PART 1: PHARMACEUTICAL DEVELOPMENT
1. INTRODUCTION
1.1 Objectives of the Guideline
This guideline describes the suggested contents for the 3.2.P.2 (Pharmaceutical Development) section of a regulatory submission in the ICH M4 Common Technical Document (CTD) format.
The Pharmaceutical Development section provides an opportunity to present the knowledge gained through the application of scientific approaches and quality risk management (for definition, see ICH Q9) to the development of a product and its manufacturing process. It is first produced for the original marketing application and can be updated to support new knowledge gained over the lifecycle* of a product. The Pharmaceutical Development section is intended to provide a comprehensive understanding of the product and manufacturing process for reviewers and inspectors. The guideline also indicates areas where the demonstration of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches. The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided.
1.2 Scope
This guideline is intended to provide guidance on the contents of Section 3.2.P.2 (Pharmaceutical Development) for drug products as defined in the scope of Module 3 of the Common Technical Document (ICH guideline M4). The guideline does not apply to contents of submissions for drug products during the clinical research stages of drug development. However, the principles in this guideline are important to consider during those stages as well. This guideline might also be appropriate for other types of products. To determine the applicability of this guideline to a particular type of product, applicants can consult with the appropriate regulatory authorities.
2. PHARMACEUTICAL DEVELOPMENT
The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space*, specifications, and manufacturing controls.
Information from pharmaceutical development studies can be a basis for quality risk management. It is important to recognize that quality* cannot be tested into products; i.e., quality should be built in by design. Changes in formulation and manufacturing processes during development and lifecycle management should be looked upon as opportunities to gain additional knowledge and further support establishment of the design space. Similarly, inclusion of relevant knowledge gained from experiments giving unexpected results can also be useful. Design space is proposed by the applicant and is subject to regulatory assessment and approval. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process.
The Pharmaceutical Development section should describe the knowledge that establishes that the type of dosage form selected and the formulation proposed are suitable for the intended use. This section should include sufficient information in each part to provide an understanding of the development of the drug product and its manufacturing process. Summary tables and graphs are encouraged where they add clarity and facilitate review.
At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified. Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have impact on the quality of the drug product.
In addition, the applicant can choose to conduct pharmaceutical development studies that can lead to an enhanced knowledge of product performance over a wider range of material attributes, processing options and process parameters. Inclusion of this additional information in this section provides an opportunity to demonstrate a higher degree of understanding of material attributes, manufacturing processes and their controls. This scientific understanding facilitates establishment of an expanded design space. In these situations, opportunities exist to develop more flexible regulatory approaches, for example, to facilitate:
• risk-based regulatory decisions (reviews and inspections);
• manufacturing process improvements, within the approved design spacedescribed in the dossier, without further regulatory review;
• reduction of post-approval submissions;
• real-time quality control, leading to a reduction of end-product release testing.
To realise this flexibility, the applicant should demonstrate an enhanced knowledge of product performance over a range of material attributes, manufacturing process options and process parameters. This understanding can be gained by application of, for example, formal experimental designs*, process analytical technology (PAT)*,and/or prior knowledge. Appropriate use of quality risk management principles can be helpful in prioritising the additional pharmaceutical development studies to collect such knowledge.
The design and conduct of pharmaceutical development studies should be consistent with their intended scientific purpose. It should be recognized that the level of knowledge gained, and not the volume of data, provides the basis for science-based submissions and their regulatory evaluation.
2.1 Components of the Drug Product
2.1.1 Drug Substance
The physicochemical and biological properties of the drug substance that can influence the performance of the drug product and its manufacturability, or were specifically designed into the drug substance (e.g., solid state properties), should be identified and discussed. Examples of physicochemical and biological properties that might need to be examined include solubility, water content, particle size, crystal properties, biological activity, and permeability. These properties could be interrelated and might need to be considered in combination.
To evaluate the potential effect of drug substance physicochemical properties on the performance of the drug product, studies on drug product might be warranted. For example, the ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances describes some of the circumstances in which drug product studies are recommended (e.g., DecisionTree #3 and #4 (Part 2)). This approach applies equally for the ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological Products. The knowledge gained from the studies investigating the potential effect of drug substance properties on drug product performance can be used, as appropriate, to justify elements of the drug substance specification (3.2.S.4.5).
