GMP in Pharmaceutical Industrial PDF

GMP Chapter I Good Manufacturing Practices Lecturer: Dr. Iman Hamdan Faculty of Pharmacy Al Zaytoonah University Definition That part of QA which ensures that products are consistently produced and controlled to the quality standards as per the specifications. ...

GMP Chapter I Good Manufacturing Practices Lecturer: Dr. Iman Hamdan Faculty of Pharmacy Al Zaytoonah University Definition That part of QA which ensures that products are consistently produced and controlled to the quality standards as per the specifications. - Good manufacturing practice (GMP) is a system for ensuring that products are consistently produced and controlled according to quality standards. - It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product. - The main risks are: unexpected contamination of products, causing damage to health or even death; incorrect labels on containers, which could mean that patients receive the wrong medicine; insufficient or too much active ingredient, resulting in ineffective treatment or adverse effects. - GMP covers all aspects of production; from the starting materials, premises and equipment to the training and personal hygiene of staff. - Detailed, written procedures are essential for each process that could affect the quality of the finished product. - There must be systems to provide documented proof that correct procedures are consistently followed at each step in the manufacturing process - every time a product is made. - WHO has established detailed guidelines for good manufacturing practice. Many countries have formulated their own requirements for GMP based on WHO GMP The early beginnings 1900’s- house-calls Home remedies, ointments and “miracle elixirs” No regulations until 1902 Public involvement 1905 - The Jungle by Upton Sinclair Exposure of unsanitary Meat packing plants. Increased Public awareness And involvement Pure Food and Drug Act False labeling became illegal A time line of GMP 1902 - Development of the Biologic Control Act 1906 - Development of the Pure Food and Drug Act 1938 - Federal Food, Drug and Cosmetic Act 1941 - Initiation of GMP 1944 - Development of Public Health Services Act 1962 - Kefauver-Harris Drug Amendments released 1963 - Establishment of GMPs for Drugs 1975 - CGMPs for Blood and Components Final Rule 1976 - Medical Device Amendments 1978 - cGMPs for Drugs and Medical Devices 1979 - GLPs Final Rule 1980 - Infant Formula Act is passed 1941 initiation of GMP Sulfathiaziole tablets contaminated with phenobarbital 1941 - 300 people died/injured FDA to enforce and revise manufacturing and quality control requirements 1941 - GMP is born Thalidomide tragedy Thousands of children born with birth defects due to adverse drug reactions of morning sickness pill taken by mothers Strengthen FDA’s regulations regarding experimentation on humans and proposed new way how drugs are approved and regulated “Proof of efficacy” law Guidelines Good Manufacturing Practices (GMP) for Drugs GMP are the part of quality assurance that ensures that drugs are consistently produced and controlled in such a way to meet the quality standards appropriate to their intended use, as required by the marketing authorization. GMP basic requirements are as follows: 1.Manufacturing processes are clearly defined and controlled to ensure consistency and compliance with approved specifications; 2.Critical steps of manufacturing processes and significant changes to the process are validated; 3.All necessary key elements for GMP are provided, including the following: qualified and trained personnel, adequate premises and space, suitable equipment and services, correct materials, containers and labels, approved procedures and instructions, suitable storage and transport.  Instructions and procedures are written in clear and clear language; Operators are trained to carry out and document procedures; Records are made during manufacture that demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the drug was as expected. Deviations are investigated and documented; Records of production, packaging, labelling, testing, distribution, importation, and wholesaling that enable the complete history of a lot to be traced are retained in a comprehensible and accessible form; Control of storage, handling, and transportation of the drugs minimizes any risk to their quality; A system is available for recalling of drugs from sale; Complaints about drugs are examined, the causes of quality defects are investigated, and appropriate measures are taken with respect to the defective drugs and to prevent recurrence.  Areas to be covered General considerations Personnel Premises Equipment Sanitation SOP’s Raw Materials Self Inspection And Audit Master Formula Records Batch Manufacturing Records Areas to be covered(cont..) Warehousing Area Reference Samples Validation and process validation Labels And Other Printed Materials QA General considerations Compliance with GMP Consistent uniform batches Location And surroundings Water system Disposal Of Waste 1- PERSONNEL Personnel Qualified Personnel a)Experienced b)Sufficient Number Written job description Trained Health a)Diseases b)Open Lesions Regulation Every lot or batch of a drug shall be fabricated, packaged/labelled, tested and stored under the supervision of personnel who, having regard to the duties and responsibilities involved, have had such technical, academic, and other training as the Director considers satisfactory in the interests of the health of the consumer or purchaser. Rationale People are the most important element in any pharmaceutical operation, without the proper personnel with the appropriate attitude and sufficient training, it is almost impossible to fabricate, package/label, test, or store good quality drugs. It is essential that qualified personnel be employed to supervise the fabrication of drugs. The operations involved in the fabrication of drugs are highly technical in nature and require constant awareness, attention to details and a high degree of competence on the part of employees. Inadequate training of personnel or the absence of an appreciation of the importance of production control, often accounts for the failure of a product to meet the required standards. 