it has led to a different approach to design and quality management. EMA, unlike the FDA, continues its existence with the national competent authority (CA) over 40 of the European Union/European Economic Area (EU/EEA) and forms an integrated network of institutions. The centralized procedure for marketing permits continues to exist together with the national level (national procedures, decentralized procedures, mutual recognition procedures) marketing authorization procedures specific to member states. EMA coordinates current scientific resources within Member States and provides an interface between all parties and works toward harmonization with the regulatory and technical requirements of the EU. Within the framework of the EMA studies, new reports were created by the EMA-PAT team, such as the weighted report on how PAT could result in real-time release and play a pioneering role in QbD. EMA has identified its focal point as PAT for the first time and deals with design by quality through participation in ICH (The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) activities.2–5

2 ICH Q8 PHARMACEUTICAL DEVELOPMENT The aim of pharmaceutical development is to design a “quality product and a production system in which this product can reproduce in a reproducible manner.” The Pharmaceutical Development and Quality Summary sections of the Common Technical Document (CTD) have critical prescription for continuous improvement and flexible operation. As noted in the Q8 guide, the design space (DS) is “the multidimensional combination and relationship of input variables and process parameters introduced to provide quality assurance.” The operation that takes place outside the DS will cause a change situation after approval.6 This guideline describes the content recommended for Section 3.2.P.2 (Pharmaceutical Development) of a regulatory presentation in the ICH M4 CTD format. The Pharmaceutical Development section provides an

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opportunity to present information obtained through the application of scientific approaches and quality risk management to the development of a product and its manufacturing process. The goal of the pharmaceutical development process is to design the manufacturing process that will ensure consistent access to a quality product and the performance anticipated for that product. The knowledge gained from pharmaceutical development studies and manufacturing experience supports the creation of DS, specifications, and manufacturing controls. The knowledge is also important for quality risk management. Quality implies that it cannot be tested in one product, that is, quality is achieved through design. Changes in formulation and manufacturing processes during the development and product lifecycle management should be seen as opportunities to provide additional information and support for the creation of the DS. It may also be useful to include information from studies that give unexpected results. The DS is proposed by the applicant and is subject to regulatory assessments and approval. Working within the DS is not considered a change, while exiting from it is considered a change and normally the post-approval modification process will be required. The Pharmaceutical Development section should contain information indicating that the dosage form chosen and the proposed formulation are appropriate for the intended use. In this phase, there should be sufficient information on the development of the drug product and the manufacturing process of it. It is useful to use the summary tables and graphs in situations where they can provide clarity and facilitate examinations. Quality-critical aspects of active substances, auxiliary substances, containerlid systems (primary packing material), and manufacturing processes should be determined and manufacturing strategies should be justified. It should be noted at what point the critical properties of the formulation and process parameters affect the quality of the drug. In addition, the applicant may conduct pharmaceutical development studies, which may provide a higher level of information on product performance, broader “material qualities, process selection, and process parameters.” The inclusion of this additional information, the provision of more information on material properties, manufacturing processes, and their controls facilitates the creation of a wide DS. In these cases, for example, there are opportunities for the development of more flexible regulatory approaches to facilitate the following: • risk-based regulatory decisions (reviews and inspections), • within the approved DS defined in the file, manufacturing process improvements without additional qualification examination,

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• •

decrease in the number of post-approval type changes, and real-time quality control efforts resulting in reduced final product release testing. To achieve this flexibility, the applicant will have more information about material properties, as well as manufacturing and process parameters. This information can be obtained through the application of PAT and/or preowned information. Implementation of quality risk management principles may also be useful in determining the priorities of the pharmaceutical development studies to obtain more information. The design and implementation of pharmaceutical development studies must be of scientific interest; not the amount of data, but the level of knowledge gained is important.4,7

3 ICH Q8(R)2 REVISION: PHARMACEUTICAL DEVELOPMENT This guide is an annex to ICH Q8 Pharmaceutical Development and further explains the key concepts outlined in the basic guideline. In addition, this annex describes the QbD principles. This guide is an annex to ICH Q8 Pharmaceutical Development and further clarifies key concepts in the main guide. In addition, this annex defines the QbD principles. When a company chooses to apply QbD and quality risk management in conjunction with an appropriate pharmaceutical quality system, there is an opportunity for a science and risk-based regulatory approach. In ICH Q8 content, QbD approach is defined as follows: “a systematic approach to drug development that emphasizes the need to start with predefined goals and understand the product and process based on sound science and quality risk management.” Thanks to the increase in process knowledge and a better understanding of the product enabled by QbD approach, the productivity of the manufacturing processes increase, and product withdrawal and compliance rules, thus costs, are reduced. It also helps to reduce the uncertainties and risks and focus resources of industry and regulatory agencies on the most critical areas. The amount of information that must be submitted to the authority after approval is reduced, as the process is included in the files that show a better understanding of the process. This approach can also facilitate the use of innovative technologies and encourage the use of new approaches such as continuous quality verification to achieve process validation.