The compatibility of the drug substance with excipients listed in 3.2.P.1 should be evaluated. For products that contain more than one drug substance, the compatibility of the drug substances with each other should also be evaluated.
2.1.2 Excipients
The excipients chosen, their concentration, and the characteristics that can influence the drug product performance (e.g., stability, bioavailability) or manufacturability should be discussed relative to the respective function of each excipient. This should include all substances used in the manufacture of the drug product, whether they appear in the finished product or not (e.g., processing aids). Compatibility of excipients with other excipients, where relevant (for example, combination of preservatives in a dual preservative system), should be established. The ability of excipients (e.g., antioxidants, penetration enhancers, disintegrants, release controlling agents) to provide their intended functionality, and to perform throughout the intended drug product shelf life, should also be demonstrated. The information on excipient performance can be used, as appropriate, to justify the choice and quality attributes of the excipient, and to support the justification of the drug product specification (3.2.P.5.6).
Information to support the safety of excipients, when appropriate, should be cross referenced (3.2.P.4.6).
2.2 Drug Product
2.2.1. Formulation Development
A summary should be provided describing the development of the formulation, including identification of those attributes that are critical to the quality of the drug product, taking into consideration intended usage and route of administration.Information from formal experimental designs can be useful in identifying critical or interacting variables that might be important to ensure the quality of the drug product.
The summary should highlight the evolution of the formulation design from initial concept up to the final design. This summary should also take into consideration the choice of drug product components (e.g., the properties of the drug substance, excipients, container closure system, any relevant dosing device), the manufacturing process, and, if appropriate, knowledge gained from the development of similar drug product(s).
Any excipient ranges included in the batch formula (3.2.P.3.2) should be justified in this section of the application; this justification can often be based on the experience gained during development or manufacture.
A summary of formulations used in clinical safety and efficacy and in any relevant bioavailability or bioequivalence studies should be provided. Any changes between the proposed commercial formulation and those formulations used in pivotal clinical batches and primary stability batches should be clearly described and the rationale for the changes provided.
Information from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) that links clinical formulations to the proposed commercial formulation described in 3.2.P.1 should be summarized and a cross reference to the studies (with study numbers) should be provided. Where attempts have been made to establish an in vitro/in vivo correlation, the results of those studies, and a cross-reference to the studies (with study numbers), should be provided in this section. A successful correlation can assist in the selection of appropriate dissolution acceptance criteria, and can potentially reduce the need for further bioequivalence studies following changes to the product or its manufacturing process.
Any special design features of the drug product (e.g., tablet score line, overfill, anticounterfeiting measure as it affects the drug product) should be identified and a rationale provided for their use.
2.2.2. Overages
In general, use of an overage of a drug substance to compensate for degradation during manufacture or a product's shelf life, or to extend shelf life, is discouraged.
Any overages in the manufacture of the drug product, whether they appear in the final formulated product or not, should be justified considering the safety and efficacy of the product. Information should be provided on the 1) amount of overage, 2) reason for the overage (e.g., to compensate for expected and documented manufacturing losses), and 3) justification for the amount of overage. The overage should be included in the amount of drug substance listed in the batch formula (3.2.P.3.2).
2.2.3. Physicochemical and Biological Properties
The physicochemical and biological properties relevant to the safety, performance or manufacturability of the drug product should be identified and discussed. This includes the physiological implications of drug substance and formulation attributes.Studies could include, for example, the development of a test for respirable fraction of an inhaled product. Similarly, information supporting the selection of dissolution vs. disintegration testing, or other means to assure drug release, and the development and suitability of the chosen test, could be provided in this section. See also ICH Q6A Specifications: Test Procedures And Acceptance Criteria For New Drug Substances And New Drug Products: Chemical Substances; Decision Tree #4 (Part 3) and Decision Tree #7 (Part 1) or ICH Q6B Specifications: Test Procedures and Acceptance Criteriafor Biotechnology/Biological Products. The discussion should cross-reference any relevant stability data in 3.2.P.8.3.
