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Generic Drug Product Development Using QbD Approaches
Narayan Kanikkannan
Xcelience, United States of America


Quality by Design (QbD) is defined in the International Conference on Harmonisation (ICH) regulatory guideline Q8 (R2) 1 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. QbD is derived from implementation of ICH guidelines in the US, EU, and Japan for Pharmaceutical Development (ICH Q8 (R2)), Quality Risk Management (ICH Q9) 2, Pharmaceutical Quality System (ICH Q10) 3, and Development and Manufacture of Drug Substances (ICH Q11) 4. It is a voluntary concept which applies to all drug products and drug substances and is not intended to create new regulatory requirements. QbD is equally important to generic and innovator products.

The generic drug industry operates at a fast pace in a very competitive environment. Some generic companies are concerned that a QbD approach will add time in early development phase which will put them at a disadvantage in making it to ‘first to file’. Significant benefits of QbD are improved product quality, better process robustness, less deviations/rejections, lower compliance risk, and regulatory flexibility.

Expectations for the generic industry have been mandated by the Office of Generic Drugs (OGD) over recent years at various meetings, workshops, and roundtables. The OGD has been working with the generic industry during the last few years to discuss and finalize the strategies for the implementation of QbD. The OGD has developed QbD examples for Immediate-Release 5 and Modified-Release6 products in collaboration with Generic Pharmaceutical Association (GPhA) and published them recently. The FDA has issued an updated draft Question based Review (QbR) in September 2012 that includes QbD elements. The revised QbR review system is expected to be implemented in the near future.

The FDA has clarified the required and optional QbD elements for Generic drugs.

Required QbD elements are:

  1. Quality Target Product Profile (QTPP) and a list of critical quality attributes (CQAs) of the drug product.
  2. A demonstration of product understanding through the identification of critical material attributes (CMAs) of the drug substance and excipients.
  3. A demonstration of process understanding through the identification of critical process parameters (CPPs).
  4. Development of a Control strategy and justification.

Optional QbD elements are:

  1. Design Space
  2. Process Analytical Technology (PAT)

Generic Drug Product Development using QbD Approaches

  1. Analysis of the Reference Listed Drug (RLD) Product

    The development of a generic product typically starts with the analysis of the physicochemical characteristics of the RLD. The proposed generic product needs to be similar to the brand product in terms of dosage form, strength, etc., (pharmaceutical equivalence) and should be bioequivalent to the RLD product, where applicable. The dissolution profile of the RLD product in appropriate media needs to be tested to understand the formulation design requirements of the generic product.

  2. QTPP for the Generic Product

    According to ICH Q8 (R2)1, QTPP forms the basis of design for the development of the product. For generic products, the target should be defined based on the properties of the drug substance (DS), dissolution, physicochemical, clinical, and pharmacokinetic characteristics of the RLD product, and consideration of the RLD label and intended patient population5. The QTPP includes all product attributes that are needed to ensure equivalent safety and efficacy to the RLD. Examples of QTPP for generic product are type of dosage form, dosage design, dosage strength, target pharmacokinetic parameters, product shelf life, and container closure system.

  3. CQAs for Generic Product

    A CQA is a physical, chemical, biological, or microbiological characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs are generally associated with the DS, excipients, intermediates (in-process materials), and drug product. The QTPP provides an understanding of what will ensure quality, safety, and efficacy of a specific product for the patient and is a starting point for identifying CQAs. During the formulation development, CQAs will have to be identified based on prior knowledge, QTPP, experimental data, and quality risk management. The list of potential CQAs can be modified when the formulation and process understanding increase. Examples of CQAs for the drug product are dissolution profile, content uniformity (CU), and degradation products.

  4. Drug Substance (DS)

    The DS to be used for the development should be characterized for all necessary attributes. Examples of DS attributes are particle size distribution (PSD), bulk density, flowability, and crystal properties (polymorphic forms). A risk assessment of the drug substance attributes is performed to evaluate the impact that each attribute could have on drug product CQAs.

    • Risk Assessment

      Risk assessment is a valuable science-based process used in quality risk assessment (ICH Q9) and can aid in identifying which material attributes and process parameters potentially have an effect on product CQAs. The relative risk that each attribute presents will be ranked as high, medium, or low. In general, the high risk attributes warrant further investigation whereas the low risk attributes require no further investigation. The medium risk attributes should be evaluated and may be considered acceptable based on available knowledge. Risk assessment will be used throughout development to identify potentially high risk formulation and process variables and to determine which studies are necessary to achieve product and process understanding in order to develop a control strategy. Each risk assessment will then be updated after development to capture the reduced level of risk based on the improved product and process understanding. According to ICH Q9 quality risk management, it is neither always appropriate nor always necessary to use a formal risk management process. The use of informal risk management processes (using empirical tools and/or internal procedures) can also be considered acceptable.