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With regard to the PAT that came up to the fore with the QbD approach, the FDA has published a guide named “PAT-A Framework for Innovative Drug Development, Manufacturing, and Quality Assurance.” This guideline covers “scientific principles and tools that support innovation” and “adaptation of regulatory strategies to bring about innovation.” Pharmaceutical development can be done empirically or with a more systematic approach, or a combination of both can be applied. According to ICH Q8, the comparison for these is as follows in Table 1. Table 1 Comparison of Approaches for Pharmaceutical Development Approach Minimal Approaches Quality by Design Approaches

General Pharmaceutical Development

Basically empirical. The development study is usually performed with one variable at a time.

Manufacturing Process

Fixed. Firstly, validation based on initial full-scale series. Focus on optimization and reproducibility.

Process Controls

Firstly, in-process tests for continuation/stop decisions. Off-line analysis.

Product Specifications

Main control tools. Based on the series data available during regulatory processes.

Systematic; relates the mechanical properties of the material properties and process parameters with drug Critical Quality Attributes (CQAs). Multivariable experiments to understand the product and process. Creation of the DS. PAT tools are used. Adjustable within DS. Validation life cycle approach and ideally, continuous process validation. Focus on control strategy and strength. Use of statistical process control methods. PAT tools used for feed forward and feedback controls. Process operations that are monitored and tend to support continuous postapproval improvement efforts. A part of the general quality control strategy. Based on the expected product performance with related supportive data. Continued

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Table 1 Comparison of Approaches for Pharmaceutical Development—cont’d Approach Minimal Approaches Quality by Design Approaches

Control Strategy

Mainly, drug quality by intermediate products (in-process materials) and final product test

Lifecycle management

Reactive (that is, problem solving and corrective action).

Drug quality provided by a risk-based control strategy for a well-understood product and process. Scrolled up quality checks with the possibility of realtime release testing or reduced end-product testing. Preventive action. Continuous improvement is facilitated.

4 ICH Q9 QUALITY RISK MANAGEMENT This document describes two basic principles of the risk management model that define the quality risk management process and explain the terminology and tools in risk assessment. There is also a short list of references [such as Failure Mode Effects Analysis (FMEA)] where detailed information on risk management methods can be found. Such tools are useful for prioritizing the PAT application. What is required from the ICH Q9 design (expected result) is that the management of potential risks to the patients should be based on science; risks involving product, process, and facility, and risks affecting the durability of the quality system are evaluated and related risk reduction (decrease) controls are performed. In addition, studies should be conducted in proportion to the potential risk level for the patient and evaluations [license applications, post-approval changes, and GMP inspections] should be made. Barriers that prevent continuous improvement are removed or reduced to increase productivity in manufacturing, ensure sustainability of product quality, and make improvements.8

5 ICH Q10 PHARMACEUTICAL QUALITY SYSTEM This guide is complementary to the establishment of a pharmaceutical quality system based on the points described in ISO 9001 and 9004. The guideline is also expected to develop harmonized definitions of the issues critical to PAT. These include continuous improvement activities, data collection methods, and system validation measurement approach.9

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6 ICH Q11—DEVELOPMENT AND MANUFACTURE OF DRUG SUBSTANCES Q11 guidelines are prepared for “drug substances” by harmonizing relevant scientific and technical principles with completion and validation of the development and manufacturing processes of active substances, including chemical and biotechnological/biological substances. This guideline defines various approaches to understanding and improving the manufacturing processes of drug substances and provides guidance on what kind of information should be provided in accordance with Sections 3.2.S.2.2–3.2.S.2.6 of CTD Module 3. Q11 also includes selection of initial materials and source materials, control strategy, guidance on process validation/evaluation, and recommendations on where to submit relevant information in the CTD format, lifecycle management, and some illustrative examples.10

