Science-based approach and quality systems for product

Risk based models incorporating science based policies and procedures can provide effective rationale for process improvement, reduction in variability and hence assurance in quality, say Mangala Kulkarni, Sunil Kanvinde in the concluding part of the article

Science-based approach provides a sound scientific base to establish specifications, to develop and improve processes and to establish consistency and quality. Science-based approach helps in assessment of risk. Regulatory authorities are orienting themselves to science-based policies and standards.

Science-based approach also leads to a robust quality system with precision. The qualitative descriptions often lead to variations in interpretations which diverts the attention to compliance rather than improvement of quality.

Science-based policies are reflected through guidance on aseptic processing, PAT approach and comparability protocol. Aseptic processing being a most critical process in pharmaceutical manufacturing, requires highest assurance of process consistency. Science-based approach helps in reducing risks in this type of processing.

Process Analytical Technology (PAT) approach involves use of modern measurement tools in development, manufacturing and quality assurance. These new technologies provide information on physical, chemical and biological properties of material/product under evaluation. This helps in measuring, predicting and controlling quality with consistency. PAT approach helps in reducing cycle time, avoiding wastage, reducing human errors through automation, increasing consistency by reducing variability. Thus PAT helps in building quality by design in the product. Comparability protocol is a document in which all the components of existing process/procedure (CMC changes) and new change is assessed to demonstrate that change is justifiable to improve process. This protocol helps to implement change without prior approval from FDA. Thus product can be placed in the market earlier.

Quality and productivity share a common element — reduction in variability through process understanding. Adopting science-based approach strengthens quality systems.

Indian manufacturer and new concepts

The Indian manufacturing facilities which have international regulatory approvals or are in the process of obtaining such approvals need to orient to the new concepts more by innovation and creativity rather than be a follower.

Risk management is a buzz word and finds prominence in seminars. The speakers exchange information but not comment in real sense. The need is to implement certain tools and evaluate effectiveness. The concept of quality by design is a concept that can be incorporated into developmental protocols. Risk based models incorporating science based policies and procedures can provide effective rationale for process improvement, reduction in variability and hence improvement in quality.

The overlap of the quality systems with the cGMP guideline has been major issue and hence US FDA has issued Draft Guidance Note — ‘‘Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations.’’ This document describes a comprehensive quality system model that manufacturer could use for compliance with cGMP regulatory requirements. It also covers the concept of risk management. The proposed model is thus a bridge between regulations and the quality systems.

US FDA’s guidance indicates the need to reconsider certain cGMP concepts. Following topics cover some important issues to which Indian manufacturer should pay attention.

VMP: is the comprehensive document expressing the company philosophy, intensions and approach for establishing performance adequacy. In the new concept, risk evaluation forms an integral part of the VMP. This not only facilitates validation experimentation but also ensures faster inspections and approvals.

Automation: Wherever possible, automation in manufacturing, packaging and testing should be of choice to avoid human errors. It provides basis for science-based approach and avoids the use of human judgments or experience popularly followed in manufacturing. This will provide better control over process. It will also provide for data management to support the process. Fortunately the Indian industry is supported by well developed equipment manufacturers.

When the discussions are on PAT in advanced countries, our manufacturers should strengthen the process control through automation and reduce variability. Process validation is gaining different dimension. The validation concept is integrated with quality by design whereby ongoing evaluation of data is considered important. The guidance note stresses that achieving and maintaining a state of control for a process begins at process development phase and continues throughout the commercial phase of the product life cycle. It clearly states that validation does not end with data on first three full scale production batches but is a continuous process. Hence periodically validation should be carried out.

Cleaning validation: CIP backed by strong validation is desirable. If CIP systems are not available, properly validated manual cleaning procedures should be adopted. In cases where there is no automation, the variations in cleaning procedure is possible due to human factor involved. Often cleaning is assigned to contractual staff and in such cases proper training is important. Adhering to validated cleaning procedure rather than residue analysis at the end of each cleaning process is desirable.

Validation of computerised processes: Automation rather than manual judgments are desired in science-based risk management. With increased automation, validation of computerised processes is essential.

Data management: In the manufacturing and analysis, a large number of data is generated. Quality systems propose annual review for monitoring and analysis of trends. Often this data is collected in a non-scientific way and expected purpose is not understood. Application of scientific methods like statistical tools will provide basis of analysis. It will help to understand the trends and possible errors in processes leading to deviations.

Contamination issues: Effective control over cross contamination can be achieved by proper designing of AHU systems. Effective control will give assurance that risk of contamination is under well control and also will lead to regulatory compliance.

Change control: Proper documentation and authorisation of changes by a proper change control system will avoid risks by preventing any quality variations. Change control refers to planned deviation and evaluation of its impact.

Non-conformity investigations: Handling of deviations and nonconformities is a key component in a quality system. These issues are often left open leading to recurrence of the incidences. This poses risk to the product quality. Customer complaints form a part of addressing non-conformities. Non-conformities require proper remedial actions or rejection and recall.

Systems backed by well defined responsibilities will help address the non-conformities. This being a risk based area; inspecting authorities critically look into non conformities and investigation approach which reflects on manufacturers understanding of quality systems.

Stability indicating methods: The Indian manufacturers need to realise the importance of stability indicating methods to establish the impurity levels at the end of shelf life of the product. These methods form a part of risk-based GMP and support quality systems.

Self inspection/internal audits: Such planned audits at regular intervals are part of quality systems. It reflects on effective implementation and maintenance of quality systems. It evaluates if processes and products meet established parameters and specifications. It is critical to maintain audit records and assign responsibility to follow up.

CGMP training: ‘People make the difference’ — a paraphrase which translates any concept into reality. People are the strength of any company. A well trained team can then exchange and implement current concepts effectively. Prope investments in this direction has to be decided so as to reflect strong management philosophy.

Unless people are trained; any amount of documentation, SOPs or modern facility cannot give desirable results. These are some of the key areas on which much focus is expected from Indian manufacturers.

Summary

The concept of risk has to be linked with patient safety to assure product quality. The outlook towards GMP therefore should lay emphasis on patient safety.

The cGMP guidelines are often interpreted differently and hence major emphasis has been on compliance rather than improvements in product quality through innovations.

Quality system concept needs to be understood as supportive to regulatory cGMP compliances. This is being adopted in inspection strategy by US FDA.

Use of risk analysis models, science based policies and developing robust quality systems can be pillars to high quality and high productivity.

Proper identification and control of areas of potential process weakness and responsive investigation systems lead to timely remediation and support well developed quality systems.

Developing on line controls is today’s challenge. On line analysis methodology (PAT) rather than off line testing is future of quality testing.

Mangala Kulkarni is with Sandoz Private Limited while Sunil Kanvinde is with Novartis India Limited