BY DESIGN: BETTER APPROACH FOR PHARMACEUTICALS QUALITY DEVELOPMENT

ABOUT AUTHORS:
Ghodke D.V*, Bhusnure O.G, Kulkarni A.A
Department Of Quality Assurance in Maharashtra College of M .Pharmacy Nilanga. Dist –Latur
Department Of Medicinal chemistry in Maharashtra College of Pharmacy Nilanga, Dist –Latur
*ghodke.deepa@gmail.com

ABSTRACT:
Quality by Design (QbD) refers to a holistic approach towards drug development, where product specifications, manufacturing process and critical parameters are included in order to ease the final approval and ongoing quality control of new drug. Nowadays many pharmaceutical implement the quality by design system to obtain the high level of assurance of the product, for increasing the efficiency of manufacturing product & to reduce manufacturing cost and product rejection, the main aim of this is to design robust process. QbD requires an understanding of how product and process variables influence product quality. QbD has become the answer to assist both industry and FDA to move towards a more scientific, risk based, holistic and proactive approach to pharmaceutical development. QbD Pharmaceutical Product/Process is Design by using Basic Sciences, Mathematics and the Engineering Science with depth understanding of the interactions of the several variables such as raw materials, drug substance, manufacturing conditions, etc. 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 andQ9 Quality risk management and the FDA process analytical technology(PAT) guidance.

REFERENCE ID: PHARMATUTOR-ART-1775

ABBREVIATIONS
Qbd         Quality By Design
FDA        Food and Drug Administration
NDA       New Drug Application
PAT        Process Analytical Technology
cGMP     Current Good Manufacturing Practices
ICH         International Conference On Harmonization
CQAS     Critical Quality Attributes
CPPS      Critical Process Parameters
FMEA    Failure Mode and Effects Analysis
TPQP    Identify Target Product Quality Profile TPQP
API        Active Pharmaceutical Ingradient

INTRODUCTION
Quality by design (QbD) encompasses designing and developing formulations and manufacturing processes which ensures predefined product specifications. In 2002, the FDA announced a new initiative (cGMP for the 21st Century: A Risk based Approach). ICH Q8 defines quality as “The suitability of a drug either substance or drug product for its intended use. This term includes such attributes as the identity, strength, and purity. “Quality by Design” 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” From guidance to Pharmaceutical Development. ICH Q8 guideline (International Conference for the Harmonization of pharmaceutical regulation). Quality by Design is a systematic scientific approach to development and design of products and processes illustrated and facilitated through the establishment of the Design Space. The FDA’s Janet Woodcock has frequently stated that QbD is derived from a combination of prior knowledge, experimental assessment, and a cause-and-effect model that links critical process parameters and critical quality attributes. Achieving the goal of manufacturing process excellence through QbD requires us to begin the work in process development. The FDA’s Process Analytical Technology (PAT) guideline shows the value of continuous learning that comes from analyzing process data when coupled with systems that support the acquisition of knowledge from those data, saying: “Continuous learning through data collection and analysis over the lifecycle of a product is important. These data can contribute to justifying proposals for post-approval changes. Approaches and information technology systems that support knowledge acquisition from such databases are valuable for the manufacturers and can also facilitate scientific communication with the Agency”.

BENEFITS OF QBD ^[6]

Better understanding of the process
Less batch failure.
Reduction of post-approval submissions.
Better innovation due to the ability to improve processes without resubmission to the FDA when remaining in the Design Space.
More efficient technology transfer to manufacturing.
Greater regulator confidence of robust products.
Innovative process validation approaches
Improved yields, lower cost, less investigations, reduced testing, etc.
Continuous improvement over the total product life cycle (i.e. controlled, patient guided variability).
Improved yields, lower cost, less investigations, reduced testing, etc.

