Importance of Critical Quality Attributes in Biopharmaceuticals Development
Dr. Kotta Kranthi Kumar*
Department of Pharmaceutics, SKU College of Pharmacutical Sciences, S. K. University Anantapuramu,
Andhra Pradesh, India.
Quality plays a major role in the pharmaceutical product development and approval. Various official procedures are required for product development. Critical quality plays a major role in the biopharmaceutical consideration. Critical quality attributes plays a major role in the process validation. Critical Quality Attributes (CQA) are chemical, physical, biological and microbiological attributes that can be defined, measured, and continually monitored to ensure final product outputs remain within acceptable quality limits. During this stage acceptable limit, baselines, and data collection and measurement protocols should be established. Data from the design process and data collected during production should be kept by the manufacturer and used to evaluated product quality and process control. The product quality issue arises, historical data would be essential in identifying the sources of errors and implementing corrective measures.
In the 1990s, the FDA’s focus shifted from regulating individual products to regulating the biotechnology industry as a whole . The 1997 FDA Modernization Act established a new approach to reporting manufacturing changes, with the intent of minimizing the differences between applications for biologics and for drug approval, this act was later transposed into guidance documents. The changes added more and more requirements for industry, resulting in increased review times. By the year 2000, the FDA realized that there were undesirable consequences of the regulatory review process  as manufacturers had become wary of implementing new technologies since it was unknown how regulators would perceive such innovation.
This in turn led to higher costs for pharmaceutical manufacture due to the maintenance of wasteful and inefficient manufacturing processes. In many cases, the FDA attributed these high costs to low manufacturing efficiencies and the difficulty of implementing manufacturing of
ICH Q8: Pharmaceutical Development
ICH Q9: Quality Risk Management
ICH Q10: Pharmaceutical Quality System
ICH Q11: Development and Manufacture of Drug Substances
Dealing with the manufacture of Drug Substances,
ICH Q11 ‘Development and Manufacture of Drug Substances (Chemical and Biotechnological/Biological entities)’ was released for public consultation in May 2011 and reached step 4 in May 2012. Importantly for biological and biotechnological products this guideline stated that most of the CQAs of a biologically derived drug product are associated with the drug substance and, thus, are a direct result of the design of the drug substance or its manufacturing process.
ICH Q11 reiterates the commitment to QbD principles in ICH Q8 and provides examples of how this process can be applied to drug substance manufacture. It then goes on to suggest where the data produced by QbD studies and risk assessments can be located in the Common Technical Document format. Dealing with the manufacture of Drug Substances,
ICH Q11 ‘Development and Manufacture of Drug Substances (Chemical and Biotechnological/Biological entities)’ was released for public consultation in May 2011 and reached step 4 in May 2012. Importantly for biological and biotechnological products this guideline stated that most of the CQAs of a biologically derived drug product are associated with the drug substance and, thus, are a direct result of the design of the drug substance or its manufacturing process. ICH Q11 reiterates the commitment to QbD principles in ICH Q8 and provides examples of how this process can be applied to drug substance manufacture. It then goes on to suggest where the data produced by QbD studies and risk assessments can be located in the Common Technical Document format. While most of
ICH Q11 is concerned with identifying what data should be presented in each section of the Common Technical Document, the appendices give some useful examples of the use of DoE experiments to establish the design space for different unit operations, both for small molecules (chemical entities) and biological products. Further codification of the QbD concept came with the release of the ICH Q8 guideline ‘Pharmaceutical Development’ in November 2004. This guideline reached ‘step 4’ – recommendation for adoption by the regulatory agencies party to the ICH – in November 2005. A further annex to the guideline, intended to clarify the concepts in the original guideline, was released for public consultation in November 2007 and reached step 4 in November 2008.
In the ICH Q8 annex that QbD is explicitly defined as, “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”
It is defined as critical quality attribute (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” The pharmaceutical market is valued at $774bn and expected to reach $1.06tn by 2022.1 Biopharmaceuticals play an important role in pharmaceutical industries i.e. this increase and their contribution is set to increase from 27% to 52% of world pharmaceutical sales, dominating the oncology and anti-rheumatics market until 2022, both in sales and R and D.1
Although the trends seem to be in favour of biopharmaceutical development, growth rates have not yet reached their full potential due to financial and technical complexities involved in the early stages of research and development, bioprocess development and preclinical testing. Compared to the 21 biologics approved by the US Food and Drug Administration (FDA) in 2015, only 14 were approved in 2016, indicating a scarcity in innovation and lack of progress in bioprocess development strategies – mainly in early-stage screening and manufacturability. This, coupled with the looming second patent expiry cliff leading to the biosimilar boom, highlights a pressing need for rapid bioprocess development strategies and faster commercialisation. The aforementioned challenges are estimated to put around $200bn of sales at risk.
Tackling these challenges will allow resources to be redirected into more innovation with a focus on drugs for rare and neglected diseases. Criticality determination relies on understanding probability of occurrence and relevance of a given attribute or process parameter; identifying product variants, understanding its biochemical/biophysical properties, and establishing its link to process parameters; and studying impact on function (e.g., binding potency, clearance, antibody-dependent cell-mediated cytotoxicity [ADCC], etc.) and safety (toxicity, immunogenicity).
