Quality By Design—Basic Considerations…!!!


Basic considerations of QbD

As far as pharmaceutical industry is considered safety of patient and providing a quality product have been given prime importance; and to achieve this target QbD assist it by thorough understanding of process which is the ultimate goal of QbD.

Advantages of QbD can be summarized as,

  • Patient safety and product efficacy are focused.
  • Scientific understanding of pharmaceutical process and methods is done.
  • It involves product design and process development.
  • Science based risk assessment is carried.
  • Critical quality attributes are identified and their effect on final quality of product is analysed.
  • It offers robust method or process.
  • Business benefits are also driving force to adopt QbD. Method design concept helps to avoid cost involved with post approval changes.
  • Elements of pharmaceutical development

QbD comprises all elements of pharmaceutical development mentioned in the ICH guideline Q8. Pharmaceutical Development section is projected to provide a complete understanding of the product and manufacturing process for reviewers and inspectors. To design a quality product and its manufacturing process to consistently deliver the intended performance of product is the aim of pharmaceutical development. The information and knowledge gained from pharmaceutical evelodpment studies and manufacturing experience provide scientific understanding to support the establishment of the specifications, and manufacturing controls .

 Different elements of pharmaceutical development include,

  • Defining an objective
  • Determination of critical quality attributes (CQA)
  • Risk assessment
  • Development of experimental design
  • Designing and implementing control strategy
  • Continuous improvement.
  • Define an objective

Quality target profile (QTP) forms the basis of QbD, which is in relation to the predefined objective criteria mentioned in the definition of QbD. As per ICH guideline Q8 R2 the Quality Target Product Profile forms the basis for design and the development of the product. Considerations for the Quality Target Product Profile could include:

  • Intended use in 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).
  • Drug product quality criteria like sterility, purity, stability and drug release as appropriate for dosage form the intended for marketing.

QbD requires a Target Product Profile; it may be called as Quality Target Product Profile (QTPP) which defines the expectations in final product. In case of analytical method development it is called as analytical target profile (ATP), it is also called as Target Product Profile (TPP). The TPP can play a central role in the entire drug discovery and development processes like optimization, planning and decision making, and designing of clinical research strategies . The Target Product Profile (TPP) can be used to design the clinical trials, safety and ADME studies, as well as to design the drug product. The TPP will help to identify critical quality attributes such as potency, purity, bioavailability or Pharmacokinetic profile, shelf-life, and sensory properties

  • Determination of critical quality attributes.(CQA)

According to ICH Q8 R2 ‘‘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 are generally linked with the drug substance, excipients, intermediates (inprocess materials) and drug product. For example CQAs of solidoral dosage forms are typically those aspects affecting product purity, strength, drug release and stability whereas for parentrals they are Sterility and clarity. The CQAs can additionally include properties like particle size distribution, bulk density that affect drug product. Mostly CQAs are derived from the Quality Target Product Profile and/or prior knowledge is used to guide the product and process development and Subsequently CQAs are accessed for risk management.

It is stated in ICH Q9 that in case of Potential drug substance CQAs are used to guide process development. Inclusion and exclusion in list of potential CQAs can be done as knowledge drug substance and process understanding increases. In case of biotechnological/biological products, most of the CQAs of the 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. Impurities are an important class of potential drug substance CQAs. A quality attribute that must be controlled within predefined limits to ensure that the product meets its intended safety, efficacy, stability and performance. It means all the factors which affect final quality and safety should be controlled. Dissolution test is crucial for a controlled release drug product and on other hand dissolution test for an immediate release drug product which belongs to the high aqueous solubility and high permeability i.e. BCS class I drug will not prove as critical attribute for quality control viewpoint . CQA differs for type process, dosage form, and type of method development hence thorough knowledge of real time data to working scientists is important

  • Risk assessment

It is commonly understood that risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. Risk assessment helps to increase quality of method or process. Also it is determinant for effect of input variable on method or processes. From risk assessment one can recognize critical attributes that are going to affect final quality of product. A risk assessment is helpful for effective communication between FDA and industry, research/development and manufacturing and among multiple manufacturing sites within company. There may be risk and uncertainty in validation of bioanalytical method though the guidelines for validation are given by various regulatory bodies there may be a variation in interpretation of those guidelines and hence in experimental method designing which leads to unfit method development for intended purpose. Risk management for excipients to determine shelf life can be done by statistical parameters

Principles of quality risk management are:

  • Scientific knowledge based evaluation of the risk to quality which eventually links to the protection of the patient.
  • Adequate effort should be taken; formality and documentation of the quality risk management process should be done with the level of risk involved. Risk management is joint responsibility of quality unit, business development, engineering, regulatory affairs, production operations, sales and marketing, legal, statistics and clinical department.