7 PREPARATION OF QBD REGISTRATION APPLICATION FILE Although in ICH Q8 guide, QbD is not specifically mentioned, the goal of the ICH Q8 expert working group (EWG) is to define a system that will provide the support to integrate the QbD continuous improvement aspects during the lifecycle of the product for the manufacturers. The guide they produce to achieve this goal describes the contents proposed in the ICH M4 CTD and the FDA electronic common technical document (eCTD) for a registration application (Section 3.2.P.2). The pharmaceutical development and quality overview sections of the CTD provide separate channels for regulatory information and process understanding of pharmaceutical scientists during the development of a new product. The information provided in these sections is important for justifying the potential for a lower area risk and helping to produce an efficient, question-based review. The question-based review is another mechanism in which the agency wants the registration process to flow and rewards manufacturers when they adopt the best practices in quality management. CTD quality summary section is the key point of the application. A reasonable explanation for everything that is critical to quality specifications should be given, and a guarantee of their awareness must be provided. It is necessary to act on the basis of previously acquired experience and information, the information used here plays a key role; but this information must

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be clearly defined in the reference file. Risk assessments performed are highly important; assessments performed using the pharmaceutical development, manufacturing process, and any risk tools and decisions made on how the risks are reduced/will be reduced should be defined clearly and step by step. Such explanations are important for the evaluators. Another important point to note is that although various experts (experts with knowledge in different fields in terms of QbD) participate in various stages of the file preparation process, from the evaluators’ perspective, file review is performed with the same criteria and based on the same information. In the QbD registration application file, the information to be included in the relative sections will be explained step by step. However, it should be noted that the file structure and the guides used remain the same (only the new—optional—guides) (Q8, Q9, Q10, Q11 are added). General differences with the content are as following; risk management method, design of experiments (DoE), manufacturing process design, risk management tools, statistical methods, PAT and control tools. The differences between QbD registration application file and current application file are given in Table 2. Table 2 Differences Between Current CTD Format and QbD Registration Application File Current CTD Application QbD Registration Application 3.2.P.1 Definition and composition of the preparation

– –

–

The description of the dosage form, A list of all components of the dosage form, quantities per unit, references to the functions and quality standards of the components (e.g., pharmacopoeia monographs or manufacturer specifications), description of the accompanying diluents Dosage form and container lid type

– – – – –

Ref. Guide: Q6A, Q6B

Quality Target Product Profile (QTPP) Critical quality aspects of the product Functional relations related to the process parameters Results of the risk analysis are presented. Summary and description of the product and process development processes which create the base of the DS(s)

3.2.P.2 Pharmaceutical Development

–

Information on the development of the work carried out to determine the dosage form, formulation, manufacturing process, container lid system, microbiological properties and instructions for use as indicated in the application.

– –

Highly developed and comprehensive information is available. Discussions on the possible effects and relationships of the quality characteristics of the drug substance and the inactive ingredients to the

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Table 2 Differences Between Current CTD Format and QbD Registration Application File—cont’d Current CTD Application QbD Registration Application

–

–

Critical process parameters that can affect the performance of the product and the quality of the preparation. Supporting data and results obtained from specific studies or published literature within or in the field of pharmaceutical development Ref. Guide: Q6A, Q6B

– – – – – –

– –

– – –

product’s quality and manufacturing process Description of the quality target profile of the product and explanations on how it was determined Critical quality aspects and the co-relation of critical process parameters, Experiment designs related to the formula development and process parameters. Risk analyses and their results. Final formulation decided/(design space) Additional information if necessary during the formulation development phase (such as BCS information, justification on pharmacokineticadministration, stability) Aim of the inclusion of inactive ingredients in the formulation. If the proposed formulation differs from the formulation used in clinical trials, discussions on how the performance of the product will be affected. Explicit and clear definitions of the entire process, initial materials, applied controls. Design of the experiments and the information acquired. Data concerning the design space and merchantability

3.2.P.2.1.1 Drug substance

– –

Explanation on the compliance of drug substance with the inactive ingredients Important physicochemical properties (e.g., water content, solubility, particle size distribution) of the drug substance, which may affect product performance

–

–

Physicochemical and biological properties of the drug substance, such as solubility, moisture content, particle size, crystal structure, biological activity, permeability Discussions of what effects the active substance characteristics may have on the performance of the product (based on information Continued

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Table 2 Differences Between Current CTD Format and QbD Registration Application File—cont’d Current CTD Application QbD Registration Application

–

Assessments on the compliance between drug substances in combination products

–

– – –

based on previous experiments or on scientific literature). Assessment on the compliance of the drug substance with the inactive ingredients to be used in the product. Explanation on which product should be selected and why. If the product contains multiple drug substances, assessment on the compliance of these drug substances Assessment about the drug substance CQAs if they affect the CQAs of the product or the manufacturing process.

