Good Manufacturing Practices (GMP) in Pharmaceutical Sector: On December 28, 2023, the Ministry of Health and Family Welfare, Government of India, revised the Drugs Rules, 1945, under Gazette Notification Number G.S.R. 922(E), introducing updated Good Manufacturing Practices (GMP) and requirements for premises, plant, and equipment in the pharmaceutical sector. The brief overview of the changes being made are
- The updated rule would be called as the Drugs (….. Amendment) Rules, 2023.
- In the place of “Good Manufacturing Practices in Rule 74 (Clause o), Rule 76 (Clause 8) and Rule 78(Clause p), the words “Good Manufacturing Practices and Requirements of Premises, Plant and Equipment for Pharmaceutical Products”will be substituted.
In Schedule M of the initial notification, 20 different topics have been covered – each licensee should follow these systems and procedures which will be documented and maintained.
1. Pharmaceutical Quality Assurance (PQS)
Manufacturers should ensure the quality of their pharmaceutical products, meeting license requirements and ensuring patient safety. This involves a quality system with senior management accountability, staff involvement across all levels, and adherence to Good Manufacturing Practices (GMP) and Quality Risk Management (QRM). The system extends throughout the product lifecycle, emphasizing innovation, continuous improvement, and a strong link between development and manufacturing. Key elements include a well-documented product quality system covering all lifecycle stages, effective management of product and process knowledge, adherence to GMP, clear managerial roles, and stringent control over materials, production, and distribution to maintain quality and compliance.
2. Quality Risk Management (QRM)
Quality Risk Management (QRM) is a methodical approach for assessing, managing, communicating, and reviewing quality-related risks in pharmaceutical products, applicable both proactively and retroactively. It emphasizes basing risk evaluations on scientific knowledge and experience, directly linking them to patient protection. The QRM process’s complexity should match the risk level. Regular quality reviews of all pharmaceutical products aim to verify process consistency, the relevance of specifications for materials and finished products, and identify potential improvements. These reviews, typically annual, cover various aspects including material sourcing, process controls, deviations, changes in processes or methods, regulatory compliance, stability monitoring, customer feedback, equipment qualification, and contractual agreements.
3.Good Manufacturing Practices
Good Manufacturing Practices (GMP) are essential components of quality management in pharmaceutical production, ensuring consistent product quality, safety, and efficacy. GMP encompasses both production and quality control, aimed at reducing manufacturing risks. Key principles include defining and reviewing manufacturing processes, conducting qualification and validation, providing necessary resources (e.g., skilled personnel, adequate facilities, and appropriate materials), maintaining clear and unambiguous procedures, and ensuring thorough training. Additionally, GMP requires record-keeping to document compliance with expected quality standards, investigation of deviations, and implementation of corrective actions.
4. Sanitation
Sanitation and hygiene are critical in all aspects of drug production, encompassing staff, facilities, equipment, production materials, containers, and cleaning agents. An exhaustive sanitation and hygiene program is needed to prevent contamination risks, ensuring the elimination of potential contaminants through coordinated and comprehensive measures
5. Product Complaints and Adverse Reactions
Pharmaceutical manufacturers must handle complaints regarding potentially defective products, following detailed procedures for review and corrective actions. A designated individual, supported by adequate staff, is responsible for managing complaints and deciding on actions, including recalls. This process involves thorough investigation of complaints, especially those indicating product defects, and documenting all details. If defects are confirmed, the manufacturer must assess whether other batches are affected and take necessary actions, including recalls. All actions and decisions related to complaints must be meticulously recorded, linked to batch records, and regularly reviewed for patterns that may necessitate further measures or product recalls. Manufacturers are also required to inform licensing authorities in cases of significant quality issues and maintain a pharmacovigilance system to report adverse drug reactions, ensuring ongoing safety and efficacy monitoring.
6. Product Recalls
An authorized individual is tasked with overseeing recall operations, backed by adequate staff to ensure swift action. Written procedures for organizing recalls are to be regularly reviewed and updated, enabling recall initiation across all distribution levels. These procedures also mandate secure storage for recalled items. Licensing authorities must be notified of recall intentions due to potential defects. Distribution records, providing detailed customer information, support an effective recall process.
8.Change Control
This system encompasses a formal process for evaluating changes in various aspects, such as raw materials, specifications, analytical methods, and more. Changes must undergo thorough documentation, review, and approval by relevant organizational and quality units. The impact of these changes on product quality is assessed, categorizing them as minor or major based on their nature and potential effects. This evaluation guides the extent of necessary testing, validation, and documentation. Following approval, meticulous documentation updates and an evaluation of the first batch post-change ensure the change’s efficacy. Additionally, the impact on product stability and expiration dates is considered, potentially necessitating accelerated or extended stability testing.
