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CURRENT TRENDS
Quality by Design
Author : Mr. P.P. Sharma
Quality by Design (QbD) was first described by Joseph M. Juranand was applied to industrial production particularly in the automotive industry. The fundamental principle behind QbD is that quality can be designed to processes through systematic implementation of an optimization strategy to establish a thorough understanding of the response of the system on quality to given variable, and the use of control strategies to continuously ensure quality.
The pharmaceutical Quality by Design (QbD) is a systematic approach to development that commences with predefined objectives and emphasizes product and process understanding and process control, based on sound science, technology and quality risk management.
The conventional approach requires continuous end product testing and inspection to determine quality. The end products are seen as fixed, averse to change and focus only on process reproducibility but QbD required identification of all critical formulation attributes and process parameters as well as determination of the extent to which variation can impact the quality of the finished product. The more information generated either on impact or on lack of impactof a component or process on products quality, safety or efficacy, the more business flexibility QbD provides.
The initiation of the cGMPs for the 21st century initiative and publication of PAT guidance in 2004 by the US FDA paved the way for new approach in pharmaceutical industry. This was followed by the ICH by publishing ICH Q8 (Pharmaceutical Development)
QbD Development process includes:
1)Determination of a target product profile (TPP) that describes the use, safety and efficacy of the product.
2)Defining of a target product quality profile that will be used by formulators and process engineers as a quantitative substitute for aspects of clinical safety and efficacy during product development.
3)Gathering relevant prior knowledge about the drug substance, potential excipients and process operations into a knowledge space.
4)Designing of a formulation and identification of the critical quality attributes (CQAs) materials and of the final product that must be controlled to meet the target product quality profile.
5)Designing of a manufacturing process to produce a final product having predefined attributes and to identify critical process parameters and material attributes of starting materials which must be controlled to attain CQAs of finished product.
6)Establishing a control strategy for the entire process including input material controls, process controls and monitors, design spaces around individual or multiple unit operations, and/or final product tests.
7)Continually monitoring and updating the process to assure consistent quality.
8)Quality by Design (QbD) is current trend to enhance the assurance of safe, effective drug supply to the consumer. QbD also offers promise to significantly improve manufacturing quality performance.
Product Quality Review
Author : Mr. P.P. Sharma
It has been recommended under the WHO GMP and EU GMP guidelines that for all medicinal products, there should be regular, periodic or rolling quality reviews including those products which are meant for export only. The objective of these reviews is the verification of the consistency of the existing process, the appropriateness of current specifications for both starting material and finished product to highlight any trends and to identify product and process improvement. It has been stated that normally, such reviews should be conducted annually and should be documented. While conducting these reviews previous reviews should be taken in to consideration and should include the following:
1) A review of starting materials (e.g. APIs, recipients) and packaging materials particularly those from new vendors;
2) A review of critical in-process controls and finished product results;
3) A review of all such batches that failed to meet the specifications and investigations carried out;
4) A review of significant non-conformances or deviations and investigations carried out and the corrective and preventive actions taken on the result of investigations;
5) A review of changes made (if any) to the processes and/ or analytical procedures;
6) A review of dossier variations submitted, granted or refused;
7) A review of the stability monitoring program, whether any adverse trend observed;
8) A review of all quality related returns, complaints, re call sand investigations made;
9) A review of previous corrective action(s) on the product processor equipment, whether adequate;
10)A review of post-marketing commitments, in case of new dossiers and variations to the dossiers; Qualification status of concerned equipment and utilities(e.g. HVAC, water, compressed gas; and
11)A review of technical agreement(s) to ensure whether they are up-to-date.
The results of the product quality reviews should be assessed by the manufacture (and also by marketing authorization holder; if it is different) to decide whether corrective and preventive action (CAPA) or any revalidation should be undertaken. The reasons for CAPA should be documented and CAPA should be completed in a time bound manner.
Quality review scan bed one group wise e.g. solid dosage forms, liquid dosage forms or sterile product, if scientifically justified.
Where marketing authorization holder and manufacturer are different parties, there should be technical agreement between them defining their respective responsibilities. Both marketing authorization holder and the qualified person should ensure that product quality reviews are taken in timely manner.