1. The individual in charge of the quality control department of a fabricator, packager/labeller, tester, importer, and distributor; and the individual in charge of the manufacturing department of a fabricator or packager/labeller; 1.1 holds a university degree or a degree recognized as equivalent by university or accreditation body in a science related to the work being carried out; 1.2 has practical experience in their responsibility area; 1.3 directly controls and personally supervises on site, each working shift during which activities under their control are being conducted; and 1.4 may delegate duties and responsibility (e.g., to cover all shifts) to a person in possession of a diploma, certificate or other evidence of formal qualifications awarded on completion of a course of study at a university, college or technical institute in a science related to the work being carried out combined with at least two years of relevant practical experience, while remaining accountable for those duties and responsibility. 2. The individual in charge of the quality control department of a wholesaler; 2.1 is qualified by pertinent academic training and experience; and 2.2 may delegate duties and responsibility to a person who meets the requirements defined under interpretation 2.1. 3. The individual responsible for packaging operations, including control over printed packaging materials and withdrawal of bulk drugs; 3.1 is qualified by training and experience; and 3.2 is directly responsible to the person in charge of the manufacturing department or a person having the same qualifications. 4. For secondary labellers, individuals in charge of labelling operations and individuals in charge of the quality control department; 4.1 are qualified by pertinent academic training and experience; and 4.2 can delegate their duties and responsibilities to a person who meets the requirements defined under 4.1. 5. An adequate number of personnel with the necessary qualifications and practical experience appropriate to their responsibilities are available on site. 5.1 The responsibilities placed on any one individual are not so extensive as to present any risk to quality. 5.2 All responsible personnel have their specific duties recorded in a written description and have adequate authority to carry out their responsibilities. 5.3 When key personnel are absent, qualified personnel are appointed to carry out their duties and functions. 6. All personnel are aware of the principles of GMP that affect them, and all personnel receive initial and continuing training relevant to their job responsibilities. 6.1 Training is provided by qualified personnel having regard to the function and in accordance with a written program for all personnel involved in the fabrication of a drug, including technical, maintenance, and cleaning personnel. 6.2 The effectiveness of continuing training is periodically assessed. 6.3 Training is provided prior to implementation of new or revised standard operating procedures (SOPs). 6.4 Records of training are maintained. 6.5 Personnel working in areas where highly active, toxic, infectious, or sensitizing materials are handled are given specific training. 6.6 The performance of all personnel is periodically reviewed. 7. Consultants and contractors have the necessary qualifications, training, and experience to advise on the subjects for which they are retained.  Personal Hygiene Purpose To prevent contamination of health supplement products by employees in the manufacturing area. I. Scope This standard operating procedure applies to employees who handle health supplement raw materials, packaging materials, in-process materials, and finished products in the manufacturing area of XXX Company. II. Responsibilities 1. It is the responsibility of the Management to appoint designated manufacturing employee(s) to perform personal hygiene inspection on all employees. Designated employee(s) involved in personal hygiene inspection shall have the relevant training and/or experience. 2. It is the responsibility of the appointed manufacturing employee(s) to carry out personal hygiene inspection, record and report. 3. It is the responsibility of the Supervisor of the relevant departments and all employees to implement adequate corrective action/preventive action and ensured that they are followed-through. III. Procedure Grooming: 1. Arrive to work with clean hair, teeth brushed and bathed daily. 2. Maintain trimmed, filed, cleaned fingernails without rough edges. No polished fingernails and artificial nails are permitted in the manufacturing area. Daily check will be conducted and recorded in Form-XX1. 3. Employees working in the manufacturing area must wash their hands properly before entering the processing area; then gloves shall be put on as required. Hands must always be washed: Before commencing work. Before wearing disposable gloves. Between performing different task. Immediately after using the toilet and returning to work station. After handling contaminated item or when unsanitary task has been performed – i.e. taking out garbage, handling cleaning chemicals, wiping tables, picking up a dropped utensils, etc. After smoking, eating or drinking. After touching face, nose, mouth, skin, hair or other exposed body parts. After sneezing, coughing or nose blowing. 4. Wash hands only in designated sinks intended for the purpose. Turn off taps in a sanitary fashion in order to prevent recontamination of clean hands. 5. Dry hands with single-use towels and dispose used towels in closed trash bin. Proper Dress: 1. Wear clean properly secured coveralls, hair restraints and gloves at all times in the manufacturing area. Coveralls shall be sufficient to cover all personal clothing. They shall be changed daily. 2. Must not wear coveralls outside the manufacturing area. Remove coveralls, hair restraints and gloves before using toilet facilities, using lunchroom and exiting the manufacturing area. 3. Wear hair restraints at all times in the manufacturing area. All hair must be covered to prevent any possible contamination of health supplement products. 4. Employees with any facial hair (beards or mustaches) must wear beard nets. 5. Change to clean, non-skid, closed-toe work shoes that are appropriate for standing and working on manufacturing floors. Work shoes must be removed before using toilet facilities, using lunchroom and exiting the manufacturing area. Footwear must be easily cleaned and maintained in a clean condition. 