As noted above, it is impractical to study all possible attributes of process and product in early stages to understand, at an individual level, its impact on function and safety. This interpretation of CQA is most applicable to in-process and finished product specification limits, which suggests that these limits must be critical given that they were designed to ensure product quality. During the early stages of process development and design, other quality attributes may be measured that, over the course of development, do not end up as either in-process or finished product tests in the commercial process. These test results may show little variation and present little to no risk to product quality. In other cases, while process duration or yield is measured, they are not related to the product quality and are, therefore, not CQAs. However, even when defined as critical, not all CQAs have equal impact on safety and effectiveness.
This is an important point. Establishing appropriate analytical/biophysical/functional tools that are fit-for-purpose for sensitivity and specificity is key to ensure the known/hypothesized impacts (on structure, function, and safety) can be studied objectively. For example, during commercial development, enrichment studies can be conducted to study impact (and hence, criticality) of one variant at a time. Another example is use of state-of-the-art higher order structure tools, when needed (not suitable for routine use), to deconvolute structural impact from multiple degradations (e.g., oxidation, isomerization) occurring at the same time.
Consider all DP quality attributes; physical attributes identification, assay, content uniformity, dissolution and drug release, degradation products, residual solvents, moisture, microbial limits, etc. Identify a CQA based on the severity of harm to a patient (safety and efficacy) resulting from failure to meet that quality attribute.
Identified before taking into account risk control does not change as a result of risk management Tools can be used to determine CQAs for biologics The pharmaceutical industry is trying to embrace quality by design (QbD) methodologies provided by the FDA’s process validation (PV) guidance and International Conference on Harmonization (ICH) Q8/Q9/Q10. Many companies are challenged by Monitoring Critical Process Parameters (CPP) and Critical Quality Attributes (CQA).
Critical Quality Attributes (CQA) is defined by the FDA as 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 (ICH Q8).
This interpretation of CQA is most applicable to in-process and finished-product specification limits, suggesting these limits must be critical given that they were designed to ensure product quality.
Key product and process considerations (including CQA and CPP) are scientifically designed to meet the desired final-quality objectives and meet the US FDA Pharmaceutical Quality Assessment System (PQAS). For a quality attribute to be designated as “not critical,” it has to have no risk to the patient (e.g., yield, process duration). Attributes that are not critical to quality are sometimes named process performance attributes to distinguish from quality attributes.
Examples of risk levels for CQAs (as stated by ICH Q8 (R2) (Pharmaceutical Development)), include:
· High: assay, immunoreactivity, sterility, impurities, closure integrity
· Medium: appearance, friability, particulates
· Low: container scratches, non-functional visual defects.
Application of QbD:
1. Biotech therapeutics, particularly complex products such as monoclonal antibodies (mAbs), can have numerous quality attributes that can potentially impact safety and/or efficacy of the product (2). Identifying CQAs for a biotech therapeutic is the first and arguably the most difficult step in implementation of quality by design (QbD) for development and production of biopharmaceuticals.
2. Even if a firm chooses not to pursue intensive studies to map out complete design spaces for their manufacturing process, and instead opts for what the International Conference on Harmonization (ICH) Guideline Q11 refers to as a “traditional approach,” the ability to differentiate between what is and is not important for a molecule can drive sound decision-making in process development, which can lead to improved efficiency, cost savings, and more consistent product quality (5). And for those sponsors who do embrace a more comprehensive, “enhanced approach” to development, a solid understanding of product quality attributes serves as the touchstone upon which process design and integrated control strategies are built.
3. Structural characterization is used to assess the CQAs of biopharmaceutical products. The structural data must be supported by functional data to establish a structure-function relationship. In turn, these data can then be used to define the structural components’ impact on the activity of the product. Furthermore, the characterization data obtained are essential for product development and regulatory acceptance. Characterization of multiple product batches is essential to demonstrate to the regulatory body that the manufacturer has control of the manufacturing process. This is achieved by analyzing a number of batches of product and comparing the data. Significant differences between batches need to be investigated and their impact on the function of the product assessed. This comparison in the QbD paradigm also centers around the CQAs.
4. The European Medicines Agency’s guideline covering “Production and Quality Control of Monoclonal Antibodies” requests that “the mAb should be characterized thoroughly” (6). “This characterization should include the determination of physicochemical and immunochemical properties, biological activity, purity, impurities, and quantity of the mAb, in line with ICH Q6B guideline” (7). The EMA mAb guideline also draws attention to a number of structural features including N- and C-termini (in particular pyroglutamic acid at the N-terminus and lysine at the C-terminus of the heavy chain), free sulfhydryl and disulphide bridge structure, glycosylation (in particular the degree of mannosylation, galactosylation, fucosylation, and sialylation), and other post-translational modifications (e.g., deamidation, oxidation, isomerisation, fragmentation, and glycation).
5. In this 30th article of the “Elements of Biopharmaceutical Production” series, the authors focus on proposing an approach towards establishing CQAs for a mAb therapeutic product.