  5. Excipients

    The excipients used in generic drug products are generally selected based on the excipients used in the RLD, excipient compatibility studies and prior use in approved products. Excipient compatibility is an important part of understanding the role of inactive ingredients in product quality.

  6. Formulation Development

    Initial risk assessment of the formulation variables (e.g., DS PSD and levels of key excipients) needs to be conducted. The relative risk that each formulation attribute presents on the drug product CQAs will be ranked as high, medium, or low. A univariate method (one factor at a time) is acceptable in case where there is no potential interaction between factors. Since this is often not known, a multivariate statistical design (Design of experiments (DOE)) is often used. The experiments will be generally conducted in a random order and responses (e.g., Dissolution and CU) will be measured. The results analyzed using ANOVA would identify the significant formulation variables affecting the CQAs of the drug product and the interaction between the formulation variables. Based on the results of DOE, acceptable ranges of high risk formulation variable will be established and included in the control strategy. Based on the results of the formulation development studies, the risk assessment of the formulation variables will be updated with justifications.

  7. Manufacturing Process Development

    All QbD approaches to process development should identify critical material attributes (CMAs) and critical process parameters (CPPs) for each process step. A sponsor may choose to do this through reference to documented prior knowledge or through empirical experiments on a range of batch sizes building towards the exhibit batch size and proposed commercial batch size. QbD emphasizes building understanding of the process to avert failures during scale-up. The first step in establishing process understanding is to identify all possible known material attributes and process parameters that may affect the CQAs of the final drug product. The next step is to identify potentially high risk attributes and process parameters using risk assessment and scientific knowledge. Then identify the levels or ranges of these potentially high risk attributes and parameters and design and conduct experiments, using DOE when appropriate. The experimental data are analyzed to determine if a material attribute or process parameter is critical. A material attribute or process parameter is critical when a realistic change in that attribute or parameter can significantly impact the identified intermediate CQAs and, ultimately, the drug product CQAs.

  8. Control strategy

    A control strategy is designed to ensure that a product of required quality will be produced consistently. The controls should be based on product, formulation, and process understanding and should include, at a minimum, control of the CPPs and material attributes.

    A control strategy can include but not limited to the following:

    1. Control of input material attributes (e.g., DS and excipients) based on an understanding of their impact on processability or product quality.

    2. Product specifications - In-process controls and finished product specifications.

    3. Controls for unit operations that have an impact on downstream processing or product quality (e.g., drying temperature, lubrication time, and hardness range).


The OGD has been strongly encouraging abbreviated new drug application (ANDA) sponsors to apply QbD principles to the formulation development for their future ANDA filings. The generic industry has responded positively to OGD. There is an increasing number of ANDAs submitted during the last several months that have used the QbD approach. A robust formulation and process developed using QbD approaches offers several advantages including regulatory flexibility, improved product quality, lower compliance risk, and reduced batch failure rates. The generic industry needs to achieve the desired balance between speed and excellence with implementing QbD approaches.


The author would like to thank Paul Skultety, Director of Pharmaceutical Development Services at Xcelience, for his valuable comments.

About the Author

Narayan “Kani” Kanikkannan is Manager of Preformulation and Formulation Development at Xcelience since January 2012. In this role, Dr. Kanikkannan provides leadership to the Preformulation and Formulation Development departments in order to meet the scientific and business objectives and goals of Xcelience. Prior to this, he was a Manager of Pharmaceutical R&D at Covidien, where he managed a team of formulation and analytical scientists in the development and commercialization of solids and liquid generic products. Dr. Kanikkannan served as the Senior Formulation Scientist at Paddock Laboratories from 2001-2006 and as a Research Scientist at Ranbaxy Laboratories from 1995-1998. He has extensive experience in the development and commercialization of a wide variety dosage forms including IR and ER Tablets and Capsules, Oral solutions and Suspensions, Topical and Parenteral products. Dr. Kanikkannan received his Bachelor’s degree in Pharmacy from Madurai Kamaraj University, India. He earned his Masters and Ph.D. degrees in Pharmaceutics from Banaras Hindu University. He did post-doctoral research at Florida A&M University (Tallahassee, FL). Dr. Kanikkannan is a certified Six Sigma Black Belt. He has authored over 25 research papers in peer-reviewed journals and written several review articles and book chapters.


  1. ICH Q8R(2)-Pharmaceutical Development
  2. ICH Q9 – Quality Risk Management
  3. ICH Q10- Pharmaceutical Quality System
  4. ICH Q11 (draft): Development and Manufacture of Drug Substances
  5. Quality by Design for ANDAs: An Example for Immediate-Release Dosage Forms, April 2012.
  6. Quality by Design for ANDAs: An Example for Modified Release Dosage Forms, December 2011.

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