Good manufacturing practices: Organization and personnel, Hygiene, Training, Contamination

Organization and personnel:
1. Personnel responsibilities Training, personal record.
2. Hygiene
Premises:
1. Design, construction and plant layout, maintenance, sanitation,
2. Environmental control, utilities and maintenance of sterile areas,
3. Control of contamination
Equipments and raw materials:
1. Equipment selection, purchase specifications, maintenance,
2. Purchase specifications and maintenance of stores for raw materials.

1. Unit 2: GMP Mr. Vinayak Bodhankar M. Pharm., Ph.D *

2. Content Organization and personnel: 1. Personnel responsibilities Training, personal record. 2. Hygiene Premises: 1. Design, construction and plant layout, maintenance, sanitation, 2. Environmenta l control, utilities and maintenance of sterile areas, 3. Control of contamination Equipments and raw materials: 1. Equipment selection, purchase specifications, maintenance, 2. Purchase specifications and maintenance of stores for raw materials.

3. Establishment and maintenance of a suitable quality assurance system for pharmaceutical products. Sufficient number of qualified personnel should be present for conducting various tasks in the manufacturing unit. Individual responsibilities should be clearly understood by the concerned person and should be recorded. The personnel should be aware of the GMPs , which if not followed will affect the manufactured product; therefore, the personnel should continuously receive training, including hygiene instructions relevant to their needs. ORGANIZATION & PERSONNEL:

4. Personnel Responsibilities Personnel in aseptic areas must wear clean uniforms and protective apparel (head, face, hands, arms) to prevent contamination. Training on proper usage is required. Maintain good sanitization and hygiene practices. Avoid jewellery and make-up in production and quality control areas to prevent contamination. Eating, drinking, smoking, and storing food, alcohol, cigarettes, or personal medication in production and storage areas are prohibited. Only authorized, trained personnel should access restricted areas . Non-employees must receive minimal training and be accompanied by company staff. Personnel must be physically fit, with pre-employment medical tests as per company policy .

5. Individuals with illnesses or open wounds that may affect drug safety or quality should not handle drug products or materials until cleared by medical personnel. Personnel must inform supervisors of any health conditions that could impact drug products. Employees returning from illness must visit the company’s medical facility before resuming work. Any equipment malfunction or process deviation should be reported to the supervisor immediately.

6. Personnel Training Personnel are the most significant part of a manufacturing system. Thus, they should be provided with standardized training to maintain a high level of proficiency and competency in the work area. Training System The following elements are needed in a strong training system: 1 ) An accurate description of the job or role, 2) Specific training requirements for each job or role, 3) Training plan to complete the training, 4) Training materials applicable to each type of training, 5) Qualified trainers to provide training, 6) Evaluations to measure the effectiveness of training system, and 7) A documentation and record-keeping system for storage and retrieval of training records and materials.

7. Personal Records The training system and processes should be documented in an SOP, and its working and the type of training included in the training system should be mentioned. Training records should be retained in a documentation system. Training documentation should be easy to retrieve. The FDA or other regulators often request an employee's training record. In such a case, the record should be presented to them within a short time period after their request. Performance evaluations should also be retained.

8. Personnel handling β-lactam antibiotics must be tested for penicillin sensitivity , and those handling cytotoxic or potent drugs should undergo regular health checks and be rotated to protect their health. Pre-employment medical exams, including eye and communicable disease tests, are required. Annual medical check-ups must be conducted, with records maintained. A qualified physician must assess the health of manufacturing personnel. Employees must be trained in personal hygiene and sanitation. Those with illnesses or open wounds should not handle materials or products until recovered. Personnel must report illnesses to supervisors for necessary action. Avoid direct contact between unprotected hands and raw, intermediate, or finished products. Personnel Hygiene

9. PREMISES: The location, environment, plant layout, design and construction of premises directly or indirectly affect the quality of pharmaceuticals, thus play a significant role in pharmaceuticals. Design and Construction The premises to be used for the manufacturing, processing, packing or holding of drug products should be of suitable size, design, construction and location . This reduces the risk of errors and allows effective cleaning and maintenance to prevent cross-contamination, accumulation of dust or dirt, and any adverse effect on the product quality. The premises should also abide by the conditions laid down in the Factories Act, 1948 .