3.2.P.2.1.2 Inactive Ingredients

–

Explanations on the inactive ingredient selection, concentration and properties that may affect the product performance in terms of function of each

–

– –

–

Information on why the inactive ingredients are selected and assessment of their compliance with each other Discussion on the possible effects of the inactive ingredient concentrations used on the end product Performance characteristics of inactive ingredients, their quality characteristics and reasons for selection by parallel evaluations with critical quality characteristics. Indication that the functions of inactive ingredients are fulfilled during the shelf life of the product and its effectiveness continues

3.2.P.2.2.1 Formulation Development

–

–

A brief summary describing the development of the preparation in consideration of the usage type and method suggested. If any, discussions on the differences between the clinical formulas and the formula defined in 3.2.P.1.

–

–

Functional relations relating the risk analysis, material specifications and process parameters with product CQAs Summary and description of the product and process development processes which create the base of the DS(s)

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Table 2 Differences Between Current CTD Format and QbD Registration Application File—cont’d Current CTD Application QbD Registration Application

–

Where appropriate, discussions on the results obtained from comparative in vitro/in vivo studies.

– – –

– –

–

– – –

Product and manufacturing process sections. A summary describing the formulation development Determination of the critical quality aspects that may affect the product quality in consideration of all specifications, usage and application methods of the product according to the target product profile. Possible factors to effect the product quality and assessment on whether these factors are critical or not. Data obtained from study designs where different factors and parameters are evaluated during the formulation development phase. Selection justifications of the inactive ingredients compliant with the drug substance, container-lid system and related dosing device. Clear definition of the manufacturing process, selection reasons for the process. Summary of formulations used in clinical trials and/or bioequivalence trials Information obtained from comparative in-vivo/in-vitro studies.

3.2.P.2.2.2 Excess dosage

–

Justifications of the excesses in the formulation

– –

Justifications of the excesses in the formulation Evaluations of product safety and effectiveness

3.2.P.2.2.3 Physicochemical and Biological Properties

–

Properties related to the performance of the preparation, such as pH, solubility, particle size distribution, polymorphism, biological activity

–

–

Functional relations relating the risk analysis, material specifications and process parameters with product CQAs Summary and description of the product and process development Continued

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Table 2 Differences Between Current CTD Format and QbD Registration Application File—cont’d Current CTD Application QbD Registration Application

–

–

–

processes which create the base of the DS(s) Physicochemical and biological properties that may be effective in terms of efficacy and safety affecting the quality of the product and related evaluations Supportive information on which studies and test methods should be selected according to critical characteristics (e.g., information supporting the selection of the dissolution test or the selection of other tools for the development of the drug test and the selected test) The information provided should also include references to stability data, and these should be used to support the assessments.

3.2.P.2.3 Manufacturing Process Development

–

– –

Explanations on how the manufacturing process is selected and optimized, and in particular its critical aspects Descriptions and reasons for the sterilization method where appropriate Discussion of differences between the manufacturing process used in the clinical series and the process described in 3.2.P.3.3, which may affect the performance of the product

– – – –

–

–

Product and manufacturing process sections of the applications Compliance of all equipment to be used must be evaluated within the manufacturing process Risk analysis that relates the design of the manufacturing process to product quality Information how the critical process parameters are controlled upon identification and justifications of the process selected for manufacturing Information on which critical process parameters are used as base and controls to be performed during the manufacturing (such as in-line) (definition of the control strategy) A summary of the effect of different operating conditions, different scales and equipment on product quality and manufacturability of the product, information on process performance

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Table 2 Differences Between Current CTD Format and QbD Registration Application File—cont’d Current CTD Application QbD Registration Application

– –

–

Risk assessments for measuring process durability, risk reduction practices Validations to be made within process improvement, applications such as measurement systems at process end points, process controls If the products to be produced are sterile, the choice of primer packing material sterilization method

3.2.P.2.4 Container-Lid System

–

The suitability of the container lid system, the suitability of the ingredients of the composition to the dosage form, the safety and performance of the ingredients of the composition