Methods of risk assessment: Some methods of risk assessment are mentioned in ICH guideline Q9 as follows:

  • Failure Mode Effects Analysis (FMEA);
  • Failure Mode, Effects and Criticality Analysis (FMECA);
  • Fault Tree Analysis (FTA);
  • Hazard Analysis and Critical Control Points (HACCP);
  • Hazard Operability Analysis (HAZOP);
  • Preliminary Hazard Analysis (PHA);
  • Risk ranking and filtering;
  • Supporting statistical tools.

ICH guideline Q9 gives description of risk management and various terminologies associated with it, like Risk Acceptance, Risk Analysis, Risk Assessment, Risk Communication, Risk Control, Risk Evaluation, Risk Identification, and Risk Management. Quality management policies should mention procedures and practices to the tasks of assessing, controlling, communicating and reviewing risk. Risk Reduction is actions taken to lessen the probability of occurrence of harm and the severity of that harm.

  • Development of experimental design

Experimental design is 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 space is proposed by the applicant and is subject to regulatory assessment and approval of ICH Q8 (R2). Pharmaceutical development scientists have began making use of computer-aided process design (CAPD) and process simulation to support process development and optimization of manufacturing. Risk assessment can guide to understand linkage and effect of process parameters and material attributes on product, and ranges for variables within which consistent quality can be achieved. These parameters or attributes are selected for addition in the design space. Information regarding reason for inclusion of some variables in design space as well as exclusion of other variable

has to be mentioned. Operation within the design space will result in a product meeting the defined quality. Independent design spaces for one or more unit operations can be applied; a single design space can be applied for multiple operations. For example impact of excipient variability on particle size distribution, blend segregation propensity can be included in experimental design. Gel was prepared using QbD approach, the design space used was developed by a optimal design from a total of 15 gel batches, with five factors ethanol, water, carbomer, acid neutralized fraction, and reactor temperature .

Different mathematical models are available for design of experiment like Placket–Burman, Box Behnken, Taguchi, Surface Design, Full and fractional factorial designs. Full factorial design was used to study the effect of formulation factors on pharmaceutical properties of tablet; in that independent variables were binder and disintegrant concentration, resistance to crushing while dependant variable was drug release. Such a multidisciplinary approach is beneficial as manufacturing process improvement can be done in previously approved space; it decreases number of variation after marketing. It is a risk based approach which is based on timely quality control rather than final testing of finished product.

  • Designing and implementing control strategy

Control strategy is required to ensure that material and process are within the expected lower and upper limits. Parameter and material are routinely controlled during production in order to assure reproducibility. The control space should be within the design space. Generally scale up is trial and error basis. During scale up processes parameters may differ but attributes which affect quality remain the same hence control strategy is required. QbD gives trace on reproducibility and robustness. Process capability index expresses reproducibility of process.

  • Process capability index = CpKÞ ¼ upper limit of specification – lower limit of specification

standard deviation and Control space should be within the design space, it is an upper and lower limit for raw material or a process within which parameter and material are regularly controlled which assures quality of product. Design space cover control space. If control space is smaller than design space it is considered as robust. Usually in process quality control tests are performed to examine quality and trace out defects but QbD approach being proactive in the initial steps the potential attributes which could possibly give out of range result and affect the quality are identified. Deliberate variations in those attributes are studied in design space.  Control strategy involves but not limited to – control on excipients, drug substance, packaging materials (inputs), specifications, operational control like drying downstream processing dissolution etc.., real time testing or in process testing, finished product testing at regular intervals.

  • Continuous improvement throughout product life cycle

Product quality can be improved throughout the product lifecycle; companies have opportunities to opt inventive approaches to improve quality. Process performance can be monitored to make sure consistency in quality. Additional experience and knowledge is gained during routine manufacture which contributes to method/process development. Periodic maintenance can be done within a company’s own internal quality system; but design space should be unchanged. The QbD approach avails the continuous improvement throughout products’ life cycle this is distinguishing point from the conventional method which is much frozen process.