10. The following guidelines should be followed during plant design and construction: 1) Walls: The walls should be positioned such that they enable orderly movement of materials and personnel. Noise levels should be kept to minimum to maintain suitable working conditions. The finish of these walls should be smooth and with enamel or epoxy paint . Pre-fabricated partitions should be used in packaging areas where flexibility of layout is required. 2) Floors: Floor coverings should be such that they are durable, easily cleanable, and resistance to the chemicals with which it would come into contact. Flooring should be washable, smooth, without cracks, and should not allow dust accumulation. Given below are some commonly used coverings: Terrazzo Ceramic and Vinyl Tiles Welded Vinyl Sheeting Epoxy Flooring

11. 3) Ceilings: In the manufacturing areas, the ceilings should be of seamless plaster or gypsum board with a smooth finish. All ceiling fixtures, like light fittings, air outlets and returns, and sprinkler heads should be designed that they permit cleaning and reduce dust accumulation. 4) Services: Adequate provisions should be made for drainage, water, steam, electricity, and other services for easy maintenance of the buildings. The design and facilities of buildings should be such that they have sufficient space for orderly arrangement of equipment and materials so that any mixups and contamination do not occur. Adequate cleaning, washing and toilet facilities should also be provided for the personnel. 5) Lighting: Adequate amount of light should reach the working surface of each area involved in the production of pharmaceuticals. There are public standards for some types of work. Normally, range of 30 to 50 foot-candles is suitable to provide work comfort and ability to perform efficiently and effectively; however, some areas demand 100 foot-candles along with special lighting for some operations, such as inspection of filled vials.

12. PLANT LAYOUT Plant layout is the area within the factory building where physical facilities like machinery, equipment, furniture, etc., are arranged such to permit quick flow of material. Importance of Plant Layout 1) It provides optimum relationship among output, floor area, and manufacturing process, 2) It allows easy production flow, 3) It provides flexibility of operation, 4) It makes economic use of building, 5) It promotes effective utilization of manpower, 8) It provides comfort at work, and 9) It provides maximum exposure to natural light and ventilation.

13. Types of Plant Layout Manufacturing unit plant layout is of the following four types: 1) Product or Line Layout: In this layout, all the equipment, machines, tools, and other items required for the processing are arranged as per the sequence in which the operations including production, testing, packaging, etc., are carried out. Product or line layout is called as one line layout as it is meant for the processing of one specific product. While designing this layout, one line should not cross the other line. 2) Process Layout: In this layout, all the equipment, machines, etc. are not arranged as per the sequence of operations; but, a specific operation like granulation, coating, mixing, etc., for all the products is carried out at a particular work station or department. The departments should be located at minimum distance to avoid long distance movement of materials. The departments should be arranged as per the convenience for inspection and supervision. 3) Fixed Position or Location Layout: In this layout, a complete product or a major part of it is produced at a fixed location. The facilities required are arranged around the particular work centre /location.

14. SANITATION Buildings used for manufacturing, processing, packing, or storing of drug products should be maintained under clean and sanitary conditions and should not be infested with rodents, birds, insects, and other vermin. Scrap and waste materials should be collected and disposed timely in a sanitary manner. The cleaning procedures should be written and validated suitably. A routine sanitation programme should be conducted, properly recorded, and should indicate the following: 1) Specific areas to be cleaned and cleaning intervals, 2) Cleaning procedure to be followed, including equipment and materials to be used for cleaning, and 3) Personnel assigned for the cleaning operation.

15. Manufacturing, packaging, and warehousing buildings must be well-maintained to ensure product quality. Cracks or holes in walls, floors, or ceilings can allow entry of pests, dirt, and microorganisms, leading to contamination. Damaged surfaces hinder cleaning and increase cross-contamination and microbial growth risks. Floor cracks can cause safety hazards and disrupt material transfers. Roof leaks can damage stored materials, equipment, and cause electrical failures or fires. Birds nesting in building holes can lead to contamination. Written procedures should be in place for using cleaning agents, rodenticides, insecticides, and fungicides. Pest control substances must be used per applicable laws. MAINTENANCE

16. ENVIRONMENTAL CONTROL The environment includes biological, physical, and social surroundings. Pharmaceutical manufacturing generates waste that can pollute the environment. Companies must take steps to reduce waste, recycle materials, and manage hazardous waste responsibly. Waste and product residues must not be released into the atmosphere or normal drainage systems. Surrounding areas and the public must be protected from hazardous substances. Liquid waste posing safety or contamination risks should be treated before disposal. Written procedures should ensure continuous monitoring of environmental conditions, temperature, and humidity in manufacturing areas. Factories should have air extraction systems with filters to control dust and protect the environment.