– –

–

–

Reason for selection of materials used The effects on the finished product quality as well as compliance to the intended use of the drug at the same time, suitability for storage and transport stages Possible characteristics that may affect the finished product and the reason for the secondary packaging materials The risks associated with the stability of the finished product of packaging materials; then appropriate controls to reduce these risks

3.2.P.2.5 Microbiological Properties

–

–

Where appropriate, discussions on the microbiological properties of the dosage form (e.g., why microbial limits are not used for nonsterile products and how protective systems in products containing antimicrobial preservatives are selected and how effective they are) Integrity of container lid system to prevent microbial contamination in sterile products

– – – –

Explanation of whether microbial limit test is performed for nonsterile products If there are antimicrobial agents, their selection and effects Compatibility with primer packaging material for sterile products Microbiological stress test in related locations and related documents

3.2.P.2.6 Compatibility

–

Compatibility of the product with the accompanying diluents or

–

Compatibility with the solvent, assessments in terms of stability Continued

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Table 2 Differences Between Current CTD Format and QbD Registration Application File—cont’d Current CTD Application QbD Registration Application

dosing devices, appropriate and supportive information for labeling

–

Pre-application comparison of the products and dilution stages

3.2.P.3 Manufacturing 3.2.P.3.3 Definition of the Manufacturing Process and Process Controls

– – – –

– –

–

–

Process flowchart Critical steps and points for process controls, intermediate tests, or finished product controls A narrative showing the steps of manufacturing process and production scale Detailed description of new processes or technologies and packaging operations directly affecting product quality Identification of the equipment where appropriate Identification of appropriate process parameters such as time, temperature or pH for the steps in the process The associated numerical values can be presented as the expected range. Reasons for numerical ranges for critical steps should be indicated in Section 3.2.P.3.4. Reasons and supportive data for the proposals of reprocessing of the materials. Ref. Guide: Q6B

– – – –

– –

– – – – – – – –

Product and manufacturing process development stages Design space and unit operations Explanations on how the critical points in the manufacturing process are determined The results of the experiments for critical operations (DoE data) and statistical analyzes, variable and fixed parameters in the design space For DOEs, it is sufficient to present the data in the form of summary tables and results rather than submitting all data. A clear description of the design space, supported by the grant, parameters and ranges and their reasons, information based on the reference or the acquired experience. Design of manufacturing process and risk analysis of its association with product quality The reasons for all the risk instruments used and the assessments made and sufficient data Explanations based on scientific information Control strategies Much more detailed explanations, especially if there are different or unexpected findings Links to control strategy of development results It is important that the risks, the design space and the control strategy developed are consistent Tools used, PAT explanations

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Table 2 Differences Between Current CTD Format and QbD Registration Application File—cont’d Current CTD Application QbD Registration Application

–

If appropriate, post-approval variation management plans/protocols

3.2.P.3.4 Controls of the Critical Steps and Intermediates

–

–

Tests performed at critical steps as determined in Section 3.2.P.3.3 and acceptance criteria (together with justifications including the experimental data) Information about the quality and control of the intermediate isolated during the process

– –

Where applicable, process critical steps and intermediates, relevant identified controls Where appropriate, critical steps and intermediates

Ref. Guide: Q2A, Q2B, Q6A, Q6B 3.2.P.3.5 Process Validation and/or Evaluation

– –

Validation and/or evaluation studies for critical steps or critical analysis used in manufacturing process Validation studies performed in the limited series Ref. Guide: Q6B

– – – – – –

May be conventional or the combination of two conditions. Validation of the design space (may be a part of the process validation). May include the testing or monitoring of the CQAs affected by the scale-dependent parameters. Design space related to the scale/ facility/equipment changes may be validated. Risk-bases approaches for the process validation plan. CPV (Continuous Process Validation); in-line, on-line, at-line controls or monitoring.

3.2.P.4 Control of the Inactive Ingredients 3.2.P.4.2 Analytical Procedures

–

Where appropriate, analytical procedures used in the testing of the inactive ingredients.

–

Controls related to the critical aspects of the inactive ingredients and their effects on the process are presented.

–

Specification and test methods are determined according to pharmaceutical development, analysis results, and stability results.