2.3 Manufacturing Process Development
The selection, the control, and any improvement of the manufacturing processdescribed in 3.2.P.3.3 (i.e., intended for commercial production batches) should beexplained. It is important to consider the critical formulation attributes, together withthe available manufacturing process options, in order to address the selection of themanufacturing process and confirm the appropriateness of the components.Appropriateness of the equipment used for the intended products should be discussed.Process development studies should provide the basis for process improvement,process validation, continuous process verification* (where applicable), and anyprocess control requirements. Where appropriate, such studies should addressmicrobiological as well as physical and chemical attributes. The knowledge gainedfrom process development studies can be used, as appropriate, to justify the drugproduct specification (3.2.P.5.6).
The manufacturing process development programme or process improvementprogramme should identify any critical process parameters that should be monitoredor controlled (e.g., granulation end point) to ensure that the product is of the desiredquality.
For those products intended to be sterile an appropriate method of sterilization for thedrug product and primary packaging material should be chosen and the choicejustified.
Significant differences between the manufacturing processes used to produce batchesfor pivotal clinical trials (safety, efficacy, bioavailability, bioequivalence) or primarystability studies and the process described in 3.2.P.3.3 should be discussed. Thediscussion should summarise the influence of the differences on the performance,manufacturability and quality of the product. The information should be presented ina way that facilitates comparison of the processes and the corresponding batchanalyses information (3.2.P.5.4). The information should include, for example, (1) theidentity (e.g., batch number) and use of the batches produced (e.g., bioequivalencestudy batch number), (2) the manufacturing site, (3) the batch size, and (4) anysignificant equipment differences (e.g., different design, operating principle, size).
In order to provide flexibility for future process improvement, when describing thedevelopment of the manufacturing process, it is useful to describe measurementsystems that allow monitoring of critical attributes or process end-points. Collection ofprocess monitoring data during the development of the manufacturing process canprovide useful information to enhance process understanding. The process controlstrategies that provide process adjustment capabilities to ensure control of all criticalattributes should be described.
An assessment of the ability of the process to reliably produce a product of theintended quality (e.g., the performance of the manufacturing process under differentoperating conditions, at different scales, or with different equipment) can be provided.An understanding of process robustness* can be useful in risk assessment and riskreduction (see ICH Q9 Quality Risk Management glossary for definition) and tosupport future manufacturing and process improvement, especially in conjunctionwith the use of risk management tools (see ICH Q9 Quality Risk Management).
2.4 Container Closure System
The choice and rationale for selection of the container closure system for thecommercial product (described in 3.2.P.7) should be discussed. Consideration shouldbe given to the intended use of the drug product and the suitability of the containerclosure system for storage and transportation (shipping), including the storage andshipping container for bulk drug product, where appropriate.
The choice of materials for primary packaging should be justified. The discussionshould describe studies performed to demonstrate the integrity of the container andclosure. A possible interaction between product and container or label should beconsidered.
The choice of primary packaging materials should consider, e.g., choice of materials,protection from moisture and light, compatibility of the materials of construction withthe dosage form (including sorption to container and leaching), and safety of materialsof construction. Justification for secondary packaging materials should be included,when relevant.
If a dosing device is used (e.g., dropper pipette, pen injection device, dry powderinhaler), it is important to demonstrate that a reproducible and accurate dose of theproduct is delivered under testing conditions which, as far as possible, simulate theuse of the product.
2.5 Microbiological Attributes
Where appropriate, the microbiological attributes of the drug product should bediscussed in this section (3.2.P.2.5). The discussion should include, for example:
• The rationale for performing or not performing microbial limits testing for nonsterile drug products (e.g., Decision Tree #8 in ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances and ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological Products);
• The selection and effectiveness of preservative systems in products containingantimicrobial preservative or the antimicrobial effectiveness of products thatare inherently antimicrobial;
• For sterile products, the integrity of the container closure system as it relates to preventing microbial contamination.
Although chemical testing for preservative content is the attribute normally includedin the drug product specification, antimicrobial preservative effectiveness should bedemonstrated during development. The lowest specified concentration ofantimicrobial preservative should be demonstrated to be effective in controlling microorganisms by using an antimicrobial preservative effectiveness test. Theconcentration used should be justified in terms of efficacy and safety, such that theminimum concentration of preservative that gives the required level of efficacythroughout the intended shelf life of the product is used. Where relevant, microbialchallenge testing under testing conditions that, as far as possible, simulate patientuse should be performed during development and documented in this section.