QBD DEVELOPMENT PROCESS MAY INCLUDE
a. Begin with a target product profile that describes the use, safety and efficacy of the product

b. Define a target product quality profile that will be used by formulators and process engineers as a quantitative surrogate for aspects of clinical safety and efficacy during product development

c. Gather relevant prior knowledge about the drug substance, potential excipients and process operations into a knowledge space. Use risk assessment to prioritize knowledge gaps for further investigation

d. Design a formulation and identify the critical material (quality) attributes of the final product that must be controlled to meet the target product quality profile

e. Design a manufacturing process to produce a final product having these critical materials attributes.

f. Identify the critical process parameters and input (raw) material attributes that must be controlled to achieve these critical material attributes of the final product. Use risk assessment to prioritize process parameters and material attributes for experimental verification. Combine prior knowledge with experiments to establish a design space or other representation of process understanding.

g. Establish a control strategy for the entire process that may include input material controls, process controls and monitors, design spaces around individual or multiple unit operations, and/or final product tests. The control strategy should encompass expected changes in scale and can be guided by a risk assessment.

h. Continually monitor and update the process to assure consistent quality

TRADITIONAL APPROACH & ENHANCED QBD APPROACH ^[6]

Aspect	Traditional approach	QbD approach
Pharmaceutical Development	Empirical, Random, Focus on optimization	Systematic, Multivariate experiments, Focus on control strategy and robustness
Manufacturing Process	Fixed	Adjustable within design space, managed by company’s quality systems
Process Control	Some in-process testing	PAT utilized, Process operations tracked and trended
Product Specification	Primary means of quality control, based on batch data	Part of the overall quality control strategy, based on desired product performance
Control Strategy	By testing and inspection	Risk-based control strategy , real-time release possible

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BUILDING BLOCKS OF QBD^[7]
The first step to implement Quality by Design is to understand critical output of QbD and after that identify critical building blocks of QbD such as improving process understanding and risk associated with it.

Critical Quality Attributes (CQAs):The critical process output measurements linked to patient needs .

Critical Process Parameters (CPPs):The process inputs (API, Excipients), process control and environmental factors that have major effects on the Critical Quality Attributes (CQAs) .

Design Space:The combination of input variables and process parameters that provide quality assurance [3].

Failure Mode and Effects Analysis (FMEA):It examines raw material variables, Identifies how a process can fail and the areas of process that remains at greatest risk of failing .

Process model:A quantitative picture of process based on fundamental and statistical relationship that predict the critical quality attribute (CQA) result .

Process Capability:It tracks process performance relative to CQA specification and provide measurement repeatability and reproducibility regarding CQAs .

Process Robustness:The ability of process to perform when faced with uncontrolled variation in process, input and environmental variables .

Process Control:It is a control procedures including statistical process control that keeps the processes and measurement system on target and within desired variations .

Raw material factors:It includes the stability and capability of raw material manufacturing processes that affect process robustness, process capability and process stability .

Risk level:It is a function of the design space, FMEA result and process and measurement capability, control and robustness .

STEPS –FOR QUALITY BY DESIGN APPROACH^[8-12]
Step 1. Idenify the Target Product Profile Profile
Step 2. Critical Quality Attributes (CQAS)
Step 3. Link the drug and excipient attributes and the process parameters to the CQAS
Step 4. Define the Design Space
Step 5. Define the Control Strategy
Step 6. Product lifecycle management & continual improvement

Step1 : Identify Target Product Quality Profile (TPQP)
The target product profile (TPP) has been defined as a “prospective and dynamic summary of the quality characteristics of a drug product that ideally will be achieved to ensure that the desired quality, and thus the safety and efficacy, of a drug product is realized”. This includes dosage form and route of administration, dosage form strength(s), therapeutic moiety release or delivery and pharmacokinetic characteristics (e.g., dissolution and Excipients meeting specification Unit operation with fixed process parameters In process specification Finished product aerodynamic performance) appropriate to the drug product dosage form being developed and drug product-quality criteria (e.g., sterility and purity) appropriate for the intended marketed product .The Target Product Quality Profile (TPQP) is a term that is a natural extension of TPP for product quality. It is the quality characteristics that the drug product should possess in order to reproducibly deliver the therapeutic benefit promised in the label. The TPQP guides formulation scientists to establish formulation strategies and keep formulation efforts focused and efficient. TPQP is related to identity, assay, dosage form, purity, stability in the label .

Step 2: Identifying CQAs
Once TPP has been identified, the next step is to identify the relevant CQAs. A CQA has been defined 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”. Identification of CQAs is done through risk assessment as per the ICH guidance Q9 Prior product knowledge, such as the accumulated laboratory, nonclinical and clinical experience with a specific product-quality attribute, is the key in making these risk assessments. Such knowledge may also include relevant data from similar molecules and data from literature references. Taken together, this information provides a rationale for relating the CQA to product safety and efficacy.