Ref. Guide: Q2A, Q6B 3.2.P.5. Control of the preparation 3.2.P.5.1 Specifications

–

Specifications of the preparation Ref. Guide: Q3B, Q6A, Q6B

Continued

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Table 2 Differences Between Current CTD Format and QbD Registration Application File—cont’d Current CTD Application QbD Registration Application

–

– –

– – –

Evidence and scientific explanations of which CQA of the product should not be tested in the process and tested on the finished product. Compliance of critical quality aspects to achieve the target quality profile specified for the product. If real-time release practices exist, how they are created and how the specifications are controlled on the process. Acceptance criteria at the control points In real-time release, it is important that all tests are applicable both on laboratory and commercial scale. Apart from this, other conventional test methods used should also be included in the file (such as stability tests)

3.2.P.5.2 Analytical Procedures

–

Analytic methods used in the testing of the preparation should be provided. Ref. Guide: Q2A, Q6B

–

–

–

–

–

Evidence and scientific explanations of which specifications of the product should not be tested in the process and tested on the finished product If real-time release practices exist, how they are created and how specifications are controlled on the process In real-time release, it is important that all tests are applicable both on the laboratory and commercial scale. Apart from this, other conventional test methods used should also be included in the file (such as stability tests) Where appropriate, references to the test method

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Table 2 Differences Between Current CTD Format and QbD Registration Application File—cont’d Current CTD Application QbD Registration Application

– – –

Acceptance criteria at the control points Stability acceptance criteria Analytical method DS (ranges), analytical target profile

3.2.P.5.3 Validation of the Analytical Procedures

–

Analytical validation information including experimental data for analytical procedures used in testing the preparation

Ref. Guide: Q2A, Q2B, Q6B

–

In the QbD framework, if the analysis methods and techniques used have changed (such as the use of PAT), the validations will also change (The issue of validation is still being discussed)

3.2.P.5.4 Series Analysis

–

Results of the series analysis Ref. Guide: Q3B, Q3C, Q6A, Q6B

– – –

Data obtained from models, results such as test results. Acceptance criteria for the used method. Method references

3.2.P.5.6 Validation of the Specifications

–

Justifications of the preparation specifications proposed

Ref. Guide: Q3B, Q6A, Q6B

–

Discussion on the relationship between design space and general control strategy

8 ASSESSMENT OF QBD REGISTRATION APPLICATION FILE Assessment process of QbD files by authorities is as in all applications. However, if necessary, the EU PAT team may be included in the assessment process on an on-demand basis to ensure consistency with the expert opinion and assessment. While in conventional applications, chemistry, manufacturing, and controls (CMC) and biopharmaceuticals evaluator are included, new approaches (QbD) are assessed by CMC evaluators from various disciplines [near infrared (NIR), chemometrics, biopharmaceuticals, etc.]. Considering QbD files are quite different than usual registration application files,

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it may be necessary to draw attention to the points that need to be focused on the review/evaluation process. For example: – Is there enough information to support the DS? – Is the DS validated for all scales and is the control strategy supports the DS? – Development, validation, and lifecycle management of various models used. – Is there sufficient information available for the process validation? – If appropriate, the suitability of real-time release tests can also be questioned. – More critical steps and more detailed information on operations (e.g., extensive data sets, statistical evaluation) are provided. – The use of quality risk management is as useful as it is from the manufacturer’s point of view. When assessing the quality of the product on the application, it is evaluated whether the product to be produced as a result of the manufacturing process is of good quality and, where applicable, is of the same quality as the series used throughout the entire cycle of the product and thus the product is of the desired efficiency and safety. Regardless of the process development and applied controls (control strategy), whether the traditional approach or the new approach (QbD) is applied, the evaluation criteria are still the same; they are not tied to different development approaches, but the new concepts such as DS, DoE, and statistical applications are that need to be considered when evaluating and that require expertise. Whether the product will reach the quality profile is evaluated. It is desirable to ensure that an effective product will emerge at the end of the proposed process by looking at the risks that may be effective in achieving the drug substance and formulation development, the manufacturing process, the proposed control strategy, the analytical procedures and the data presented on the stability, and the QTPP (Quality Target Product Profile).