Product risk assessments:
Identification of CQAs is often performed through a series of product risk assessments conducted over the program lifecycle, the first of which should be performed early in development to bring clarity to the goals of the Phase I process. Although the criticality of some attributes at this stage may still be somewhat based on speculation, these “potential CQAs” (pCQAs) serve as both a baseline for development to proceed and a gap analysis to identify which attributes would benefit from further in-vitro or in-vivo studies to ascertain their true impact on efficacy and safety. As the molecule progresses through development and more is learned about the relationship between product attributes and their impact (or non-impact) on potency, pharmacokinetics (PK), or safety, these pCQAs can be further refined and accordingly designated as CQAs as the product approaches the licensure application.
Because assigning criticality to an attribute hinges upon the question of risk posed to product safety and efficacy, a well-rounded product risk-assessment team should include representatives with expertise in PK, toxicology, in-vivo biology, and clinical management. A risk-ranking and filtering approach developed on the firm’s experiences and regulatory feedback may be used. Many such tools have been presented in the literature, and a firm can pick a tool of their choice as long as the basis is rational and it has been justified that the tools are used consistently (8, 9). The risk-assessment team first compiles a list of all the quality attributes of the product and systematically evaluates each attribute with regards to two factors: impact and uncertainty.
For impact, the team determines the severity of the consequences that would be associated with failure to control the attribute. The team considers the effects of the attribute not only on potency with respect to the intended mechanism of action, but also PK, pharmacodynamics (PD), immunogenicity, off-target effects, and direct impact to safety. The data used in the impact assessment may come from structure-activity relationship (SAR) studies, nonclinical studies, clinical exposure history, and toxicology reports (4). For platform molecules, or new products with structural homology to established classes (e.g., Fc fusion proteins, pegylated proteins), the team can leverage information from related proteins. Conversely, the more novel the protein is, the less opportunity there may be to apply knowledge across products.
After assigning an impact score, the team then evaluates the quantity and relevance of the body of data used in its assessment and assigns an uncertainty score to the attribute. The team considers its degree of reliance on in-vitro vs. in-vivo data, the availability of molecule-specific data pertaining to potency and PK, the relevance of data leveraged from related molecules, and the range of clinical exposure. Process additives undergo a similar assessment, which focuses on the sufficiency of toxicology data and the additives’ history of use. In general, the assessment of product quality attributes for novel proteins will have a higher degree of uncertainty than platform molecules in early development. For these products, one should strongly consider conducting the initial product risk-assessment exercise early in the development cycle to align the organization on a commonly-recognized target product profile. Otherwise, cell culture, purification, and drug product development may put undue importance on meeting certain criteria that are ultimately not critical, resulting in suboptimal processes that make unnecessary trade-offs between attributes.
Once the impact and uncertainty scores have been assigned, the product of these two values constitutes the risk priority number (RPN) for the attribute (9). Although the scoring system may define a numerical threshold for which attributes would receive a CQA or pCQA designation, the degree of confidence in assigning the impact and uncertainty scores must be kept in mind to avoid over-interpretation of the analysis. Instead, the authors have found that viewing a product’s quality attributes from a more holistic view, using the scores to generally characterize their degree of criticality with labels such as “high,” or “moderate-to-low,” is preferable (4). This is also consistent with guidance from regulators, who encourage firms to view attributes as lying along a “continuum of criticality,” in which attributes warrant different degrees of control depending on how critical they are and how readily they can be controlled through the process. It should be highlighted that while an attribute can be “less critical”, it does not mean that a control strategy is silent with regards to its control; every attribute requires a control strategy commensurate with its degree of risk.
It is also important to note that within the context of a product risk assessment, it is generally a good practice to exclude process capability considerations and the extent to which they can mitigate the risk. The fact that a highly critical attribute is easily controlled through the process, even to the point of not requiring routine testing, should be captured separately in process risk assessments and in the overall control strategy design and justifications. By evaluating attribute criticality solely on the basis of impact and uncertainty, the product risk assessment only needs to be revised when new information is discovered regarding the biology or toxicity of the attributes themselves, and not every time a process change is made.
8Approach to Identify Material Attributes and Process Parameters
From the above I conclude QbD approaches for development and assessment of problems in the product and can be beneficial to improve quality drug products to patient, robust manufacturing quality and reduce batch failures and hence auspicious scientific implementation in quality assurance for pharmaceutical industry.
1. www.fda.gov/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm122879.htm
2. USFDA. Revised guidance for industry. www.fda.gov/downloads/Drugs/GuidanceCompliance Regulatory Information/ Guidances/ucm072349.pdf
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3. PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance" (PDF). Food and Drug Administration. Retrieved 10 December 2014.
4. Process Validation (P2V) Validation Online. Retrieved 22 November 2014.
2. 6."Defining Critical Quality Attributes in the Pharmaceutical Manufacturing Process". GXP-CC. Retrieved 10 November 2014.
3. 7."Critical Quality Attributes (CQA)". Atris Information Systems. Retrieved 10 November 2014.
4. 8."Continuous Process Verification". Atris Information Systems. Retrieved 17 November 2014.
Received on 11.01.2019 Accepted on 28.02.2019
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