6. Remove make-up, wrist watch and jewelry when entering the manufacturing area. 7. Proper attire will be checked daily and record in Form-XX1. 8. Store personal clothing and belongings in designated locker facility. Food, drinks, tobacco materials and personal medicine are not allowed to be stored in this locker facility. Illness and lesion: 1. Employees shall not be a carrier of or diagnosed of being ill with the following communicable diseases: Tuberculosis, Cholera, Typhoid fever, Chickenpox, Dysentery, Measles, Mumps, Leprosy, Jaundice, Red eye, Lymphatic filariasis, Hepatitis and infectious skin diseases. Employees with these diseases must not be allowed in the manufacturing facilities and local health regulatory agency must be notified. 2. Report any flu-like symptoms, fever, diarrhea, sore throat, constant sneezing, coughing, runny nose and/or vomiting to the supervisor. Employees with these symptoms will be sent home or re-assigned nonfood related duties or sick leave, whichever is most appropriate (FormXX2). 3. Report any lesions on the hand, wrist, or any exposed body part to supervisor (Form-XX2). 4. Minor cut and abrasion may be properly treated and bandaged. When hands are bandaged, disposable gloves must be worn to cover the entire bandaged area before commencing work. 5. Employees with serious lesions must not be allowed to handle raw materials, packaging materials, in-process materials, and finished products until the condition is improved. Smoking, eating, and gum chewing: 1. Smoke only in designated areas. No smoking or chewing of tobacco shall occur inside manufacturing facilities. 2. Eat and drink in designated areas only. 3. Refrain from chewing gum or eating candy during work in the manufacturing area. IV. Monitoring A designated employee will inspect subordinate employees when they report to work daily or at appropriate interval to be sure that each employee is following this SOP. The designated employee will monitor that all subordinate employees are adhering to the personal hygiene policy during all hours of operation. V. Corrective Action Any employee found not following this procedure will be retrained at the time of the incident.  3- Premises Points to be Consider Location Design Construction  Premises Location Geography, climate, and economic factors Neighbours a) What do they do? Premises must be located to minimize risks of cross-contamination, e.g. not located next to a malting factory with high airborne levels of yeast Pollution/effluent control  Premises Design Maximum protection against entry of insects, birds and animals Specific Areas 1) Production areas 2) Quality control areas 3) Weighing areas 4) Storage areas 5) Ancillary areas  Premises Hygiene Eating, Drinking, Smoking Should not be allowed in the Production area.  Premises Construction Measures should be taken to prevent cross-contamination Dust control measures (including extraction of dust and air) No areas for dust accumulation Easily cleanable surfaces Proper air supply Use of HEPA filter’s (High Efficiency Particulate Air filter)  Premises Finishing floors, walls, and Ceilings Should be smooth, impervious, hard-wearing, easy to clean Premises Premises Regulation The premises in which a lot or batch of a drug is fabricated, packaged/labelled or stored shall be designed, constructed and maintained in a manner that (a) permits the operations therein to be performed under clean, sanitary and orderly conditions; (b) permits the effective cleaning of all surfaces therein; and (c) prevents the contamination of the drug and the addition of extraneous material to the drug.  1. Buildings in which drugs are fabricated or packaged are located in an environment that, when considered together with measures being taken to protect the manufacturing processes, presents a minimal risk of causing any contamination of materials or drugs. 2. The premises are designed, constructed, and maintained such that they prevent the entry of pests into the building and also prevent the migration of extraneous material from the outside into the building and from one area to another. 2.1 Doors, windows, walls, ceilings, and floors are such that no holes or cracks are apparent (other than those intended by design). 2.2 Doors giving direct access to the exterior from manufacturing and packaging areas are used for emergency purposes only. These doors are adequately sealed. Receiving and shipping area(s) do not allow direct access to production areas. 2.3 Production areas are segregated from all non-production areas. Individual manufacturing, packaging, and testing areas are clearly defined and if necessary segregated. Areas where biological, microbiological or radioisotope testing is carried out require special design and containment considerations.  2.4 Laboratory animals' quarters are segregated. 2.5 Engineering, boiler rooms, generators, etc. are isolated from production areas. 3. In all areas where raw materials, primary packaging materials, in-process drugs, or drugs are exposed, the following considerations apply to the extent necessary to prevent contamination. 3.1 Floors, walls, and ceilings permit cleaning. Brick, cement blocks, and other porous materials are sealed. Surface materials that shed particles are avoided. 3.2 Floors, walls, ceilings, and other surfaces are hard, smooth and free of sharp corners where extraneous material can collect. 3.3 Joints between walls, ceilings and floors are sealed. 3.4 Pipes, light fittings, ventilation points and other services do not create surfaces that cannot be cleaned. 3.5 Floor drains are screened and trapped. 3.6 Air quality is maintained through dust control, monitoring of pressure differentials between production areas and periodic verification and replacement of air filters. The air handling system is well defined, taking into consideration airflow volume, direction, and velocity. Air handling systems are subject to periodic verification to ensure compliance with their design specifications. Records are kept.  4. Temperature and humidity are controlled to the extent necessary to safeguard materials. 