2.6 Compatibility
The compatibility of the drug product with reconstitution diluents (e.g., precipitation,stability) should be addressed to provide appropriate and supportive information forthe labelling. This information should cover the recommended in-use shelf life, at therecommended storage temperature and at the likely extremes of concentration.Similarly, admixture or dilution of products prior to administration (e.g., productadded to large volume infusion containers) might need to be addressed.
3. GLOSSARY
Continuous Process Verification
An alternative approach to process validation in which manufacturing processperformance is continuously monitored and evaluated.
Design Space
The multidimensional combination and interaction of input variables (e.g., materialattributes) and process parameters that have been demonstrated to provide assuranceof quality. Working within the design space is not considered as a change. Movementout of the design space is considered to be a change and would normally initiate aregulatory post approval change process. Design space is proposed by the applicantand is subject to regulatory assessment and approval.
Formal Experimental Design
A structured, organized method for determining the relationship between factors affecting a process and the output of that process. Also known as "Design of Experiments".
Lifecycle
All phases in the life of a product from the initial development through marketing until the product’s discontinuation.
Process Analytical Technology (PAT)
A system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.
Process Robustness:
Ability of a process to tolerate variability of materials and changes of the process and equipment without negative impact on quality.
Quality
The suitability of either a drug substance or drug product for its intended use. This term includes such attributes as the identity, strength, and purity (from ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances).
PART II: PHARMACEUTICAL DEVELOPMENT - ANNEX
1. INTRODUCTION
This guideline is an annex to ICH Q8 Pharmaceutical Development and provides further clarification of key concepts outlined in the core guideline. In addition, this annex describes the principles of quality by design1 (QbD). The annex is not intended to establish new standards or to introduce new regulatory requirements; however, it shows how concepts and tools (e.g., design space1) outlined in the parent Q8 document could be put into practice by the applicant for all dosage forms. Where a company chooses to apply quality by design and quality risk management (ICH Q9, Quality Risk Management), linked to an appropriate pharmaceutical quality system, opportunities arise to enhance science- and risk-based regulatory approaches (see ICH Q10 , Pharmaceutical Quality System).
Approaches to Pharmaceutical Development
In all cases, the product should be designed to meet patients’ needs and the intendedproduct performance. Strategies for product development vary from company tocompany and from product to product. The approach to, and extent of, developmentcan also vary and should be outlined in the submission. An applicant might chooseeither an empirical approach or a more systematic approach to product development,or a combination of both. An illustration of the potential contrasts of these approachesis shown in Appendix 1. A more systematic approach to development (also defined asquality by design) can include, for example, incorporation of prior knowledge, resultsof studies using design of experiments, use of quality risk management, and use ofknowledge management (see ICH Q10) throughout the lifecycle1 of the product. Sucha systematic approach can enhance achieving the desired quality of the product andhelp the regulators to better understand a company’s strategy. Product and processunderstanding can be updated with the knowledge gained over the product lifecycle.
A greater understanding of the product and its manufacturing process can create abasis for more flexible regulatory approaches. The degree of regulatory flexibility ispredicated on the level of relevant scientific knowledge provided in the registrationapplication. It is the knowledge gained and submitted to the authorities, and not thevolume of data collected, that forms the basis for science- and risk-based submissionsand regulatory evaluations. Nevertheless, appropriate data demonstrating that thisknowledge is based on sound scientific principles should be presented with eachapplication.