Corrective Action and Preventive Action
Author : Mr. P.P. Sharma
Corrective action and preventive action, popularly known as CAPA is an important element of quality systems. These forms apart of ISO: 9001-2000 which has been revised and, at present, ISO: 9001-2008 is in force. In this standard, CAPA system has been strengthened and it has been recommended that effectiveness of corrective action and preventive action should be reviewed.
Quality system applicable to devices under the code of Federal Regulations (21 CFR 820) which is like GMP for finished products has laid down corrective and preventive action requirement sunder sub-part J.
What is CAPA? As the name suggests it is a system in which corrective actions are taken to fix a problem and preventive actions are taken to identify a problem and take preventive actions. In fact, it is fundamental management tool that should be used in every quality system. The CAPA program provides a simple step by step process for completing and documenting corrective or preventive action. When implemented, this program will result in a complete well documented investigation and solution which will satisfy regulatory requirements and will also form the basis for an effective continual improvement plan for any company.
It is important to understand as to what corrective action is and what preventive action is. A corrective action is a term which includes the process of reacting to product problem, customer complaints, or other non-conformities and fixing them. The process includes:
1) Reviewing and defining the problem or non conformity;
2) Finding the cause of problem;
3) Developing an action plan to correct the problem and prevent its recurrence;
4) Implementing the plan;
5) Evaluation of the effectiveness of action taken.
6) Preventing action, on the other hand is a process for detecting potential problems or non-conformities and eliminating them. The process includes:
7) Identifying the potential problem(s) or non-conformities;
8) Finding the cause of potential problem(s);
9) Developing a plan to prevent their occurrence;
10)Implementing the plan;
11)Reviewing the action taken and assessing its effectiveness in preventing the problem(s).
Quality Risk Management (QRM)
Author : P P Sharma
Risk management principles are utilized in several areas of business and government working, for example, finance, insurance, public health, pharmacovigilance by the industries and regulatory agencies regulating them. Although compliance withgood manufacturing practices (GMP), drug regulatory activities and inspections together with supply chain regulation throughout the product life cycle provide good assurance that risks are controlled to a large extent. However, when control is less effective, patients may be put at risk through the production of medicines of inadequate quality. It is in this context that quality risk management (QRM) is relevant. QRM is a process that is relevant to all countries and should provide a rationale to understand risk and to take steps to mitigate risk through appropriate controls. Since 2000, several initiatives have been taken to try to address the risks presented by drugs from manufacturing perspective. Important ones are given below:
1) 2001, Annexure 15 to the EUGMP Guide was published relating to qualification and validation which explicitly required risk assessment in validation activities.
2) 2001, ISPE GAMP 4 Risk assessment approach for Computerized systems appeared.
3) 2002 and onwards, US FDA took several important initiatives directly or indirectly related to QRM.
4) 2005, International Conference on Harmonization of Technical Requirement for Registration of Pharmaceuticals for Human Use, popularly known as ICH brought out a document ICH Q9 Quality Risk management. This document gave industry and regulating agencies an internationally accepted framework in which to apply QRM principles and concepts in their work. In fact, ICH developed three inter-related documents, the following
- ICH Q8 : Pharmaceutical Development;
- ICH Q9 : Quality Risk Management
- ICH Q10: Pharmaceutical QualitySystem.
These documents are the outcome of a vision statement developed by all parties of the ICH at the meeting held in Brussels. In July 2003, the vision statement was, Develop a harmonized pharmaceutical quality system applicable across the life cycle of the product emphasizing an integrated approach to risk management and science. The objective of ICH Q9 is to assist in development and implementation of effective QRM covering activities like research and development (R&D), sourcing of materials, manufacturing, packaging, testing, storage and distribution.
QUALITY RISK MANAGEMENT
QRM is a systematic process for the assessment, control, communication and review of risks to the quality of drug (medicine) across the product life cycle. There are two primary principles of QRM, the following:
- The evaluation of the risk to quality should be based on scientific knowledge and ultimately linked to the protection of the patient; and
- The level of effort, formality and documentation of QRM process should be commensurate with the level of risk.
QRM principles can be applied to both regulatory agencies and pharmaceutical manufacturers. For example,
- Systematic and structural planning of reviews and inspections that are risk based by the regulatory agencies;
- Making QRM an integral element of the pharmaceutical quality system (PQS) in the design, development, manufacturing and distribution of pharmaceutical products by drug manufacturers.
Science based decision making can be embedded into the QRM process.