5. Rest, change, wash-up, and toilet facilities are well separated from production areas and are sufficiently spacious, well ventilated, and of a type that permits good sanitary practices. 6. Premises layout is designed to avoid mix-ups and generally optimize the flow of personnel and materials. 6.1 There is sufficient space for receiving and all production activities. 6.2 Working spaces allow the orderly and logical placement of equipment (including parts and tools) and materials. 6.3 Where physical quarantine areas are used, they are well marked, with access restricted to designated personnel. Where electronic quarantine is used, electronic access is restricted to designated personnel. 6.4 A separate sampling area is provided for raw materials. If sampling is performed in the storage area, it is conducted in such a way as to prevent contamination or cross-contamination.  Premises Design(cont..) Maximum protection against entry of insects, birds and animals Specific Areas 1) Production areas 2) Quality control areas 3) Weighing areas 4) Storage areas 5) Ancillary areas PREMISES PRINCIPLE Premises must be located, designed, constructed, adapted and maintained to facilitate proper operations. Their layout and design must aim to minimize risk of confusion, cross- contamination and other error and permit effective cleaning, sanitation and maintenance in order to avoid cross-contamination, build up of dust or dirt and, in general, any adverse effect on the quality of products. GENERAL Premises should be located as to avoid contamination from the surrounding environment such as air, earth and water pollutant as well as from nearby activities which could adversely affect the quality of products. If the premises were unsuitably located, effective measures should be taken to avoid such contamination. Premises should be so constructed, equipped and maintained to afford maximum protection against weather, flood, ground seepage and the access entry and harbouring of insects, birds, rodents, vermin, or other animals. There should be a procedure for rodent and pest control. Premises should be carefully maintained. They should be cleaned and, where applicable, disinfected according to detailed written procedures. Records should be maintained. All premises, including production areas, laboratories, stores, passage ways and external surroundings should be maintained in a clean and tidy condition. The conditions of buildings should be reviewed regularly, and repaired where necessary. Special care should be exercised to ensure that building repair or maintenance operations do not adversely affect the products. Electrical supply, lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the pharmaceutical products during their manufacture and storage, or the accurate functioning of equipment. The premises design and lay-out should ensure : the compatibility of other manufacturing operations that may be carried out in the same or adjacent premises; and avoiding use of production areas as a general traffic for personnel and materials or for storage other than the materials in process. Steps should be taken in order to prevent the entry of unauthorized people. Production, storage and quality control areas should not be used as a right of way by personnel who do not work in them. Defined areas for the following operations are required : materials receiving; incoming goods quarantine; starting materials storage; weighing and dispensing; processing; equipment washing; equipment storage; storage of bulk products; packaging; quarantine storage before the final release of finished products; product shipping; and control laboratory WEIGHING AREAS The weighing of starting materials and the estimation of yield by weighing should be carried out in separate weighing areas specially designed for that use. Such areas may be part of either storage or production areas. PRODUCTION AREAS In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials. The production of other products, such as certain antibiotics (e.g. penicillins), sex hormones, certain cytotoxics, certain highly active drugs, biological preparations (e.g. from live micro- organisms) and non-pharmaceutical products, should be conducted in separate buildings. The production of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of pharmaceutical products. Premises should preferably be laid out in such a way as: to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations, the requisite cleanliness levels; to avoid crowding and disorder; and to allow effective communication and supervision. The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components, to avoid cross-contamination and to minimize the risk of omission or wrong application of any of the manufacturing or control steps. Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection. The floor in processing areas should be made of impervious materials, laid to an even surface and should allow prompt and efficient removal of any spillages. The coving of junctions between walls and floors in processing areas is necessary. Pipe work, light fittings, ventilation points and other services should be designed and installed in such a way to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the production areas. Exposed pipes should not touch walls but be suspended from or be supported by brackets, sufficiently separated to allow thorough cleaning. Exposed overhead roof joints, pipes and ducts should be avoided. Where they are unavoidable, special cleaning procedures and schedules should be prepared and followed. Air intakes and exhausts, and associated pipe work and ducting should be installed in such a way to avoid product contamination. Drains should be of adequate size, designed and equipped with trapped gullies to prevent back-flow. Open channels should be avoided where possible, but if necessary, they should be shallow to facilitate cleaning and disinfection. Production areas should be effectively ventilated, with air control facilities including filtration of air to a sufficient level to prevent contamination and cross-contamination, as well as control of temperature and, where necessary, humidity appropriate both to the products handled and to the operations undertaken within them and to the external environment. These areas should be regularly monitored during both production and non-production