Lawrence X. Yu is deputy director for science in the Office of Generic Drugs (OGD) at the US Food and Drug Administration, 7519 Standish Place, Rockville, MD 20855.

Lawrence X. Yu

The US Food and Drug Administration's Office of Generic Drugs (OGD) and the Generic Pharmaceutical Association (GPhA) held a two-day workshop in June 2009 in Maryland, on pharmaceutical quality by design (QbD) for generic-drug products. The purpose of the workshop was for scientists from FDA and the generic-drug industry to discuss QbD for generic drugs in the context of the International Conference on Harmonization Q8(R1) 

 and its Annex (1). The specific objectives of this workshop were to identify gaps in the understanding of QbD between FDA and industry and to build a common understanding of certain key aspects of QbD, including:  

The quality target product profile (QTPP) and critical quality attributes (CQAs)

Manufacturing process design and development

Identification of critical process parameters (CPPs) and critical material attributes (CMAs)

This article summarizes the outcome of the workshop and identifies issues that require further clarification and discussion. 

Quality target product profile and critical quality attributes

The QTPP is a prospective summary of the quality characteristics of a drug product that will ideally be achieved to ensure the desired quality, taking into account the safety and efficacy of the drug product. According to ICH Q8(R1), it:  

"Could include the intended use in a clinical setting, route of administration, dosage form, delivery systems, dosage strength(s), container-closure system, therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance) appropriate to the drug product dosage form being developed, and drug product quality criteria (e.g., sterility, purity, stability and drug release) appropriate for the intended marketed product" (1). 

 Before the publication of ICH Q8(R1), the QTPP was called the target product quality profile (TPQP) (2, 3). 

Two key questions about the QTPP came up during the workshop: should the QTPP be assessed qualitatively or quantitatively and should the QTPP be expected to change during the course of pharmaceutical development? Some participants thought that some elements of the QTPP should have quantitative targets. At the meeting, there was criticism of the value of QTPP because it restates obvious aspects of product quality. Generic-drug manufacturers are currently using QTPP concepts under different names such as development goals or design constraints. 

Many of the QTPP elements such as dosage form, strength, route of administration, identity, assay, and content uniformity are expected to be constant during development because there are regulatory requirements that these elements be the same as the reference listed drug or meet compendial standards. Other QTPP elements such as dissolution may change based on knowledge gained during development.  

The QTPP is different from the product specification because the QTPP may include elements such as a container–closure system and information about pharmacokinetics and bioequivalence that are not part of a product specification. The specification may include tests not found in the QTPP. Tablet hardness, for example, may be included in the specification for process monitoring but may not be included in the QTPP. In general, the QTPP should only include patient-relevant product-performance elements.  

 Identification of CQAs is the next step after developing a QTPP in drug-product development. 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 should only include product attributes that have the potential to be altered by changes to process parameters or formulation variables during pharmaceutical development and that are directly related to the safety and efficacy of a drug product. For example, assay, content uniformity, dissolution, and impurities are common CQAs for an immediate-release tablet product. The QTPP may include other quality attributes of a drug product such as strength and dosage form. These attributes are not considered to be CQAs because they will not change during the pharmaceutical development process even though they are essential elements of a marketable product.  

 is reserved for attributes of the drug product. The term 

 is used for attributes of drug substance, excipient, and in-process materials. During the workshop, FDA and industry scientists agreed that generic-drug manufacturers should define the QTPP and CQAs before starting development work and share this information with FDA as a part of pharmaceutical development. If the QTPP or CQAs change during development, the change(s) should be indicated in the product-development report. 

To consistently achieve the drug-product quality specified in the label, the drug substance needs to be thoroughly characterized with respect to its physical, chemical, biological, and mechanical properties such as solubility, polymorphism, stability, particle size, and flow properties (2). It is well recognized that excipients could be a major source of variability. Characterization and understanding of excipients' pharmaceutical properties depend on the function and utility of excipients. Drug-excipient compatibility knowledge and information are valuable in the design of formulation and manufacturing processes. Such information may be gained through theoretical investigation and experimental studies. It was noted during the workshop that mechanistic understanding of degradation kinetics provides more value in predicting stability than experimental data collected under artificial stress conditions.  

Not all prototype formulations can be evaluated in human subjects, which means that developing sensitive 

 dissolution methods is crucial to an effective development program (4). FDA's recommended 

dissolution method is generally used for quality control. Generic-drug sponsors report using in-house methods for pharmaceutical development (some mentioned using as many as five biorelevant dissolution conditions) to evaluate formulations and processes before performing bioequivalence studies. FDA participants in the workshop found it compelling that pharmaceutical scientists develop a battery of biorelevant dissolution methods to accelerate drug-product development. Further, generic-drug industry participants noted that the Biopharmaceutics Classification System is valuable in guiding formulation development (2). 

To establish formulation robustness, sponsors of abbreviated new drug applications (ANDAs) generally evaluate relevant quality attributes of product manufactured at the laboratory scale. The availability of drug substance may influence the number of studies and therefore, product understanding. It was suggested during the workshop that QbD should rely on the relevance of individual studies rather than the number of studies because one of the objectives of QbD is to understand how the material attributes of the drug substance and excipient influence product quality. ANDA sponsors generally agreed that a formulation design space (preapproved ranges) would be valuable to industry if appropriate regulatory flexibility is granted. However, the establishment of formulation design space should not delay FDA's approvals. It was suggested that FDA consider the establishment of formulation design space as a postapproval activity.  