8.1 Pharmaceutical Development Since the properties of the active substance are important in the development of the formulation in terms of the selected target product quality profile and the choice of dosage form, additional information may be presented if necessary during the formulation development phase [such as Biopharmaceutics Classification System (BCS) information,

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pharmacokinetics—justification can be made about the application of the dose, or why the controlled dosage form is selected, stability, compatibility with inactive ingredients, etc.]. Sufficient explanations should be given in the file for the compatibility of the drug substances with the selected excipients, and why the inactive ingredients are included in the formula should be indicated. If the proposed formulation differs from the formulation used in clinical trials, how it will affect the performance of the product should be discussed. When evaluating, it is important that the whole process, initial materials, the controls applied are clearly defined and explained. It is assessed whether there is any condition to create toxicity; it is checked whether the tests and analysis methods for the specified specifications of the product are sufficient; the process controls are examined and the submitted data on the applicability of a DS and the applicability in the commercial dimension are evaluated to support all of them. The application of the DS formulation phase involves testing various compositions and different parameters. Formulas are optimized by experimenting with different formulas. While submitting the formula, it is evaluated how much the experiment designs and other acquired information are presented in the file.11

8.2 Manufacturing Process Development Since the manufacturing process will be quite different in the QbD file (risk assessments, control strategies, etc.), it is important to provide all the risk instruments used together with the reasoning of the assessments and sufficient data. When assessing the entire risk management process, process design and control strategies together with risk assessments, the evaluators need to have explanations (based on scientific information), not just graphics and/or tables, to understand them. The charts and tables presented in the risk assessment are helpful elements for the evaluators to understand the qualities that affect the quality of the product and the critical points of the process.12 If there are particularly different or unexpected findings, a more detailed description should be included in the file. It is important that the risks, the DS, and the control strategy developed are consistent. Experimental data to support the DS must be presented in the file. Test results for critical operations, statistical analysis, which parameters are variable in the DS and which are kept fixed should be indicated.

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8.3 Proposed Control Strategy and Real-Time Release Compliance of critical quality aspects to achieve the target quality profile specified for the product should be assessed Control strategy created based on the risk assessments related to critical quality aspects, tests included in the control strategy and the sufficiency of the tests should be checked. Tests involved for the control of the inactive ingredients should be reviewed and if there are real-time release applications, creation method and how the specifications identified are controlled over the process should be assessed. If PAT is used, related details should be provided. For this reason, experts may be required for the evaluation of this section. In real-time release, it is important that all tests are applicable both on the laboratory scale and commercial scale, and that analytical procedures are validated and the products have the proper sustainability. Apart from this, other conventional test methods used should also be included in the file (such as stability tests).

8.4 Design Space DS should be clearly defined and explained in the application. DS boundaries must be explicitly defined (parameters and ranges), statistical data must be presented. The presentation of the results of the study in a comprehensive, clear, and concise manner and the fact that the reasons are based on scientific information are of great importance for the evaluation of the files. Justifications of the determination of the critical level should be based on the quality risk management or the experimental results, and these should be clearly identified. Regardless of the process development and applied controls (control strategy), whether the traditional approach or the new approach is applied, the evaluation criteria are still the same; they are not tied to different development approaches, but the new concepts such as DS, experiment designs, and statistical applications are that need to be considered when evaluating and that require expertise. Whether the product will reach the quality profile is evaluated. It is desirable to ensure that an effective product will emerge at the end of the proposed process by looking at the risks that may be effective in achieving the drug substance and formulation development, the manufacturing process, the proposed control strategy, the analytical procedures and the data presented on the stability, and the target product quality profile.13,14

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8.5 Control of the Preparation Compliance of critical quality aspects to achieve the target quality profile specified for the product should be assessed Control strategy created based on the risk assessments related to critical quality aspects as presented in the previous sections, tests included in the control strategy and the sufficiency of the tests should be checked. If real-time release practices exist, how they are created and how the specified specifications are controlled on the process should be assessed. If PAT is used, related details should be provided. For this reason, experts may be required for the evaluation of this section. In real-time release, it is important that all tests are applicable both on the laboratory scale and commercial scale, and that analytical procedures are validated and the products have the proper sustainability. Apart from this, other conventional test methods used should also be included in the file (such as stability tests). In order to maintain the lifecycle management of the product and ensure continuous development, quality system principles are implemented for the drug. Related information should also be included in the application. Quality risk management may be used at different stages during the product and process development and manufacturing operations. Assessments used to guide and determine the development decisions may be included in the relative sections of P.2.