periods to ensure compliance with their design specifications. In cases where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of dry products), specific provisions should be taken to avoid cross- contamination and facilitate cleaning. Premises for the packaging of pharmaceutical products should be specifically designed and laid out so as to avoid mix-ups or cross-contamination. Productions areas should be well lit, particularly where visual on-line controls are carried out. In-process controls may be carried out within the production area provided they do not carry any risk for the production. Doors that lead from production areas directly to the outside, e.g. fire exits, should be sealed. They should be secured in such a way that they can be used only as an emergency exit. Where internal doors are a barrier to cross contamination, they should be closed when not in use. STORAGE AREAS Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products: starting and packaging materials, intermediate, bulk and finished products, products in quarantine, released, rejected, returned or recalled. Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean, dry and sufficiently lit and maintained within specified temperature limits. Where special storage conditions are required (e.g. temperature, humidity) these should be provided, controlled, monitored and recorded where appropriate. Receiving and dispatch bays should protect materials and products from the weather. Receptions areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage. Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorized personnel. Any system replacing the physical quarantine should give equivalent security. There should normally be a separate sampling area for starting materials in a controlled environment. If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination. Adequate cleaning procedures should be in place for the sampling areas. Segregated and locked areas should be provided for the storage of rejected, recalled or returned materials and products. Highly active materials and radioactive materials, narcotics, other dangerous drugs, and substances presenting special risks of abuse, fire or explosion should be stored in safe and secure areas. Narcotics and other dangerous drugs should be stored under lock. Printed packaging materials are considered critical to the conformity of the pharmaceutical products to its labelling and special attention should be paid to the safe and secure storage of these materials; particularly, labels should be stored under lock. QUALITY CONTROL AREAS Quality control laboratories should be separated from production areas. Areas where biological, microbiological or radioisotope test methods are employed should be separated from each other. Quality control laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and cross-contamination. There should be adequate suitable storage space for samples, reference standards (if necessary, under controlled temperature), solvents, reagents and records. A separate room may be needed for instruments to protect them against electrical interference, vibration, contact with excessive moisture (humidity) and other external factors, or where it is necessary to isolate the instruments. The design of the laboratories should take into account the suitability of construction materials, prevention of fumes and ventilation. There should be separate air supply to laboratories and production areas. Separate air-handling units and other provisions are needed for biological, microbiological and radioisotope laboratories. ANCILLARY AREAS Rest and refreshment rooms should be separated from production and quality control laboratory areas. Facilities for changing clothes and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not directly communicate with production or storage areas. Changing rooms should be directly connected to but separated from production areas. Maintenance workshops should as far as possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use. Animal houses should be well isolated from other areas, with separate entrance (animal access) and air handling facilities.  Working areas are well lit. 7. Utilities and support systems [e.g., Heating, Ventilating, and Air Conditioning (HVAC), dust collection, and supplies of purified water, steam, compressed air, nitrogen, etc.] for buildings in which drugs are fabricated or packaged/labelled are qualified and are subject to periodic verification. Further guidance is provided in Health Canada's document entitled Validation Guidelines for Pharmaceutical Dosage Forms (GUI-0029). 8. Outlets for liquids and gases used in the production of drugs are clearly identified as to their content. 9. Premises are maintained in a good state of repair. Repair and maintenance operations do not affect drug quality. 10. Where necessary, separate rooms are provided and maintained to protect equipment and associated control systems sensitive to vibration, electrical interference, and contact with excessive moisture or other external factors. 11. Fabricators and packagers must demonstrate that the premises are designed in such a manner that the risk of cross-contamination between products is minimized. 11.1 Campaign production can be accepted where, on a product by product basis, proper justification is provided, validation is conducted and rigorous validated controls and monitoring are in place and demonstrate the minimization of any risk of cross- contamination. 11.2 Self-contain facilities are required for: 11.2.1 certain classes of highly sensitizing drugs such as penicillins and cephalosporins. 11.2.2 other classes of highly potent drugs such as potent steroids, cytotoxics, or potentially pathogenic drugs (e.g., live vaccines), for which validated cleaning or inactivation procedures cannot be established (e.g., the acceptable level of residue is below the limit of detection by the best available analytical methods) 11.3 For the types of products listed in interpretations 11.2.1 and 11.2.2, external contamination with drug product residues of the final container and primary packaging does not exceed established limits. 