QbD & PAT tools — Lifeline during the life cycle of Pharma Products
“Our future success is directly proportional to our ability to understand, adapt and integrate new technology into our work” -Sukant Ratnakar
Preamble:
Across the Globe, the Pharmaceutical industry has always been striving for product Quality, Efficacy, and safety, and now one step ahead process automation is also under transformation by using artificial intelligence. However, in the past, these attributes were not so much focused or mandatory. In earlier days the traditional quality by testing (QbT) approach was being followed, the product quality and performance are predominantly ensured by end product testing, with limited understanding of the product, process, and critical process parameters understanding. In recent days the quality, safety & efficacy of the products are the prime focus, thus the Regulatory bodies are emphasizing implementing quality by design (QbD) and Process analytical tools (PAT), the science-based approach for better products & process understanding by reducing process variation and the enabling process-control strategies. In this regard, the pharmaceutical industry is currently undergoing a significant transformation to streamline its R&D process, provide greater manufacturing flexibility and control, and reduce regulatory hindrances. However, to date, there is limited understanding and major concerns regarding the implementation of QbD principles and PAT in the pharmaceutical arena. The objective of this article is therefore to provide a comprehensive understanding of various aspects of QbD and PAT in the product life cycle, along with addressing the concerns related to its implementation to achieve pharmaceutical process automation.
OVERVIEW:
For the Pharmaceutical dosage form the previous concept of Quality determination was by testing only, which means from a batch of dosage form little Random quantity of representative samples will be withdrawn for testing, and the results will determine the quality of the product. But the quality of each unit dosage is very crucial from the patient’s perspective. So Now the recent concept of Quality is ‘Quality by design” So that quality is inbuilt by design from the product inception stage onwards. It means the design of Specifications of raw material, packing material, and Finished Goods and the Formulation design, Process design, Process Parameters design space, etc., is to be considered or designed scientifically by using the relevant and effective scientific tools i.e. DOE to maintain quality by design throughout the product life cycle. The conventional development process uses an empirical approach that requires continuous end-product testing and inspection to determine quality. This approach ignores real-world variability in materials and process controls. At present, there is a different approach than yesterday. It’s called Quality by Design (QbD). This is very scientific and logical. PAT is an integral part of the QbD in the area of Process Control. In the absence of these two important elements i.e. QbD and PAT pharmaceutical process Automation is highly impossible in product life cycle management. The QbD approach is now fully applicable for generic drug Development, to achieve it. The regulatory authority always insists on implementing the ICH Q 8 to Q11, in the relevant area of each part. To address the subject article we need to understand thoroughly both QbD and PAT.
what is QbD-
As per ICH Q8, Quality by Design (QbD) is 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 uses a systematic approach to ensure quality by developing a thorough understanding of the compatibility of a finished product with all of the components and processes involved in manufacturing that product. Instead of relying on finished product testing alone, QbD provides insights upstream throughout the development process. As a result, a quality issue can be effectively analyzed and its root cause quickly identified. QbD requires the identification of all critical formulation attributes and process parameters as well as determining the extent to which any variation can impact the quality of the finished product. The more information generated on the impact — or lack of impact — of a component or process on a product’s quality, safety, or efficacy, the more business flexibility Quality by Design provides.
The following are the very important Elements of QbD-
Quality Target Product Profile (QTPP) — The product Design: the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, Quality Target Product Profiles (QTPP) are patient and clinical outcome metrics, it is different from CQA.
Critical Process Parameter (CPP) — The Process variables which have an impact on a critical quality attribute (CQA)
Critical Quality Attributes(CQA)- physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality
Critical Material Attribute (CMA)- A material whose variability has an impact on a critical quality attribute.
Design Space- the combination of materials and process conditions that provides assurance of quality for a pharmaceutical Product,
ICH Q8 (R2) defines Design Space as: “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
Design of experiments (DOE)- is a statistical tool that can be used to evaluate single changes or multiple changes to a process at once and predict the resulting change to the output of the process by using single to multiple factors and levels.
Control strategy- a planned set of controls that are taken from a current product and a thorough understanding of its production process. A control strategy ensures the process performs as it should and maintains quality
Quality risk management (QRM)- the process of identifying, evaluating, and mitigating recognized risks connected with medicines and healthcare goods, Quality risk is the potential for losses due to quality that fails to meet your quality goals
Operating Space or Range- a region around the target operating conditions that contain common operational variability
Process Validation — As Per ICH Q7- defined as documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes, as per recent FDA Guidance the process validation concept evolved as Continuous Process Verification(CPV) in three Stages as-
Stage 1 — Process Design.
Stage 2 — Process Validation or Process Qualification.
Stage 3 — Continued Process Validation.