Pharmaceutical development should include, at a minimum, the following elements:
• Defining the quality target product profile1 (QTPP) as it relates to quality,safety and efficacy, considering e.g., the route of administration, dosage form,bioavailability, strength, and stability;
• Identifying potential critical quality attributes1 (CQAs) of the drug product, sothat those product characteristics having an impact on product quality can bestudied and controlled;
• Determining the critical quality attributes of the drug substance, excipientsetc., and selecting the type and amount of excipients to deliver drug product ofthe desired quality1;
• Selecting an appropriate manufacturing process ;
• Defining a control strategy1
An enhanced, quality by design approach to product development would additionallyinclude the following elements:
• A systematic evaluation, understanding and refining of the formulation andmanufacturing process, including;
- Identifying, through e.g., prior knowledge, experimentation, and riskassessment, the material attributes and process parameters that canhave an effect on product CQAs;
- Determining the functional relationships that link material attributesand process parameters to product CQAs;
• Using the enhanced product and process understanding in combination withquality risk management to establish an appropriate control strategy whichcan, for example, include a proposal for a design space(s) and/or real-timerelease testing1
As a result, this more systematic approach could facilitate continual improvement and innovation throughout the product lifecycle (See ICH Q10).
2. ELEMENTS OF PHARMACEUTICAL DEVELOPMENT
The section that follows elaborates on possible approaches to gaining a moresystematic, enhanced understanding of the product and process under development.
The examples given are purely illustrative and are not intended to create newregulatory requirements.
2.1 Quality Target Product Profile
The quality target product profile forms the basis of design for the development of theproduct. Considerations for the quality target product profile could include:
• Intended use in clinical setting, route of administration, dosage form, deliverysystems;
• Dosage strength(s);
• Container closure system;
• Therapeutic moiety release or delivery and attributes affectingpharmacokinetic characteristics (e.g., dissolution, aerodynamic performance)appropriate to the drug product dosage form being developed;
• Drug product quality criteria (e.g., sterility, purity, stability and drug release)appropriate for the intended marketed product.
2.2 Critical Quality Attributes
A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs are generally associated with the drug substance, excipients, intermediates (in-process materials) and drug product.
CQAs of solid oral dosage forms are typically those aspects affecting product purity, strength, drug release and stability. CQAs for other delivery systems can additionallyinclude more product specific aspects, such as aerodynamic properties for inhaled products, sterility for parenterals, and adhesion properties for transdermal patches.For drug substances, raw materials and intermediates, the CQAs can additionally include those properties (e.g., particle size distribution, bulk density) that affect drug product CQAs.
Potential drug product CQAs derived from the quality target product profile and/or prior knowledge are used to guide the product and process development. The list of potential CQAs can be modified when the formulation and manufacturing process are selected and as product knowledge and process understanding increase. Quality risk management can be used to prioritize the list of potential CQAs for subsequentevaluation. Relevant CQAs can be identified by an iterative process of quality risk management and experimentation that assesses the extent to which their variation can have an impact on the quality of the drug product.
2.3 Risk Assessment: Linking Material Attributes and Process Parameters to Drug Product CQAs
Risk assessment is a valuable science-based process used in quality risk management(see ICH Q9) that can aid in identifying which material attributes and processparameters potentially have an effect on product CQAs. Risk assessment is typicallyperformed early in the pharmaceutical development process and is repeated as moreinformation becomes available and greater knowledge is obtained.
Risk assessment tools can be used to identify and rank parameters (e.g., process,equipment, input materials) with potential to have an impact on product quality,based on prior knowledge and initial experimental data. For an illustrative example,see Appendix 2. The initial list of potential parameters can be quite extensive, but canbe modified and prioritized by further studies (e.g., through a combination of design ofexperiments, mechanistic models). The list can be refined further throughexperimentation to determine the significance of individual variables and potentialinteractions. Once the significant parameters are identified, they can be furtherstudied (e.g., through a combination of design of experiments, mathematical models,or studies that lead to mechanistic understanding) to achieve a higher level of processunderstanding.
2.4 Design Space
The relationship between the process inputs (material attributes and processparameters) and the critical quality attributes can be described in the design space(see examples in Appendix 2).
2.4.1 Selection of Variables
The risk assessment and process development experiments described in Section 2.3 can lead to an understanding of the linkage and effect of process parameters andmaterial attributes on product CQAs, and also help identify the variables and theirranges within which consistent quality can be achieved. These process parametersand material attributes can thus be selected for inclusion in the design space.
A description should be provided in the application of the process parameters andmaterial attributes considered for the design space, those that were included, andtheir effect on product quality. The rationale for inclusion in the design space shouldbe presented. In some cases it is helpful to provide also the rationale as to why someparameters were excluded. Knowledge gained from studies should be described in thesubmission. Process parameters and material attributes that were not varied throughdevelopment should be highlighted.