11.3.1 Storage in common areas is allowed once the products are enclosed in their immediate final containers and controls are in place to minimize risks of cross- contamination 11.4 No production activities of highly toxic non-pharmaceutical materials, such as pesticides and herbicides, are conducted in premises used for the production of drugs.  Premises Design Minimize risks of errors Permit effective cleaning Permit effective maintenance Avoid cross-contamination, build-up of dirt and dust Maximum protection against entry of insects, birds and animals Separate facilities for other products such as some antibiotics, hormones, cytotoxic substances Equipment  4- Equipment Equipment shall be located, designed, constructed, adapted and maintained to suit the operation to be carried out. Should be made of non reactive material, such as High grade of steel(316,302) Equipment should be- a) Calibrated b) Checked c) Labelled d) Sterilized Equipment Regulation The equipment with which a lot or batch of a drug is fabricated, packaged/labelled or tested shall be designed, constructed, maintained, operated, and arranged in a manner that (a) permits the effective cleaning of its surfaces; (b) prevents the contamination of the drug and the addition of extraneous material to the drug; and (c) permits it to function in accordance with its intended use. Rationale The purpose of these requirements is to prevent the contamination of drugs by other drugs, by dust, and by foreign materials such as rust, lubricant and particles coming from the equipment. Contamination problems may arise from poor maintenance, the misuse of equipment, exceeding the capacity of the equipment and the use of worn-out equipment. Equipment arranged in an orderly manner permits cleaning of adjacent areas and does not interfere with other processing operations. It also minimizes the circulation of personnel and optimizes the flow of materials. The fabrication of drugs of consistent quality requires that equipment perform in accordance with its intended use. 1. The design, construction and location of equipment permit cleaning, sanitizing, and inspection of the equipment. 1.1 Equipment parts that come in contact with raw materials, in-process intermediates or drugs are accessible to cleaning or are removable. 1.2 Tanks used in processing liquids and ointments are equipped with fittings that can be dismantled and cleaned. Validated Clean-In-Place (CIP) equipment can be dismantled for periodic verification. 1.3 Filter assemblies are designed for easy dismantling. 1.4 Equipment is located at a sufficient distance from other equipment and walls to permit cleaning of the equipment and adjacent area. 1.5 The base of immovable equipment is adequately sealed along points of contact with the floor. 1.6 Equipment is kept clean, dry and protected from contamination when stored. 2. Equipment does not add extraneous material to the drug. 2.1 Surfaces that come in contact with raw materials, in-process intermediates or drugs are smooth and are made of material that is non-toxic, corrosion resistant, non-reactive to the drug being fabricated or packaged and capable of withstanding repeated cleaning or sanitizing. 2.2 The design is such that the possibility of a lubricant or other maintenance material contaminating the drug is minimized. 2.3 Equipment made of material that is prone to shed particles or to harbour microorganisms does not come in contact with or contaminate raw materials, in- process drugs or drugs. 2.4 Chain drives and transmission gears are enclosed or properly covered. 2.5 Tanks, hoppers and other similar fabricating equipment are equipped with covers. 3. Equipment is operated in a manner that prevents contamination. 3.1 Ovens, autoclaves and similar equipment contain only one raw material, in-process drug or drug at a time, unless precautions are taken to prevent contamination and mix- ups. 3.2 The location of equipment precludes contamination from extraneous materials. 3.3 The placement of equipment optimizes the flow of material and minimizes the movement of personnel. 3.4 Equipment is located so that production operations undertaken in a common area are compatible and cross-contamination between such operations is prevented. 3.5 Fixed pipework is clearly labelled to indicate the contents and, where applicable, the direction of flow. 3.6 Dedicated production equipment is provided where appropriate. 3.7 Water purification, storage, and distribution equipment is operated in a manner that will ensure a reliable source of water of the appropriate chemical and microbial purity. 4. Equipment is maintained in a good state of repair. 4.1 Where a potential for contamination during fabrication or packaging of a drug exists, surfaces are free from cracks, peeling paint and other defects. 4.2 Gaskets are functional. 4.3 The use of temporary devices (e.g., tape) is avoided. 4.4 Equipment parts that come in contact with drugs are maintained in such a manner that drugs are fabricated or packaged within specifications. Equipment used for significant processing or testing operations is maintained in accordance with a written preventative maintenance program. Maintenance records are kept 5. Equipment is designed, located, and maintained to serve its intended purpose 5.1 Measuring devices are of an appropriate range, precision and accuracy. Such equipment is calibrated on a scheduled basis, and corresponding records are kept. 5.2 Equipment that is unsuitable for its intended use is removed from fabrication, packaging/labelling, and testing areas. When removal is not feasible unsuitable equipment is clearly labelled as such. 5.3 Equipment used during the critical steps of fabrication, packaging/labelling, and testing, including computerized systems, is subject to installation and operational qualification. Equipment qualification is documented. Further guidance is provided in Health Canada's document entitled Validation Guidelines for Pharmaceutical Dosage Forms (GUI- 0029) and PIC/S Annex 11: Computerised Systems. 