THE CHALLENGES OF ADOPTING QbD:
Despite the many financial and operational benefits of QbD, and even with the new FDA recommendations, not all companies have adopted this approach. As the saying goes “you either pay now or pay later.” Implementing QbD beginning at the development phase requires a dedicated, disciplined, and sustained commitment by an organization. Understanding the effort necessary to implement QbD is a key component to successful adoption. Some of the most common barriers to adoption include Insufficient understanding of the process and its benefits, Organizational resistance to change, Denial of the need (Our process is under control), Competing priorities, and Lack of resources and expertise in QbD.
When you consider the tremendous potential financial gain, faster time to market, process improvements, and quality assurance generated by a successful implementation of QbD, these obstacles seem to pale in comparison.
The FDA expects at least these QbD components in all submissions:
• Quality Target product profile (QTPP)
• List of critical quality attributes (CQAs)
• List of critical material attributes of drugs and excipients (CMAs)
• List of critical process parameters (CPPs)
• A control strategy that ensures the product’s reliability meets its predefined objectives.
The FDA clearly sees QbD as the way to enhance the quality of drug products for the benefit of everyone involved: Manufacturers will save time and money developing and producing drugs. Regulators will save time and resources approving drug applications, conducting inspections, and troubleshooting quality issues. Patients will be assured of more consistent, high-quality drug products that always meet safety and efficacy requirements. In the eyes of the FDA and the many advocates of QbD, the approach represents a way to “do more with less” and gain a winning outcome for manufacturers, regulators, and patients. Proper implementation of QbD can potentially provide several benefits for development and manufacturing:
• More efficient use of development time and costs.
• Ability to meet FDA submission guidelines and expectations.
• Reduced approval times — and fewer queries –from the FDA.
• Rapid response to any manufacturing deviation.
. Prevention of commercial batch failure during the Product life cycle.
The impact of poor development that spirals out of control for the marketed product can be shocking. Fortunately, these costs and delays can be avoided by using QbD, a more modern, scientific & Logical approach that formalizes product design and development and eliminates troubleshooting by trial and error. Despite the numerous tangible benefits of QbD, most companies do not understand the concept, appreciate its value, or know how to implement it effectively. Successful implementation of QbD requires dedicated, disciplined, stubborn commitment and effort. Additionally, a sense of urgency now exists as the FDA began strongly encouraging all drug product applicants to use QbD. Deficiency letters will now explicitly cite the lack of QbD. QbD is a scientific method to define product and process design during the development stage to produce consistent quality during the product life cycle, however in the product life cycle to monitor and control the critical and key process parameters in turn quality of the drug product, the role of PAT tools is very important. So it is very obvious to establish the relationship between QbD and PAT tools, especially when we are depending on process automation for the quality, safety, and efficacy of the product.
What is PAT-
Process analytical tools (PAT) are Advance tools for designing, analyzing, and controlling the Pharmaceutical Manufacturing Processes through timely measurements (i.e. line, offline, in line) of Critical Quality and performance attributes for raw and process Materials & processes with the objective of ensuring the product’s desired quality. The concept of PAT is based on the identification and control of risks during the manufacturing of drug products
Importance of PAT:
It effectively inbuilt the quality into products; also helped to run the process parameters within the defined design space to eliminate the process variation, eventually resulting in process safety. It also helps to understand the manufacturing process and its control in totality.
Different levels of PAT Implementation:
The preliminary stage is Capturing Manufacturing Process Parameters. Scale up stage is the Evaluation of process parameters Data. The Provisional Stage is Process Understanding. The permanent Stage is Actual process Monitoring and Process control by Implementing PAT Tools.
PAT Analysis is preferred over conventional Laboratory Analysis:
Followings are the reason, why PAT is preferred that are Faster or online results are available, which helps to take the decision to release the batches for consumption, PAT eliminate Human error, It is safe for to product, Human, and Environment, It increases the productivity and During analysis, sample integrity exists.
PAT Applications in Pharmaceutical Process:
Unit Operation
PAT Tools ( On-Line)
Raw Material Identification
Near InfraRed (NIR), Raman
High Shear Wet Granulation process
Torque meter, NIR, PARSUM, Acoustic Emission, FBRM
Low shear Wet Granulation (FBP)
PARSUM, FBRM, NIR
Reaction Monitoring
NIR
Crystallization
FBRM
Fluidized Bed Drying
NIR
Mixing, Blending, and Lubrication
NIR
Tablet Compression
NIR
Coating
Droplet Size measurement, NIR
The online PAT tools have the capability to monitor & control the process as per defined parameters; hence such online PAT tools are very helpful for Process Automation. Therefore if such online PAT tools are employed in the process to monitor the process we can ensure process control without human interference, which is eventually termed process automation. for example, the process is defined as per design space, in the running process due to the influence of any factor if the process parameters deviate from the defined process and if process equipment is looped through the PAT tools then in that case because of vigilance and backward intimation capability of PAT tools to the HMI/PLC, the process parameters will be always within the range of Design Space.