Step 3: Link the drug and excipient attributes and the process parameters to the CQAs
Inputs to the process control variability of the Output. Y= f(X) Where, X - Inputs i.e. process parameters (people, Equipment, Measurement, process, material, and environment, Y- Quality attributes is the output. Design of experiments is an efficient method to determine relevant parameters & interactions. The experimental approach for identifying parameters can includes the following methods
(1) To choose experimental design,
(2) Conduct randomized experiments
(3) To analyze data

To Link the drug and excipient attributes and the process parameters to the CQAs there includes a formal risk management process.

Step 4: 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. It’s a Key for claiming Process understanding (pharmaqbd.com, 2011), which establishes a link between the attributes of the drug product and process parameters, process attributes and material attributes of the active pharmaceutical ingredient (API) and excipients that go into the drug product. From a practical standpoint, process understanding, and the associated design space, entails: identifying and explaining all critical sources of variability; managing variability by the process via measurement and control of critical process variables; and reliably and accurately predicting and controlling product attributes within specifications (achieve quality). Process understanding is Key for Quality Risk Management & QRM is the base for any Control Strategy.

Step: 5 Define the Control Strategy
Justification of necessary controls of input material attributes (e.g., drug substance, adhesive polymer, primary packaging materials) based on an understanding of their impact on process ability or product quality In-Process Controls & End Product Controls (if necessary).It is based on Process and Formulation Understanding that Drives the Process in the Design Space Based on Quality Risk Management to ensure conforming Quality according Specifications.

Step: 6 Product lifecycle management and continual improvement
Use accumulating manufacturing data as the basis to modify and improve the process within the design space. At this stage, the underlying concepts and rationale for implementing quality-by-design practices are well understood and accepted. Despite this progress, there remain critical impediments to QbD implementation including the following:
From a practical standpoint, what comprises and how does one acquire process understanding? From a practical standpoint, how does one decide that a process parameter is critical? And most importantly, how do we know that the identified design space of the process links to the clinical design space of the patient? After all, the aim is to design a process that meets the needs of safety and efficacy for the patient.

CONCLUSION
Quality by design is an essential part of the modern approach to pharmaceutical quality. QbD is novel approach which is currently being used in pharmaceutical industry than empirical approaches of the product development because it reduces the product variability.A prospective and dynamic summary of the quality characteristics of a drug product that ideally will be achieved to ensure that the desired quality, and hence the safety and efficacy, of a drug product is realized.

REFERANCES
1. Food and Drug Administration. Final Report on Pharmaceutical cGMPs for the 21st Century – A Risk Based Approach, fda.gov/ cder/ gmp/ gmp 2004/ GMP_ final report 2004
2. ICH Q8 — Guidance for Industry, Pharmaceutical Development, May 2006.
3. ICH Q8 (R1) — Pharmaceutical Development Revision 1, November 2007.
4. Juran Jm. Juran on quality by design The new steps for planing quality into goods and services newyork free press 1992 p.no-1-2.
5. US Food and Drug Administration. Guidance for Industry. PAT—A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance. Pharmaceutical cGMPs,Rockville, Pharmaceutical cGMPs. MD, 2004 Sept., 1–21.
6. Pharmaceutical “Quality by Design” (QbD): An Introduction, Process Development and Applications ,august 21, 2012, Process Validation, Validation Articles.
7. Snee Ronald ,Building a framework for quality by design.
8. Moheb M. Nasr “Quality by Design (QbD) – A Modern System Approach to Pharmaceutical Development and Manufacturing –FDA Perspective/ fda.gov
9. Delasko, J.M., Cocchetto, D.M., Burke. L.B., Target Product Profile: Beginning Drug Development with the End in Mind. January/February, Issue 1, 2005, fdli.org
10. Food and Drug Administration CDER. Draft Guidance for Industry and Review Staff: Target Product Profile- A Strategic Development Tool (March 2007).
11. Food and Drug Administration Office of Generic Drugs. Model Quality Overall Summary for IR Product, fda.gov/ cder/ ogd/OGD_Model-QoS_IR_Product.pdf (Accessed March 31, 2006)
12. US Food and Drug Administration. Guidance for industry: Q8 Pharmaceutical Development, US Department of Health and Human Service, FDA, Rockville, MD, May 2006

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