5.4 Equipment used for significant processing and testing operations is calibrated, inspected or checked in accordance with a written program. Records are kept. 5.5 For equipment used for significant processing or testing operations, usage logs are maintained. These logs should include identification of products, dates of operation, and downtime due to frequent or serious malfunctions or breakdowns. The information should be collected to facilitate the identification of negative performance trends. DESIGN AND CONSTRUCTION The design and construction of equipment should fulfill the following requirements: equipment should be designed and constructed to suit its intended purpose; equipment surfaces coming into contact with any starting material, intermediate, bulk or finished product should not be reactive, additive, or absorptive so as to alter its identity, quality or purity beyond the established limits; materials required for specific equipment operations, such as lubricants or coolants should not come into contact with any in-process materials so as to alter the identity, quality, or purity of starting material, intermediate, bulk or the finished product; equipment should not adversely affect the product through leaking valves, lubricant drips and the like; or through inappropriate repairs, maintenance, modifications or adaptations; equipment should be designed so that it can be easily and thoroughly cleaned. It should be cleaned according to detailed and written procedures and stored only in a clean and dry condition; washing and cleaning equipment should be chosen and used in order not to be a source of contamination; equipment should not present any hazard to the products. The parts of the equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard; all equipment designated for use with flammable substances or chemicals or in areas where flammable materials are used should be equipped with explosion-proof electrical parts and should be properly grounded; balances and measuring equipment of an appropriate range and precision should be available for production and control operations. Equipment employed for weighing, measuring, testing and recording should be regularly checked for accuracy and calibrated according to an appropriate program and procedure. The result of the checking and calibration should be recorded. The records should be kept properly; filters for liquid filtration used in the processing of products should not release fibers into such products. An asbestos containing filter with or without subsequent use of a specific non-fiber releasing filter should not be used; and distilled, de-ionized and, where appropri-ate, other water pipes should be sanitized according to written procedures that detail the action limits for microbiological contamination and the measures to be taken. INSTALLATION AND LOCATION Equipment should be suitably located to minimize possible cross-contamination by substances used in the same area. Equipment should be installed in such a way as to prevent any risk of error or of contamination. Equipment should be located at a sufficient distance from other equipment to avoid congestion and to ensure that products do not become admixed or confused with one another. All open mechanical belts and pulleys should be equipped with safety guards. Water, steam and pressure or vacuum and other lines should be installed so as to be easily accessible during all phases of operation. Fixed pipe work should be clearly labeled to indicate the contents and, where applicable, the direction of flow. Each piece of major equipment should be clearly marked with an identifying number. This number will be used on all batch directions to designate the particular unit or apparatus used it that specific batch. Exception is made where a piece of equipment is solely used for one type of product. Defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labeled as defective. MAINTENANCE Equipment should be maintained at appropriate intervals to prevent malfunctions or contaminations which could alter the identity, quality, or purity of the product. Repair and maintenance operations should not present any hazard to the quality of the products. Coolants, lubricants and other chemicals such as thermal probe solutions should be evaluated and approved by a formal process. Written procedures should be established and followed for maintenance of equipment. A written record of major equipment maintenance and use should be included in individual equipment logs which also identifies the date, time, product, strength and batch or lot number of each batch processed. For equipment used solely for one product the record can be included in the production batch records  Sanitation Written procedures hygiene, health and clothing practices waste disposal Implementation and training Sanitation Practices not permitted a)eating, smoking b) unhygienic practices Sanitation Regulation 1. Every person who fabricates or packages/labels a drug shall have a written sanitation program that shall be implemented under the supervision of qualified personnel. 2. The sanitation program referred to in subsection (1) shall include: (a) cleaning procedures for the premises where the drug is fabricated or packaged/labelled and for the equipment used in the fabrication or packaging/labelling of the drug; and (b) instructions on the sanitary fabrication and packaging/labelling of drugs and the handling of materials used in the fabrication and packaging/labelling of drugs. Rationale Sanitation in a pharmaceutical plant, as well as employee attitude, influences the quality of drug products. The quality requirement for drug products demand that such products be fabricated and packaged in areas that are free from environmental contamination and free from contamination by another drug. A written sanitation program provides some assurance that levels of cleanliness in the plant are maintained and that the provisions of Sections 8 and 11 of the Next link will take you to another Web site Food and Drugs Act are satisfied. 1. Every person who fabricates or packages/labels a drug shall have a written sanitation program available on the premises. 2. The sanitation program contains procedures that describe the following: 2.1 cleaning requirements applicable to all production areas of the plant with emphasis on manufacturing areas that require special attention; 2.2 requirements applicable to processing equipment; 2.3 cleaning intervals; 2.4 products for cleaning and disinfection, along with their dilution and the equipment to be used; 2.5 the responsibilities of any outside contractor; 2.6 disposal procedures for waste material and debris; 2.7 pest control measures; 2.8 precautions required to prevent contamination of a drug when rodenticides, insecticides, and fumigation agents are used; 2.9 microbial and environmental monitoring procedures with alert and action limits in areas where susceptible products are fabricated or packaged; and 2.10 the personnel responsible for carrying out cleaning procedures. 