For instance let us assume the Pelletization process in Wurster coater, where the bed moisture is a very critical requirement for the Pelletization process. At particular bed moisture content, only the process will run smooth, or else there will be an occurrence like agglomeration or static charge generation. In this particular case, the NIR can be employed as one of the effective PAT tools, where NIR will measure the pellet bed moisture online and will interlink with control measures for the moisture like Inlet temperature, Inlet air flow, Spray rate, etc as electronic backward intimation and control the desired the bed moisture content. Thus the PAT tools play a very critical role in process automation.
Few more Advance examples of online and offline PAT Tools-
Real-Time Product Temperature Monitoring in Freeze Drying
Wireless, Real-time Temperature Sensors for Lyophilization(Reproduced from www.tempris.com)
Product temperatures are a critical quality attribute in freeze-drying processes, employed in the manufacturing of many pharmaceuticals. For example, product temperature above the critical formulation temperature during primary drying frequently results in severe damage to the product. Wireless and battery-free temperature sensors (e.g. Tempris) serve as important PAT tools during lyophilization processes as they measure temperature in real-time and are feasible for installation in a cGMP environment across different scales of operation as well as aseptic manufacturing conditions. Due to wireless construction, the sensors can be pre-sterilized, placed into vials, and introduced into freeze dryers through automatic loading systems.
(Above info, taken from Temperature Freeze Drying Monitoring in Real-time with Tempris sensors)
Headspace Inspection of Parenterals-
Headspace analysis is a very useful technique to generate statistical processes and product data in all stages of the product life cycle, from development to manufacturing and quality control of pharmaceuticals. Aseptic manufacturing facilities implement various analytical systems and inspection processes to ensure the quality of finished products and to monitor production processes. Automated 100% laser-based inspection of sealed parenteral containers to measure headspace oxygen, moisture, and carbon dioxide levels function as useful PAT tools in production lines. Maximum throughputs at 150 containers per minute help in efficient online monitoring of the production processes.
Automated 100% Headspace Inspection System(Ref: LIGHTHOUSE Instruments)Above Information was taken from PULSAR Headspace Inspection | Lighthouse Instruments
PAT Tools — Offline:
The powder Flow Meter parameter is used to characterize the Powder’s physical properties like Flow Rate and Angle of repose. The Powder Rheometer parameter is used to characterize the Powder’s physical Properties and measures the Energy and force like Basic flow energy, Aeration Energy, Permeability Energy, Compressibility, Shear Cell force, Wall friction force, and Stability energy.
THE BENEFITS OF QbD and PAT:
A. QbD:
Proper implementation of QbD can potentially provide three main benefits for development that are a more efficient use of development time and costs, the ability to meet FDA submission guidelines and expectations and reduced approval times, and fewer queries from the FDA.
Likewise, QbD can potentially provide significant benefits in manufacturing. Even after the drug has gained FDA approval, during the product life cycle routine QC testing may detect an out-of-specification (OOS) result. However, it is very easy to address the OOS & has effective CAPA in presence of sufficient QbD data. But for a company that did not use a QbD approach, an OOS result can mean a seemingly endless quest to find the root cause. Absent the data that QbD provides, test results may be suspected, the questions difficult to answer, and long delays inevitable. Without knowing where to look, the team may resort to a trial-and-error approach to resolve any OOS occurrences.
Even that could cause a 4- to 9-fold increase in testing to clear up an OOS investigation — a costly affair and time-consuming prospect on a commercial scale. The impact of poor quality development work that spirals out of control into an OOS event during the product life cycle can be horrendous.
For manufacturers, there are potentially huge external costs for delayed product launches or approvals, or severe actions such as consent decrees, the internal costs of wasted raw materials, scrap batches, and the cost of investigation and remediation.
Importantly the damage to the brand such an event would have. To add further insult, the company may have to spend an enormous amount of money just to get your product back to the market, and overall business loss and reputation are at stake.
QbD minimizes these risks by mapping all the possible variables of the product attributes and processes into a known control space. This means that if any quality issues occur, the scientific team can use specific methods to quickly pinpoint the scientific variables that are most likely causing the issues.
The business benefits can be significant, including; fewer lost batches, resulting in revenue, market share & Business loss. Fewer manufacturing deviations, saving hundreds of costly hours. Faster time to market and more reliable supply, when each day on the market could generate revenue. Fewer inspections of manufacturing sites. A many-fold ROI via cost savings and increased revenue.
B. PAT — It improves productivity, exterminates human intervention as a result upturns the automation, ensures the operator’s safety, corrects online the process variation so resulting in the elimination of the variability in the process, and creates the data bank and in turn guides for continuous improvement plan.
Conclusion: -
· QbD designs the process and the process parameters, However, PAT has the capability to monitor and control the process.
· So to make an error-free robust process the joint role of both QbD and PAT is very significant
Both the QbD and PAT are very imperative to each other in the process.
That is how the QbD and PAT both are playing a very significant role in Pharmaceutical Process Automation. Hence the QbD & PAT tools — Lifeline during the life cycle of Pharma Products
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