2.4.2 Describing a Design Space in a Submission
A design space can be described in terms of ranges of material attributes and processparameters, or through more complex mathematical relationships. It is possible todescribe a design space as a time dependent function (e.g., temperature and pressurecycle of a lyophilisation cycle), or as a combination of variables such as components ofa multivariate model. Scaling factors can also be included if the design space isintended to span multiple operational scales. Analysis of historical data cancontribute to the establishment of a design space. Regardless of how a design space isdeveloped, it is expected that operation within the design space will result in aproduct meeting the defined quality.
Examples of different potential approaches to presentation of a design space arepresented in Appendix 2.
2.4.3 Unit Operation Design Space(s)
The applicant can choose to establish independent design spaces for one or more unitoperations, or to establish a single design space that spans multiple operations. Whilea separate design space for each unit operation is often simpler to develop, a designspace that spans the entire process can provide more operational flexibility. Forexample, in the case of a drug product that undergoes degradation in solution beforelyophilisation, the design space to control the extent of degradation (e.g.,concentration, time, temperature) could be expressed for each unit operation or as asum over all unit operations.
2.4.4 Relationship of Design Space to Scale and Equipment
When describing a design space, the applicant should consider the type of operationalflexibility desired. A design space can be developed at any scale. The applicant shouldjustify the relevance of a design space developed at small or pilot scale to the proposedproduction scale manufacturing process and discuss the potential risks in the scale-upoperation.
If the applicant proposes the design space to be applicable to multiple operationalscales, the design space should be described in terms of relevant scale-independentparameters. For example, if a product was determined to be shear sensitive in amixing operation, the design space could include shear rate, rather than agitationrate. Dimensionless numbers and/or models for scaling can be included as part of thedesign space description.
2.4.5 Design Space Versus Prove Acceptable Ranges
A combination of proven acceptable ranges1 does not constitute a design space.However, proven acceptable ranges based on univariate experimentation can provideuseful knowledge about the process.
2.4.6 Design Space and Edge of Failure
It can be helpful to determine the edge of failure for process parameters or materialattributes, beyond which the relevant quality attributes cannot be met. However,determining the edge of failure or demonstrating failure modes are not essential partsof establishing a design space.
2.5 Control Strategy
A control strategy is designed to ensure that a product of required quality will beproduced consistently. The elements of the control strategy discussed in Section P.2 ofthe dossier should describe and justify how in-process controls and the controls ofinput materials (drug substance and excipients), intermediates (in-process materials),container closure system, and drug products contribute to the final product quality.These controls should be based on product, formulation and process understandingand should include, at a minimum, control of the critical process parameters1 andmaterial attributes.
A comprehensive pharmaceutical development approach will generate process andproduct understanding and identify sources of variability. Sources of variability thatcan impact product quality should be identified, appropriately understood, andsubsequently controlled. Understanding sources of variability and their impact ondownstream processes or processing, in-process materials, and drug product qualitycan provide an opportunity to shift controls upstream and minimise the need for endproduct testing. Product and process understanding, in combination with quality riskmanagement (see ICH Q9), will support the control of the process such that thevariability (e.g., of raw materials) can be compensated for in an adaptable manner todeliver consistent product quality.
This process understanding can enable an alternative manufacturing paradigm wherethe variability of input materials could be less tightly constrained. Instead it can bepossible to design an adaptive process step (a step that is responsive to the inputmaterials) with appropriate process control to ensure consistent product quality.
Enhanced understanding of product performance can justify the use of alternativeapproaches to determine that the material is meeting its quality attributes. The use ofsuch alternatives could support real time release testing. For example, disintegrationcould serve as a surrogate for dissolution for fast-disintegrating solid forms withhighly soluble drug substances. Unit dose uniformity performed in-process (e.g., using weight variation coupled with near infrared (NIR) assay) can enable real time releasetesting and provide an increased level of quality assurance compared to thetraditional end-product testing using compendial content uniformity standards. Realtime release testing can replace end product testing, but does not replace the reviewand quality control steps called for under GMP to release the batch.