9. Governance of Contract Manufacturing and Analysis in Pharmaceuticals
In pharmaceutical manufacturing, the delegation of production, analysis, and other activities under contract or loan license necessitates strict, clearly defined, and controlled agreements to prevent quality issues. These arrangements must align with the product’s licensing requirements and allow for audits by the contract giver. Contracts should detail all operations, ensuring GMP compliance and emphasizing the importance of mutual understanding of responsibilities, especially regarding product safety and hazards. The contract giver oversees assessing the contractor’s qualifications and managing outsourced activities, including performance monitoring and compliance with quality standards. Similarly, the contractor must possess the appropriate credentials, facilities, and expertise to fulfill their obligations without subcontracting without approval. A written contract, prepared by knowledgeable individuals, must explicitly outline each party’s responsibilities, the scope of work, communication protocols, and the specifics of production and analysis conformity to licensing agreements. This includes maintaining essential records and samples, managing subcontracting, and detailing procedures for handling non-conformities, thereby ensuring product integrity and regulatory compliance.
10. Self-Inspection, Supplier Audit, Quality Audit and Approval
The self-inspection program in pharmaceutical manufacturing is designed to ensure compliance with Good Manufacturing Practices (GMP) by identifying and correcting any discrepancies in all aspects of production and quality control. This includes regular and special inspections by a team of objective experts, with a mandate to implement corrective actions. The program encompasses a wide range of operational areas, including personnel, premises, equipment maintenance, storage, production controls, quality control, documentation, hygiene, validation programs, instrument calibration, recall procedures, complaints management, and label control. An annual self-inspection report outlines the findings, conclusions, and corrective measures, which are then reviewed and acted upon by company management. Additionally, external quality audits by independent specialists or teams complement these self-inspections, potentially extending to suppliers and contractors, to further assess and improve the quality system. The approval process for suppliers involves a thorough evaluation of their history, the quality of materials supplied, and their GMP compliance, ensuring only those meeting established specifications are selected.
11. Personnel
The manufacturer must ensure a sufficient number of adequately qualified and experienced staff, ensuring no individual is overloaded with responsibilities to the point where quality could be compromised. Detailed job descriptions, an organizational chart, and continuous GMP training reinforce this structure. Key personnel, including production and quality heads and the authorized person, must possess specific qualifications and experience in relevant scientific fields to uphold high quality standards. Their shared responsibilities cover a wide range of quality-related activities, from approving procedures to ensuring product compliance and overseeing validation efforts. Training programs are essential for all personnel, emphasizing GMP principles, personal hygiene, and continuous assessment of training effectiveness. Special attention is given to personal hygiene and health, with strict guidelines to prevent contamination and ensure product integrity, encompassing comprehensive policies on attire, and prohibiting personal items in critical areas.
12. Pharmaceutical Premises Design and Maintenance
Pharmaceutical premises must be strategically designed, constructed, and maintained to support quality manufacturing, aligning with the Factories Act, 1948. The layout prioritizes error minimization, effective cleaning, maintenance to prevent cross-contamination, and controlled environmental conditions. Facilities must ensure good sanitation, with HVAC systems properly maintained. Storage, weighing, and production areas are designed to maintain product integrity, with dedicated spaces for sensitive materials to prevent cross-contamination. Quality Control laboratories are segregated, equipped to avoid mix-ups, and built to accommodate safe and effective testing procedures.
13. Equipments
Pharmaceutical equipment standards emphasize the need for equipment to be specifically positioned, designed, constructed, adapted, and maintained to facilitate intended operations. This encompasses minimizing error risks, enabling effective cleaning, and preventing cross-contamination or product quality degradation. Equipment installation aims to reduce error or contamination chances, with clear labeling on fixed pipework for content identification and flow direction. Special measures ensure non-interchangeable connections for hazardous substances, and precision measuring tools are essential, requiring regular calibration. Strict cleaning schedules for production equipment and suitability of laboratory instruments for their intended tests are mandated. Equipment selection must avoid contamination risks, ensuring that any product contact does not compromise quality. Defective equipment must be clearly marked and isolated, with a preference for closed systems to limit contamination. Thorough cleaning of non-dedicated equipment is required to prevent cross-contamination, supported by current critical equipment and system schematics.
14. Materials
Pharmaceutical manufacturing necessitates strict management of materials, from procurement to product completion, ensuring they meet quality standards. This includes quarantine, storage under specified conditions, and careful handling to avoid contamination. The process encompasses starting and packaging materials, with a significant focus on water purity for manufacturing use, adhering to pharmacopeial specifications. Supplier selection is critical, requiring materials to be procured from approved sources and subjected to thorough inspection upon receipt. Packaging and labeling are meticulously managed to prevent mix-ups, ensuring materials are correctly dispensed and used within their shelf-life. Additionally, quality control extends to reagents and culture media, emphasizing accurate preparation, labeling, and application.
