QBD…basic approach

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Quality by Design (QbD)

Over the past three years, the US Food and Drug Administration has introduced the concept of Quality by Design (QbD), intended for improving quality assurance and control in pharmaceutical manufacturing. ICH Q8 defines quality as “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.” ICH Q6A emphasizes the role of specifications stating that “Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.” Woodcock defined a high quality drug product as a product free of contamination and reproducibly delivering the therapeutic benefit promised in the label to the consumer. This definition of product quality focuses on the performance of the drug product while the ICH definition focuses on specifications. To achieve a high quality product of predefined specification, QbD is a current terminology used in pharmaceutical industry. Pharmaceutical QbD is a systematic, scientific, risk-based, holistic and proactive approach to pharmaceutical development that begins with predefined objectives and emphases product and processes understanding and process control. It means designing and developing formulations and manufacturing processes to ensure predefined product quality objectives. QbD identifies characteristics that are critical to quality from the perspective of patients, translates them into the attributes that the drug product should possess, and establishes how the critical process parameters can be varied to consistently produce a drug product with the desired characteristics. In order to do this the relationships between formulation and manufacturing process variables (including drug substance and excipient attributes and process parameters) and product characteristics are established and sources of variability identified. This knowledge is then used to implement a flexible and robust manufacturing process that can adapt and produce a consistent product over time.

USFDA perspective on quality by design

The adoption of quality by design (QbD) in the pharmaceutical industry is an evolving process. To facilitate the implementation of QbD, the US Food and Drug Administration launched a pilot program in 2005 to allow participating firms an opportunity to submit chemistry, manufacturing, and controls (CMC) information demonstrating application of QbD. FDA launched the CMC pilot in July 2005 to evaluate the utility of comprehensive Quality Overall Summary as part of a new drug application (NDA) and to implement new concepts such as QbD, design space, and real-time release contained in the International Conference on Harmonization’s guidance’s, Q8 Pharmaceutical Development and Management and the FDA process analytical technology (PAT) guidance PAT:A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance. The pilot has allowed FDA and industry to work together to explore various ways to implement ICH Q8, ICH Q9, ICH Q10 and FDA PAT guidance. All these guidelines help the industries to achieve the desired state of product quality.

Following figure (1) shows the ICH quality road map to achieve desired state of quality.

Fig.1: ICH quality road map to achieve desired quality of product

It is expected that companies who adopt QbD, together with a quality system as described in the draft International Conference on Harmonization (ICH) Q10 document, “Pharmaceutical Quality Systems,” will achieve this “desired state” of pharmaceutical manufacturing. FDA outlines the following key elements of quality by design:

  • Target the product profile
  • Determine critical quality attributes (CQAs)
  • Link raw material attributes and process parameters to CQAs and perform risk assessment
  • Develop a design space
  • Design and implement a control strategy
  • Manage product life cycle, including continual improvement.

The bottom line benefits of QBD and process understanding

When fully implemented QBD means that all the critical sources of process variability have been

identified, measured and understood so that they can be controlled by the manufacturing process itself. The resulting business benefits are significant:

  1. Reduced batch failure rates, reduced final product testing and lower batch release costs
  2. Lower operating costs from fewer failures and deviation investigations
  3. Increased predictability of manufacturing output and quality
  4. Reduced raw material, WIP and finished product inventory costs
  5. Faster tech transfer between development and manufacturing
  6. Faster regulatory approval of new product applications and process changes
  7. Fewer and shorter regulatory inspections of manufacturing sites
  8. Real tome release of the product

These benefits translate into significant reductions in working capital requirements, resource

costs and time to value. The bottom line gains, in turn, pave the way for additional top line growth.

Pharmaceutical quality by testing vs pharmaceutical quality by design:

Pharmaceutical quality by testing is a current approach in the pharmaceutical system, product quality is ensured by raw material testing, drug substance manufacturing, a fixed drug product manufacturing process, in-process material testing, and end product testing. The quality of raw materials including drug substance and excipients is monitored by testing. If they meet the manufacturer’s proposed and FDA approved specifications or other standards such as USP for drug substance or excipients, they can be used for the manufacturing of the products. Because of uncertainty as to whether the drug substance specification alone is sufficient to ensure quality, the drug substance manufacturing process is also tightly controlled. A change to the drug substance manufacturing process may require the drug product manufacturer to file supplements with the FDA. Finished drug products are tested for quality by assessing whether they meet the manufacturer’s proposed and FDA approved specifications. If not, they are discarded. Root causes for failure are usually not well understood. The manufacturers risk ongoing losses of the product until the root causes of failure are understood and addressed or FDA approves supplements to revise (e.g., widen) the acceptance criteria to pass the previously failed batches. Typical specifications for an immediate release oral solid dosage form, for example, include assay, uniformity, impurities, moisture, and dissolution. Under the current paradigm, the specification is tight because it is used to assure consistency of manufacturing processes. The stringent specification has resulted in recalls and drug shortages. But pharmaceutical QbD is a systematic, scientific, risk-based, holistic and proactive approach to pharmaceutical development that begins with predefined objectives and emphases product and processes understanding and process control. QbD allows the real time release of the product because it has no scope of product failure with respect to quality. Under the QbD, batches may not be actually tested against the specification as the process understanding and/or process control provides sufficient evidences that the batches will meet the specification if tested, which allows the real time release of the batches. Further, the specification under the QbD is solely used for the confirmation of product quality, not manufacturing consistency and process control.

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