A control strategy can include, but is not limited to, the following:
• Control of input material attributes (e.g., drug substance, excipients, primarypackaging materials) based on an understanding of their impact onprocessability or product quality;
• Product specification(s);
• Controls for unit operations that have an impact on downstream processing orproduct quality (e.g., the impact of drying on degradation, particle sizedistribution of the granulate on dissolution);
• In-process or real-time release testing in lieu of end-product testing (e.g.measurement and control of CQAs during processing);
• A monitoring program (e.g., full product testing at regular intervals) forverifying multivariate prediction models.
A control strategy can include different elements. For example, one element of thecontrol strategy could rely on end-product testing, whereas another could depend onreal-time release testing. The rationale for using these alternative approaches shouldbe described in the submission.
Adoption of the principles in this guideline can support the justification of alternativeapproaches to the setting of specification attributes and acceptance criteria asdescribed in Q6A and Q6B.
2.6 Product Lifecycle Management and Continual Improvement
Throughout the product lifecycle, companies have opportunities to evaluate innovative approaches to improve product quality (see ICH Q10).
Process performance can be monitored to ensure that it is working as anticipated to deliver product quality attributes as predicted by the design space. This monitoring could include trend analysis of the manufacturing process as additional experience is gained during routine manufacture. For certain design spaces using mathematical models, periodic maintenance could be useful to ensure the model’s performance. The model maintenance is an example of activity that can be managed within a company‘s own internal quality system provided the design space is unchanged.
Expansion, reduction or redefinition of the design space could be desired upon gaining additional process knowledge. Change of design space is subject to regional requirements.
3. SUBMISSION OF PHARMACEUTICAL DEVELOPMENT AND RELATED INFORAMTON IN COMMON TECHNICAL DOCUMENTS (CTD) FORMAT
harmaceutical development information is submitted in Section P.2 of the CTD. Other information resulting from pharmaceutical development studies could be accommodated by the CTD format in a number of different ways and some specific suggestions are provided below. However, the applicant should clearly indicate where the different information is located. In addition to what is submitted in the application, certain aspects (e.g., product lifecycle management, continual improvement) of this guideline are handled under the applicant’s pharmaceutical quality system (see ICH Q10).
3.1 Quality Risk Management and Product and Process Development
Quality risk management can be used at different stages during product and process development and manufacturing implementation. The assessments used to guide and justify development decisions can be included in the relevant sections of P.2. For example, risk analyses and functional relationships linking material attributes and process parameters to product CQAs can be included in P.2.1, P.2.2, and P.2.3. Risk analyses linking the design of the manufacturing process to product quality can be included in P.2.3.
3.2 Design Space
As an element of the proposed manufacturing process, the design space(s) can be described in the section of the application that includes the description of the manufacturing process and process controls (P.3.3). If appropriate, additional information can be provided in the section of the application that addresses the controls of critical steps and intermediates (P.3.4). The product and manufacturing process development sections of the application (P.2.1, P.2.2, and P.2.3) are appropriate places to summarise and describe product and process development studies that provide the basis for the design space(s). The relationship of the design space(s) to the overall control strategy can be discussed in the section of the application that includes the justification of the drug product specification (P.5.6).
3.3 Control Strategy
The section of the application that includes the justification of the drug product specification (P.5.6) is a good place to summarise the overall drug product control strategy. However, detailed information about input material controls and process controls should still be provided in the appropriate CTD format sections (e.g., drug substance section (S), control of excipients (P.4), description of manufacturing process and process controls (P.3.3), controls of critical steps and intermediates (P.3.4)).
3.4 Drug Substance Related Information
If drug substance CQAs have the potential to affect the CQAs or manufacturing process of the drug product, some discussion of drug substance CQAs can be appropriate in the pharmaceutical development section of the application (e.g., P.2.1).
4. GLOSSARY
Control Strategy
A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10)
Critical Process Parameter (CPP)
A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.
Critical Quality Attribute (CQA)
A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.
Design Space
The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval (ICH Q8).
Lifecycle
All phases in the life of a product from the initial development through marketing until the product’s discontinuation (ICH Q8).
Proven Acceptable Range
A characterised range of a process parameter for which operation within this range, while keeping other parameters constant, will result in producing a material meeting relevant quality criteria.
