Production Operations
GENERAL
Production operations must comply with good manufacturing practices (GMP) to manufacture quality product that meets regulatory requirements. GMP for manufacturing operations include requirements for the prevention of cross-contamination during production, process validation, and environmental conditions, based on the types of manufacturing performed. These GMP should be written and approved, with procedures and documentation for production operations. The GMP for production operations include:
• Access to production premises should be restricted to designated personnel.
• Before any processing operation is started, steps are taken and documented to ensure that the work area and equipment are clean and free from any raw materials, products, product residues, labels, or documents not required for the current operation.
• At all times during processing, all materials, bulk containers, major items of equipment, and the rooms used are labeled or otherwise identified with an indication of the product or material being processed, its strength, and the batch number or status. The processing status of major units of equipment should be indicated either on the individual units of equipment or by appropriate documentation, computer control systems, or alternative means.
• Contemporaneous and complete batch production documentation is necessary.
• Process steps must be verified by a second person. Process steps can be performed using a validated computer system.
• Other critical activities should be witnessed or subjected to an equivalent control.
• Any deviation from instructions or procedures is avoided. Any deviation should be documented and explained. Any critical deviation should be investigated. Qualified personnel write a report that describes the deviation, the investigation, the rationale for disposition, and any follow-up activities required. The report is approved by quality control (QC).
• Rejected materials and products are clearly marked as such and are either stored separately in restricted areas or controlled by a system that ensures that they are either returned to their vendors or, where appropriate, reprocessed or destroyed. Actions taken are recorded.
Provided that changeover procedures are validated and implemented, nonmedicinal products may be fabricated or packaged/labeled in areas or with equipment that is also used for the production of pharmaceutical products.
PROCESS VALIDATION
Process validation includes the validation and security of computerized or automated data handling systems. Validation studies are conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions is prepared, evaluated, approved, and maintained.
APPLICATION FACTORS
Human Drugs
Production requirements for human drugs are regulated by 21 CFR 211, while production requirements for biologics are regulated by 21 CFR 600, 601, and 610. Animal drugs are regulated by 9 CFR. Sterile drugs are susceptible to particulate, pyrogenic, and microbiological contamination. Due to the health hazard associated with the use of contaminated sterile products, special precautions are required in the production of these products. The skill, training, and competency of all personnel involved are critical. Quality assurance (QA) is important, and the production must follow carefully established and validated methods of preparation and sterilization.
To maintain product sterility, it is essential that the environment in which aseptic operations (for example, equipment setup, filling) are conducted be maintained in a controlled manner and at an appropriate quality. Activities conducted in critical areas include manipulations (for example, aseptic connections, sterile ingredient additions) of sterile materials before and during filling and closing operations.
High-efficiency particulate air (HEPA)–filtered air should be supplied in critical areas at a velocity sufficient to sweep particles away from the filling/closing area and to maintain unidirectional airflow during operations. The velocity parameters established for each processing line should be justified and appropriate to maintain unidirectional airflow and air quality under dynamic conditions within the critical area.
Supporting clean areas can have various classifications and functions. Many support areas function as zones in which non-sterile components, formulated products, in- process materials, equipment, and container/closures are prepared, held, or transferred. These environments are soundly designed when they minimize the level of particle contaminants in the final product and control the microbiological content (bioburden) of articles and components that subsequently are sterilized.
The nature of the activities conducted in a supporting clean area determines its classification. The United States Food and Drug Administration (FDA) recommends that the area immediately adjacent to the aseptic processing line meet, at a minimum, class 10,000 (ISO 7) standards under dynamic conditions. Manufacturers can classify this area as class 1000 (ISO 6) or maintain the entire aseptic filling room at class 100 (ISO 5). An area classified at a class 100,000 (ISO 8) air cleanliness level is appropriate for less-critical activities (for example, equipment cleaning). European Union (EU) GMP recommend that the supporting areas cascade, so that supporting area from grade A is grade B, which cascades down to grade C, and again down to grade D.
Non-sterile Manufacturing and Manufacturing of Liquids, Creams, and Ointments
Production prevention of microbiological contamination of drug products purporting to be sterile, including the validation of any sterilization process, is the prevention of objectionable microorganisms in non-sterile drug products. FDA guidance is found in sections of 21 CFR regarding topical drug products, and similar information can be found in Eudralex Volume 4, Parts I and II and Annexes.
SANITIZATION AND PROTECTION
Gowning Requirements
Every person entering the manufacturing areas should wear protective garments appropriate to the operations to be carried out. Where a potential for the contamination of a raw material, in-process material, or drug exists, individuals wear clean clothing and protective covering. Personal hygiene procedures, including the use of protective clothing, apply to all persons entering production areas. The hygiene program clearly defines clothing requirements and hygiene procedures for personnel and visitors.
Clothing used in clean and aseptic areas should be laundered or cleaned in such a way that it does not gather additional particulate contaminants that can later be shed. Separate laundry facilities for such clothing are desirable. If fibers are damaged by inappropriate cleaning or sterilization, the risk of shedding particles is increased. Washing and sterilization operations follow standard operating procedures (SOPs), and repair of clothing is done using appropriate materials (for example, non-shedding thread). Cleanroom gowning requirements as specified by EU GMP, International Conference on Harmonization (ICH), and Health Canada are listed in Table 43.1.
Sanitization and Hygiene
Clean areas should be cleaned thoroughly according to documented procedures. Detailed hygiene programs should be established. They should include procedures relating to the health, hygiene practices, and clothing of personnel. Hygiene procedures should be understood and followed in a very strict way by every person whose duties take him/her into the production and control areas. The hygiene program should be promoted by management and discussed during training sessions. Every person entering the manufacturing areas should wear protective garments appropriate to the operations to be carried out. Where a potential for the contamination of a raw material, in-process material, or drug exists, individuals wear clean clothing and protective covering. Unsanitary practices such as eating, drinking, chewing gum, or smoking, or the storage of food, drink, smoking materials, or personal medication in the production and storage areas should be prohibited. Requirements concerning personal hygiene, with an emphasis on hand hygiene, are outlined and are followed by employees. Personnel should be instructed to use the hand-washing facilities. Direct skin contact between the operator’s hands and raw materials, primary packaging materials, intermediate or bulk drug, or exposed product, as well as with any part of the equipment that comes into contact with the products, should be avoided. Houseplants are not permitted in fabrication, packaging/labeling, and storage areas or in any other areas where they might adversely influence product quality. Requirements concerning cosmetics and jewelry worn by employees are outlined and are observed by employees. Soiled protective garments, if reusable, are stored in separate containers until properly laundered and, if necessary, disinfected or sterilized. Steps should be taken to ensure as far as is practicable that no person affected by an infectious disease or having open lesions on the exposed surface of the body is engaged in the manufacture of medicinal products. Personal hygiene procedures, including the use of protective clothing, apply to all persons entering production areas. The hygiene program clearly defines clothing requirements and hygiene procedures for personnel and visitors. It must be the manufacturer’s responsibility to provide instructions ensuring that health conditions that can be of relevance to the quality of products are brought to the manufacturer’s attention. In general, any unhygienic practice within the manufacturing areas or in any other area where the product might be adversely affected should be forbidden.
In addition, some jurisdictions require medical examinations, particularly at time of recruitment. After the first medical examination, examinations should be carried out when necessary for the work and personal health.
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