17. MAINTENANCE OF STERILE AREAS The manufacturing areas for sterile pharmaceutical products should be cleaned and disinfected as per the applicable SOPs, and such activities should be recorded in writing and retained in archive. QC must evaluate and validate cleaning agents and disinfectants for effectiveness in removing contaminants. SOPs should cover application, schedules, safety precautions, and storage of cleaning tools. Agents for Grade A/B areas must be sterilized and contamination-controlled. In-house and commercial disinfectants must follow SOPs, with proper records of preparation, dilution, storage, and sterilization. Surfaces and equipment in direct contact with products must be free from cleaning residues after disinfection. Disinfectants should have expiration dates and be used before expiry.

18. CONTROL OF CONTAMINATION Contamination is the presence of any foreign substance in the products . It may be: 1 ) Physical: Hair , foreign objects , dirt , dust , and pollens . 2 ) Chemical: Cleaning agents , lubricants , and other products. 3 ) Microbiological: Bacteria , moulds , spores , and yeasts. Cross contamination of any product is caused by: 1 ) Contamination of a batch with a previous batch of the same product , 2 ) Contamination with a different product through carryover of production lines , 3 ) Contamination by a foreign starting material of the dispensary or in the store. Main Sources of Contamination Following are the major sources of contamination : 1) Environment in which the product is formulated and filled, 2) Equipment used in formulation and filling, 3) Operators, 4) Raw materials and packaging materials,

19. Raw Materials Storage Maintain Cleanliness: Regularly clean storage areas to prevent dust accumulation and pest infestation. Proper Material Placement: Store materials off the floor on designated racks to avoid damage and contamination. Immediate Spill Response: Clean up spills promptly to prevent cross-contamination. Clear Labeling: Label all materials accurately to prevent mix-ups and ensure traceability. Use of Computer Systems Computer systems are often used to control inspection and test status if materials and products do not have physical status labels. Such systems should be validated and thoroughly documented. All the operators should be trained in using these systems .

20. Maintenance Department Protective Clothing: Required maintenance staff should wear clean, appropriate attire to minimize contamination. 2. Controlled Access: Keep doors closed to restrict dust and pest entry. 3. Immediate Spill Management: Address spills without delay to prevent contamination spread . 4. Pest Control Implementation: Regularly conduct pest control measures throughout the facility.

21. Dispensary Operator Hygiene : Ensure staff wear clean gowns and adhere to hygiene protocols. Controlled Environment : Keep doors closed and prevent simultaneous opening of multiple doors to maintain air quality. Exhaust Systems Maintenance : Install and regularly service exhaust fans to control dust and contaminants. Equipment Cleaning : Establish procedures for cleaning ducts, grills, and fans to prevent contamination sources. Filling Department Air Quality Control : Utilize and maintain air handling units to supply clean air. Proper Garments : Require specific work clothing to prevent cross-contamination. Equipment Maintenance : Regularly service machinery to prevent product container damage. Discard Dropped Products : Do not return any dropped items to the production line .

22. Machinery Contamination Prevention Regular Cleaning : Clean machines after each use and inspect for cleanliness before operation. Monitor for Malfunctions : Be vigilant for leaks, drips, that could lead to contamination. Use Food-Grade Lubricants : Employ appropriate lubricants to minimize contamination risks. Implement Preventive Maintenance : Schedule regular maintenance to ensure optimal machine performance.

23. Air Quality Control Air Filtration Systems : Install and maintain HEPA filters to remove airborne contaminants. Environmental Monitoring : Regularly assess air quality to detect and address contamination sources. Temperature and Humidity Control : Maintain optimal conditions to prevent microbial growth. Restricted Access : Limit entry to processing and storage areas to essential personnel only . Packaging Department Secure Label Storage : Keep labels in sealed containers within restricted areas when not in use. Clear Identification : Use signage to distinctly identify products during packaging to prevent mix-ups. Segregate Operations : Separate different products to avoid cross-contamination. Conduct Line Clearance : Perform thorough checks before starting new packaging operations.

24. Personnel Contamination Control Health Screening : Ensure staff handling exposed materials are free from contagious diseases and open lesions. Strict Personal Hygiene : Enforce rigorous hygiene practices among all personnel. Avoid Direct Contact : Prevent direct hand contact with exposed products and clean containers.