Workshop participants noted that process development and formulation design cannot be separated because a formulation cannot become a product without a prescribed process. Process design is the initial stage of process development, in which an outline of the commercial manufacturing processes is documented, including the intended scales of manufacturing. The outline should include all the factors that need to be considered for the design of the process, including facility, equipment, material transfer, and manufacturing variables. Other factors to consider during process development are the QTPP and CQAs. Depending upon the product being developed, type of process, and process knowledge the development scientists have, it may be necessary to conduct preliminary feasibility studies before completing the process development. The selection of the type of process depends upon the formulation and the properties of the materials. 

Identification of critical process parameters and critical material attributes

A pharmaceutical manufacturing process usually consists of a series of unit operations to produce the desired quality product. A unit operation is a discrete activity such as mixing, milling, granulation, drying, compression, or coating, that involves physical or chemical changes. A physical, chemical, or microbiological property or characteristic of an input or output material is defined as a material attribute. Process parameters include the type of equipment and equipment settings, operating conditions (e.g., time, temperature, pressure, pH, and speed), and environmental conditions such as moisture. The output of a process depends on the process parameters and the input material attributes. 

Process robustness is the ability of a process to demonstrate acceptable quality of the product and tolerate variability in inputs at the same time. The effects of variations in process parameters and input material attributes are evaluated in process-robustness studies. The analysis of these experiments identifies CPPs and CMAs that could affect product quality and establishes limits for these CPPs and CMAs within which the quality of drug product is assured. When the limits on CPPs and CMAs are scale-independent, they may form the basis of a design space as defined in ICH Q8(R1) (1). Even when a design space is not established, multivariate experiments are valuable because they identify CPPs and CMAs and support a conclusion of process robustness. 

Process parameters and material attributes are critical when a realistic change can result in failure for the product to meet the QTPP or a CQA that is outside an acceptable range. Process parameters are not critical when there is no trend to failure and there is no evidence of significant interactions within the proven acceptable range (3). 

Although workshop participants generally agreed that it was necessary to conduct process robustness studies for each unit operation, some viewed this effort as overkill. The primary reason for this claim was that some generic-drug sponsors have sufficient prior knowledge to determine whether a process parameter or material attribute is critical or not and to know when process operating conditions will be robust. Workshop participants are generally in agreement that process-robustness studies should be risk-based, that is, more studies with complex products and fewer studies with simple low-risk dosage forms. 

The manufacturing and use of a drug product necessarily entail some degree of risk... The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the therapeutic benefit to the patient. The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk (5). 

Performing a risk assessment before pharmaceutical development helps manufacturers decide which studies to conduct. Risk assessments are often driven by knowledge gaps or uncertainty. Study results determine which variables are critical and which are not, which then guide the establishment of control strategy for in-process, raw-material, and final testing. There were questions during the workshop about how risk-assessment processes should be described and included in regulatory submissions. 

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 (1).  

Because design space is potentially scale- and equipment-dependent, the design space determined at the laboratory scale may not be relevant to the process at the commercial scale. Therefore, design-space verification at the commercial scale becomes essential unless it is demonstrated that the design space is scale-independent. Currently, generic-drug sponsors obtain information about acceptable ranges for individual CPPs and CMAs at laboratory or pilot scales. Sponsors may occasionally conduct these studies with appropriate design of experiments, including multivariate interactions, which will create a design space at the laboratory or pilot scale. Such a design space, however, will have limited regulatory flexibility because the regulatory scientists will be unable to determine whether the design space is still valid at the commercial scale unless sponsors can provide additional information that shows the design space is scale-independent or actual verification data at the commercial scale. 

Workshop discussions demonstrated that there is confusion among industry and regulatory scientists about the connection between design space and QbD. Many believe design space and QbD are interchangeable terms. This is incorrect. For generic-drug applications, design space is optional. QbD can be implemented without a design space because product and process understanding can be established without a formal design space (6). It should be pointed out that implementation of QbD is strongly encouraged by FDA. For some complex drug substances or drug products, implementation of QbD is considered a required component of the application. 

Currently, the mechanistic understanding of pharmaceutical unit operations is limited. Scale-up is largely based on general rule-of-thumb and trial-and-error approaches. During scale-up, process parameters may vary while material attributes will not. Workshop participants agreed that QbD offers many more advantages for complex products than for simple ones. It was noted that scale-up can be done without QbD, but with much higher risk. 

 ICH Q8(R1) defines control strategy as:  

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 (1). 

Specifically, the control strategy may include:    

Control of input material attributes, in terms of CMAs 

Controls for unit operations (CPPs and process endpoints)

A monitoring program (intermittent testing) for verifying multivariate prediction models (1).

Workshop participants agreed with the definition of control strategy. There was some confusion, however, about how the control strategy is different from a specification and whether the control strategy should reflect target ranges or the acceptable ranges. This issue merits further discussion. 

The two-day FDA-OGD and GPhA workshop led to a common understanding of several specific topics related to QbD for generic drugs. These issues include CQAs; drug substance and excipient properties, as well as their compatibility studies; formulation design and development; manufacturing process design and development; CPPs and CMAs; risk assessment; and scale-up process and control strategy. It is believed that ANDAs should include these elements. The following topics require further discussion:   

Articles

The authors relay the outcome of a two-day workshop that brought together regulators and generic-drug industry representatives.