9 CONCERNS, PROBLEMS, AND QUERIES ABOUT QBD Cost: The industry still has concerns about the cost and the possible effect of the product in the market position. There is a sense of perception that change will not bring benefits; a general reluctance of the industry to bring changes into regulatory agencies. Harmonization: The new paradigm must be fully understood and realized. The lack of harmonization across all countries leads to the idea that ICH Q8-Q9-Q10 and Q11 guidelines will have a negative impact on the future situation. In the case of variations in products, different variant application procedures will also come to the fore. Expertise/New Techniques: Regulatory authorities, evaluators, and those who work in the industry should be trained on the DoE where more comprehensive approaches and different techniques are adopted, as well as QbD where statistical tools are used. Assessment of the QbD registration

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application files and other QbD-implemented post-approval applications requires expertise to evaluate the data presented. Dialog between the Industry and Authority: The continuous dialog between the industry, the evaluators, and the auditors needs to be maintained and they should be in constant communication. GMP: It should be noted that QbD application does not change the regulatory requirements; it only provides a flexible approach both for the applicants and the evaluators. GMP requirements should be applied under every circumstance.15

10 SOLUTIONS AND BENEFITS PROVIDED BY QBD QbD applications, above all, establish a win-win-win policy. From the manufacturers’ point of view, better understanding of the product/process, the development of more efficient processes, and fewer regulatory requirements are possible. Providing regulatory flexibility in a way that does not reduce quality is also important for the regulators. And as the focus is always the patient, it is also possible to ensure an increase in the product quality assurance.8 The PAT initiative is one of the most important steps in quality in the pharmaceutical industry. Implementation of PAT in new manufacturing procedures and current manufacturing operations will provide cost-related and competitive advantages; it will play a key role in saving the pharma industry from this challenging situation. With the QbD approach, the quality of the product is not tested at the end of the manufacturing process; quality is built during product design, and quality is incorporated into the product. Rather than controlling the quality, assurance of quality—which is more important—is ensured. With complete understanding of the process, manufacturing through constant fixed procedures has been terminated; now, through applications performed with approaches based on scientific data and previous knowledge, and also by determining the critical points in terms of the product and process, it is possible the process is brought to life. Development and innovation are hampered due to unchanged processes and systems. However, the DS of the QbD approach is now part of the process for change with the flexibility of real-time release. As a result of these changes, the process is proved to function and the confidence in the system is increased.7

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REFERENCES 1. Singh SK, Venkateshwaran TG, Simmons SP. Oral controlled drug delivery: quality by design (QbD) approach to drug development. In: Wen H, Park K, eds. Oral Controlled Release Formulation Design and Drug Delivery: Theory to Practice. New Jersey: John Wiley & Sons, Inc.; 2010:279–303. 2. Aksu B, et al. Strategic funding priorities in the pharmaceutical sciences allied to quality by design (QbD) and process analytical technology (PAT). Eur J Pharm Sci. 2012;47: 402–405. 3. Schmitt S. Quality by Design: Putting Theory into Practice. USA: PDA, Davis Healthcare International Publishing, LLC; 2011. 4. Cogdill RP. Case for Process Analytical Technology: Regulatory and Industrial Perspectives. In: Gad SC, ed. Pharmaceutical Manufacturing Handbook: Regulations and Quality. New York: John Wiley and Sons, Inc.; 2008:313–352. 5. Gaspar R, Aksu B, Cuine A. Towards a European strategy for medicines research (2014–2020): The EUFEPS position paper on horizon 2020. Eur J Pharm Sci. 2012;47:979–987. 6. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Pharmaceutical Development Guideline. 2009;Q8(R2). 7. Buket A. Quality by design (QbD) roadmap. CRS Indian Local Chapter. 2015;7:25–28. 8. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Quality Risk Management Guideline, Q9; 2005. 9. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Pharmaceutical Quality System (PQS), Q10; 2008. 10. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Q11 Development and Manufacture Drug Substances Report dated 25 March 2008 (endorsed on 11 April 2008). 11. Aksu B, Aydog˘an M, Kanik B, Aksoy E. A flexible regulatory approach for different raw materials suppliers using QbD principles. RJPBCS. 2013;4(4):358–372. € 12. Mesut B, Ozsoy Y, Aksu B. The place of drug product critical quality parameters in quality by design (QbD). Turk J Pharm Sci. 2015;12(1):75–92. 13. Aksu B, Mesut B. Quality by design (QbD) for pharmaceutical area. J Fac Pharm. 2015;45(2):233–251. 14. Buket A, Paradkar A, Matas M, et al. A quality by design approach using artificial intelligence techniques to control the critical quality attributes of Ramipril tablets manufactured by wet granulation. Pharm Dev Technol. 2013;18(1):236–245. € 15. Aksu B, Yegen G. New quality concepts in pharmaceuticals. MUSBED. 2014;4(2): 96–104.