25. EQUIPMENT & RAW MATERIALS: Equipment Selection Design and Size : Choose equipment with appropriate design and capacity to ensure efficient manufacturing of intermediates and Active Pharmaceutical Ingredients (APIs). Material Construction : Utilize construction materials that do not react with raw materials, intermediates, or APIs, preserving their quality within established standards. Location and Accessibility : Position equipment to facilitate its intended use, cleaning, sanitation, and maintenance, minimizing contamination risks. Operational Qualification : Ensure equipment operates within its qualified range to maintain consistent product quality.

26. Purchase Specifications for Equipment User Requirement Specification (URS) Compatibility : Confirm that equipment aligns with the URS, meeting operational needs and compliance requirements. Purpose and Functionality : Assess the necessity of the equipment, whether for new facilities, capacity expansion, or technological upgrades, and define its intended operations. Capacity and Performance : Determine equipment capacity based on production targets, such as output per shift, ensuring it meets production demands. Cleaning and Validation : Evaluate the equipment's cleaning procedures and address any challenges in validating the cleaning process to prevent cross-contamination.

27. Maintenance of Equipment Installation and Labeling : Install equipment in such a place so as to minimize contamination and errors, clearly labeling should be there. Calibration and Precision : Use balances and measuring devices with appropriate range and precision, calibrating them regularly to maintain accuracy. Scheduled Cleaning : Implement a routine cleaning schedule to ensure equipment is free from contaminants, maintaining product integrity. Material Compatibility : Ensure that product-contact surfaces are non-reactive, non-additive, and non-absorptive to prevent adverse effects on product quality.

28. PURCHASE SPECIFICATIONS FOR RAW MATERIALS Written Procedures : Establish clear procedures for receiving, identifying, quarantining, storing, handling, sampling, testing, and approving or rejecting materials. Supplier Evaluation : Implement a system to evaluate and approve suppliers of critical materials to ensure consistent quality. Agreed Specifications : Purchase materials based on agreed specifications from suppliers approved by the quality unit. Manufacturer Details : If the supplier and manufacturer are different, the manufacturer’s name and address should be known for traceability. Visual Inspection : Upon receipt, inspect each container for correct labeling, damage, broken seals, or signs of contamination.

29. Quarantine Before Use : Quarantine materials until they are sampled, tested, and approved for use to avoid contamination. Mixing Precautions : Before mixing new materials with existing stock, verify their identity, test them, and release for use only if they meet the required standards. Cross-Contamination Prevention : Prevent cross-contamination by obtaining a cleaning certificate, testing for impurities, or auditing the supplier. Proper Identification : Clearly label each container or batch with a unique code, batch, or receipt number to maintain traceability. Status Tracking : Use a system to identify and track the status of each batch throughout the storage and handling process.

30. Detailed guidelines defining the operational, physical, and/or chemical properties as well as the quality and quantity of a specific item are needed. Mode of Purchasing 1 ) By inspection , 2 ) By description of brand , Steps of Purchasing 1 ) Purchase requisition or application , 2 ) Selection of supplies , 3 ) Inviting quotation , 4 ) Placing the order , 5 ) Receiving the material , 6 ) Checking the invoice or bill , 7 ) Recording of bills in books , and 8 ) Releasing the payment to the supplier .

31. Handling and Storage : Store materials to prevent degradation, adulteration, and cross-contamination. Keep fibre drums, bags, or boxes off the floor with enough space for cleaning and inspection. Store under suitable conditions to maintain quality and follow the First-In-First-Out (FIFO) rule. Storage Area Specifications : Sufficient capacity with clean, dry, and temperature-controlled conditions. Designated areas for receiving, quarantining, sampling, and segregating rejected or returned materials. Secure area for narcotics or hazardous materials. Apply FIFO and First-Expiring-First-Out (FEFO) principles. Storage Conditions : Room temperature: 30°C, 60% Relative Humidity (R.H.). A.C. storage: 25±2°C, 45-55% R.H. Low temperature: 2-8°C for specific materials. Store light-sensitive materials in amber containers and use hermetically sealed containers when necessary. MAINTENANCE OF STORES FOR RAW MATERIALS

32. Labelling of Materials : Include product name, internal code, batch number, status, and expiry or retest date. Check List Before Storage : Verify package integrity and seal condition. Confirm correspondence between order, delivery, and supplier labels. Check List During Storage : Keep rejected, recalled quarantined, and on-test materials separate. Regularly check the quality of stored materials. Quality Control (QC) Release : Materials should be released for use only by the QC unit.