15. Reference Standards
These standards must be sourced from authoritative bodies like the Indian Pharmacopoeia Commission and utilized strictly as outlined in their specific monographs. When official standards are not available, manufacturer-prepared standards are subject to rigorous testing, release procedures, and secure storage under designated oversight. Secondary or working standards, created for internal use, require regular validation against these official references to maintain their accuracy. Essential labeling on all reference standards includes material name, batch or lot numbers, preparation date, shelf-life, potency, and specified storage conditions, ensuring they remain effective and reliable for use. Regular standardization against official references ensures the integrity and quality of pharmaceutical products.
16.Waste Materials
Pharmaceutical manufacturing facilities must ensure proper, safe storage and disposal of waste materials. Toxic and flammable wastes are stored separately in designed enclosures to mitigate risk. Accumulation of waste is avoided by frequent, safe disposal practices, aligning with environmental and bio-medical waste management regulations. This includes adherence to guidelines from the Environmental Pollution Control Board and compliance with the Bio-Medical Waste (Management and Handling) Rules, 2016, to prevent contamination of manufacturing elements and products.
17. Documentation
Documentation is essential to the quality assurance system in pharmaceutical manufacturing, ensuring detailed specifications and procedures for all materials, manufacturing processes, and quality control. This comprehensive approach guarantees that all manufacturing personnel understand their roles, facilitates informed batch release decisions, and provides a complete audit trail for traceability, validation, and analysis. Documents must be designed, approved, and regularly reviewed, with clear, unambiguous content that is easily verifiable. Alterations to documents are strictly controlled, with any changes clearly signed and justified. Electronic data systems, where used, include safeguards against unauthorized access and loss of data, ensuring integrity and availability over time.
18. Good Manufacturing Practices in Production
Pharmaceutical production adheres to stringent Good Manufacturing Practices (GMP) to ensure product quality and safety. Key practices include strict adherence to documented procedures, effective management of deviations, and meticulous yield reconciliations. Cross-contamination is rigorously prevented through controlled production environments and dedicated areas for sensitive products. Equipment and production areas are distinctly labeled and access is restricted to authorized personnel only, ensuring a clear operational workflow and minimizing error risks. Regular in-process controls and validations maintain product integrity throughout production. Packaging processes are carefully executed to prevent mix-ups, with thorough investigations conducted for any anomalies.
19. Good Practices in Quality Control
In pharmaceutical manufacturing, strict adherence to predefined procedures and documented protocols is essential for maintaining product quality and safety, from material receipt through to distribution. This includes clean work areas and equipment, managed deviations, controlled access, prevention of cross-contamination, and meticulous record-keeping. Before processing, cleanliness and equipment readiness are verified, with in-process and environmental controls documented. Equipment failures are addressed immediately, ensuring equipment is cleaned and stored appropriately post-use. Filling containers undergo pre-cleaning to remove contaminants. Significant yield deviations and equipment connections are checked and verified. Sanitization protocols for water pipes and regular calibration of measuring instruments are maintained. In packaging, risk of cross-contamination and mix-ups is minimized through segregation and clean operations, with clear product labeling and verification of printing accuracy.
20. Computerized Systems
Computerized systems in GMP settings must undergo validation to ensure their suitability for specific tasks, with the validation’s depth varying based on the system’s complexity and criticality. Commercial software already qualified may require less testing, while systems not validated upon installation might undergo retrospective validation if adequate documentation exists. Such systems need robust controls against unauthorized data access or modifications, including safeguards against data loss and comprehensive logs of data changes, including details of the change, the changer, and the timing. Procedures for system operation and maintenance must be documented, and critical manual data entries should be verified for accuracy either by another individual or automatically by the system. Incidents affecting product quality or record reliability must be recorded and investigated. System modifications must follow a formal procedure, with thorough documentation and testing to ensure ongoing validation. A backup system is essential to prevent irreversible data loss, with protective measures for all computerized systems. Additionally, data recording may complement computer systems through alternative means.
Conclusion
Navigating the complexities of GMP compliance in radiopharmaceutical production demands a comprehensive approach, from ensuring qualified personnel and designing compliant facilities to implementing quality assurance and control measures. Morulaa HealthTech’s expert consultancy provides a pathway for manufacturers and importers to meet CDSCO regulations, facilitating the production of safe, effective radiopharmaceuticals. Contact us on admin@morulaa.com or Click Here.