3. The sanitation program is implemented and is effective in preventing unsanitary conditions. 3.1 Cleaning procedures for manufacturing equipment are validated based on the Health Canada document entitled Cleaning Validation Guidelines (GUI-0028) 3.2 Residues from the cleaning process itself (e.g., detergents, solvents, etc.) are also removed from equipment. 3.3 Evidence is available demonstrating that routine cleaning and storage does not allow microbial proliferation; Where necessary, sanitizers and disinfectants are filtered to remove spores (e.g., isopropyl alcohol). 3.4 Analytical methods used to detect residues or contaminants are validated. Guidance on analytical method validation can be obtained from publications such as the International Conference on Harmonisation (ICH) document entitled Next link will take you to another Web site ICH Q2(R1): Validation of Analytical Procedures: Text and Methodology, or in any standard listed in Schedule B to the Food and Drugs Act. 3.5 A cleaning procedure requiring complete product removal may not be necessary between batches of the same drug provided it meets the requirements of interpretation 3.1. 4. Individuals who supervise the implementation of the sanitation program; 4.1 are qualified by training or experience; and 4.2 are directly responsible to a person who has the qualifications described under Regulation C.02.006, interpretation 1. 5. Dusty operations are contained. The use of unit or portable dust collectors is avoided in fabrication areas especially in dispensing, unless the effectiveness of their exhaust filtration is demonstrated and the units are regularly maintained in accordance with written approved procedures. Interpretation 1. Minimum health requirements are available in writing. 1.1 Personnel who have access to any area where a drug is exposed during its fabrication or packaging/labelling must undergo health examinations prior to employment. Medical re-examinations, based on job requirements take place periodically. Note: A person who is a known carrier of a disease in a communicable form should not have access to any area where a drug is exposed. The likelihood of disease transmission by means of a drug product would depend on the nature of the disease and the type of work the person carries out. Certain diseases could be transmitted through a drug product if proper hygiene procedures are not followed by an infected person handling the product. However, a person may also be a carrier of a communicable disease and not be aware of it. Therefore, in addition to strict personal hygiene procedures, systems should be in place to provide an effective barrier that would preclude contamination of the product. These procedures must be followed at all times by all personnel. In the event that an employee is found to be a carrier of a communicable disease, the company is to contact Health Canada and perform a risk assessment to determine if there is any product impact. 1.2 Employees are instructed to report to their supervisor any health conditions they have that could adversely affect drug products. 1.3 Supervisory checks are conducted to prevent any person who has an apparent illness or open lesions that may adversely affect the quality of drugs from handling exposed raw materials, primary packaging materials, in-process drugs or drugs until the condition is no longer judged to be a risk. 1.4 When an employee has been absent from the workplace due to an illness that may adversely affect the quality of products, that employee's health is assessed before he or she is allowed to return to the workplace. 1.5 A procedure in place which describes the actions to be taken in the event that a person who has been handling exposed raw materials, primary packaging materials, in-process drugs or drugs is identified as having a communicable disease. 1.6 Periodic eye examinations and/or periodic requalification are required for personnel who conduct visual inspections. Sanitation Practices not permitted a)eating, smoking b) unhygienic practices VERIFICATION, QUALIFICATION AND VALIDATION APPLY TO BOTH DRUGS AND DEVICES All operational methodologies and procedures utilized in manufacturing and testing be validated to demonstrate they can function as intended Validation activities must be conducted I accordance with approved protocols and appropriate guidances Process validation ensures that product quality, safety and effectiveness are designed and built into the final product (batch to batch output uniformity)  PROCESS VALIDATION Guidance for Industry: Process Validation: General Principles and Practices Stage 1 – Process Design: The commercial process is based on knowledge gained through development and scale-up activities. Stage 2 – Process Qualification: The process qualification is confirmed as being capable of reproducible commercial manufacturing. Stage 3 – Continued Process Verification: Ongoing assurance that the process remains in a state of control during routine production. Requires an ongoing program to collect and analyze product and process data that relate to product quality (21CFR211.180(e)) Requires an interdisciplinary team approach (process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics “Begin with the end in mind”  METHOD VALIDATION Draft Guidance for Industry: Analytical Procedures and Methods Validation – Chemistry Manufacturing and Controls Documentation Generics - USP Each method used to analyze the drug or biologic must have associated validation: -to support the documentation of drug substance, -product identity, -strength, -purity, -and potency KEY GMP CONCEPTS KEY GMP CONCEPTS  KEY GMP CONCEPTS IF IT WAS NOT WRITTEN DOWN, THEN IT WAS NOT DONE  References Blackwell, John. 1906: Rumble Over ‘The Jungle’. 31 Aug. 2008. http://www.capitalcentury.com/1906.html FDA Food and Drug Administration. GMP Combination Handbooks. 31 Aug. 2008. http://images.google.com WHO Technical Report Series, No. 929, 2005