Quality
The suitability of either a drug substance or a drug product for its intended use. This term includes such attributes as the identity, strength, and purity (ICH Q6A).
Quality by Design (QbD)
A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
Quality Target Product Profile (QTPP)
A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.
Real Time Release Testing
The ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls.
Appendix 1. Differing Approaches to Pharmaceutical Development
The following table has been developed to illustrate some potential contrasts betweenwhat might be considered a minimal approach and an enhanced, quality by designapproach regarding different aspects of pharmaceutical development and lifecyclemanagement. The comparisons are shown merely to aid in the understanding of arange of potential approaches to pharmaceutical development and should not beconsidered to be all-encompassing. The table is not intended to specifically define theonly approach a company could choose to follow. In the enhanced approach,establishing a design space or using real time release testing is not necesserilyexpected. Current practices in the pharmaceutical industry vary and typically liebetween the two approaches presented in the table.
Appendix 2. Illustrative Examples
A. Use of a risk assessment tool
For example, a cross-functional team of experts could work together to develop anIshikawa (fishbone) diagram that identifies potential variables which can have an impact on the desired quality attribute. The team could then rank the variables based on probability, severity, and detectability using failure mode effects analysis (FMEA) or similar tools based on prior knowledge and initial experimental data.Design of experiments or other experimental approaches could then be used to evaluate the impact of the higher ranked variables, to gain greater understanding of the process, and to develop a proper control strategy.
B. Depication of interactions
The figure below depicts the presence or absence of interactions among three processparameters on the level of degradation product Y. The figure shows a series of twodimensionalplots showing the effect of interactions among three process parameters(initial moisture content, temperature, mean particle size) of the drying operation of agranulate (drug product intermediate) on degradation product Y. The relative slopesof the lines or curves within a plot indicate if interaction is present. In this example,initial moisture content and temperature are interacting; but initial moisture contentand mean particle size are not, nor are temperature and mean particle size.
C. Presentations of design space
Example 1: Response graphs for dissolution are depicted as a surface plot (Figure 1a)and a contour plot (Figure 1b). Parameters 1 and 2 are factors of a granulationoperation that affect the dissolution rate of a tablet (e.g., excipient attribute, wateramount, granule size.)
Two examples are given of potential design spaces. In Figure 1c, the design space isdefined by a non-linear combination of parameter ranges that delivers the dissolutioncritical quality attribute. In this example, the design space is expressed by theresponse surface equation resolved at the limit for satisfactory response (i.e.,80%dissolution). The acceptable range of one parameter is dependent on the value of theother. For example:
- If Parameter 1 has a value of 46, then Parameter 2 has a range of 0 and 1.5
- If Parameter 2 has a value of 0.8, then Parameter 1 has a range of 43 and 54
The approach in Figure 1c allows the maximum range of operation to achieve thedesired dissolution rate. In Figure 1d, the design space is defined as a smaller range,based on a linear combination of parameters.
- Parameter 1 has a range of 44 and 53
- Parameter 2 has a range of 0 and 1.1
While the approach in Figure 1d is more limiting, the applicant may prefer it foroperational simplicity.This example discusses only two parameters and thus can readily be presentedgraphically. When multiple parameters are involved, the design space can bepresented for two parameters, in a manner similar to the examples shown above, atdifferent values (e.g., high, middle, low) within the range of the third parameter, thefourth parameter, and so on. Alternatively, the design space can be explainedmathematically through equations describing relationships between parameters forsuccessful operation.
Example 2: Design space determined from the common region of successfuloperating ranges for multiple CQAs. The relations of two CQAs, i.e., tablet friabilityand dissolution, to two process parameters of a granulation operation are shown inFigures 2a and 2b. Parameters 1 and 2 are factors of a granulation operation thataffect the dissolution rate of a tablet (e.g., excipient attribute, water amount, granulesize). Figure 2c shows the overlap of these regions and the maximum ranges of theproposed design space. The applicant can elect to use the entire region as the designspace, or some subset thereof.
Example 3: The design space for a drying operation that is dependent upon the pathof temperature and/or pressure over time. The end point for moisture content is 1-2%.Operating above the upper limit of the design space can cause excessive impurityformation, while operating below the lower limit of the design space can result inexcessive particle attrition.
