GMP Lecture 5 PDF

Good Manufacturing Practice (GMP) Lecture V How to implement the regulations of GMP  How to implement the regulations of GMP I- Sanitation and hygiene: A high level of sanitation and hygiene should be practiced...

Good Manufacturing Practice (GMP) Lecture V How to implement the regulations of GMP  How to implement the regulations of GMP I- Sanitation and hygiene: A high level of sanitation and hygiene should be practiced in every aspect of the manufacture of drug products it must covers personnel, premises, equipment and apparatus, production materials and containers, products for cleaning and disinfection II- Qualification and validation Validation studies are an essential part of GMP and should be conducted in accordance with predefined and approved protocols. Qualification and validation programme of a company should be clearly defined and documented in a validation master plan. The premises, supporting utilities, equipment and processes have been designed in accordance with the requirements for GMP (design qualification, installation qualification, operational qualification and performance qualification. Any changes of the previous should be qualified and validated  How to implement the regulations of GMP III-Complaints All complaints and other information concerning potentially defective products should be carefully reviewed according to written procedures and the corrective action should be taken. A person responsible for handling the complaints with sufficient supporting and authorized person, should be made aware of any complaint, investigation or recall Written procedures describing the different causes of complaints and the action to be taken. All decisions should be recorded and referenced to the corresponding batch records. The competent authorities should be informed if a manufacturer is considering action following possibly faulty manufacture, product deterioration, counterfeiting or any other serious quality problems with a product.  How to implement the regulations of GMP IV- Product recalls Principle. There should be a system to recall from the market, promptly and effectively, products known or suspected to be defective. An authorized person with a sufficient staff should be responsible for the execution and coordination of recalls with the appropriate degree of urgency. A written procedures regularly reviewed and updated, for the organization of any recall activity. An instruction included in the written procedures to store recalled products in a secure segregated area while their fate is decided. All competent authorities of all countries should be promptly informed of any intention to recall the product because it is, or is suspected of being, defective The progress of the recall process should be monitored and recorded. including the disposition of the product. A final report should be issued, including a reconciliation between the delivered and recovered quantities of the products.  How to implement the regulations of GMP V- Contract production and analysis Principle. Contract production and analysis must be correctly defined, agreed and controlled in order to avoid misunderstandings that could result in a product or work or analysis of unsatisfactory quality. The contract manufacture should be in accordance with the marketing authorization including any proposed changes in technical or other arrangements. The contract should permit the contract giver to audit the facilities of the contract accepter and all information necessary y. The contract giver is responsible for assessing the competence of the contract accepter in successfully carrying out the work or tests required ensuring that the principles of GMP described in this guide are followed. The contract giver should ensure that all processed products and materials comply with their specifications and released by the authorized person.  How to implement the regulations of GMP V- Contract production and analysis - The contract accepter must have adequate premises, equipment, knowledge, and experience and competent personnel to carry out the work ordered by the contract giver. - The contract accepter should not pass to a third party any of the work entrusted to him without the contract giver’s prior evaluation and approval of the arrangements. - If that accepted ;it should ensure that the manufacturing and analytical information is made available in the same way as between the original contract giver and contract accepter - The contract accepter should cease any activity that may adversely affect the quality of the product manufactured and/or analyzed for the contract giver. - There must be a written contract between the contract giver and the contract accepter which clearly establishes the responsibilities of each party. - The contract must clearly state all details required for the marketing authorization including the certificate of analysis, exercises ….. That made by the authorized person. - Technical aspects of the contract should be drawn up by competent persons suitably knowledgeable in pharmaceutical technology, analysis and GMP.  How to implement the regulations of GMP VI- Self-inspection and quality audits Principle. The purpose of self-inspection is to evaluate the manufacturer’s compliance with GMP in all aspects of production and quality control Self-inspections should be performed routinely, and special occasions, e.g. iproduct recalls or repeated rejections. The team responsible for self-inspection should consist of personnel who can evaluate the implementation of GMP objectively. Written instructions for self-inspection should be established to fluffy GMP requirement including ; (a) personnel; (b) premises (c) maintenance of buildings and equipment; (d) storage of materials and products (e) equipment; (f) production and in-process controls (g) quality control; (h) documentation; (i) sanitation and hygiene; (j) validation (k) calibration of instruments (l) recall procedures; (m) complaints management; (n) labels control; (o) results of previous self-inspections and any corrective steps taken Self-inspection team consisting of experts in their respective fields and familiar with GMP. Self-inspection report should include: (a) self-inspection results; (b) evaluation and conclusions; (c) recommended corrective actions. A quality audit is usually conducted by outside or independent specialists who can extend to suppliers and contractors. Suppliers’ audits and approval should determine the supplier’s ability to conform with GMP standards.  How to implement the regulations of GMP VII-Personnel Principle. The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture and control of pharmaceutical products and active ingredients rely upon people. General The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. All responsible staff should have their specific duties recorded in written descriptions and adequate authority to carry out their responsibilities. No gaps or unexplained overlaps in the responsibilities of personnel concerned with the application of GMP. All personnel should be aware of the principles of GMP and receive initial and continuing training, including hygiene instructions, relevant to their needs unauthorized people should be prevented from entering production, storage and quality control areas. VII-Personnel How to implement the regulations of GMP Key personnel Key personnel include a. The head of production b. The head of quality control c. The authorized person. - Normally, key posts should be occupied by full-time personnel. - The heads of production and quality control should be independent of each other. - some of the functions can be delegate; however, the responsibility cannot be delegated. - Key personnel responsible for supervising the manufacture and quality control of pharmaceutical products should possess the qualifications of a scientific education and practical experience required by national legislation. e.g combination of: (a) chemistry (analytical or organic) or biochemistry; (b) chemical engineering; (c) microbiology; (d) pharmaceutical sciences and technology; (e) pharmacology and toxicology; (f) physiology; (g) other related sciences. - They should also have adequate practical experience in the manufacture and quality assurance of pharmaceutical products  How to implement the regulations of GMP VII-Personnel Key personnel a) The head of the production The head of the production generally has the following responsibilities: (a) To ensure that products are produced and stored according to the appropriate documentation. (b) To approve the instructions relating to production operations, including the in-process controls, and to ensure their strict implementation. (c) To ensure that the production records are evaluated and signed by a designated person. (d) To check the maintenance of the department, premises, and equipment. (e) To ensure that the appropriate process validations and calibrations of control equipment are performed and recorded and the reports made available. (f) To ensure that the required initial and continuing training of production personnel is carried out and adapted according to need.  How to implement the regulations of GMP VII-Personnel Key personnel B)The head Quality control The head of the quality control generally has the following responsibilities: (a) To approve or reject starting materials, packaging materials, and intermediate, bulk and finished products in relation to their specifications. (b) To evaluate batch records. (c) To ensure that all necessary testing is carried out. (d) To approve sampling instructions, specifications, test methods and other quality control procedures. (e) To approve and monitor analyses carried out under contract. (f) To check the maintenance of the department, premises and equipment. (g) To ensure that the appropriate validations, including those of analytical procedures, and calibrations of control equipment are carried out. (h) To ensure that the required initial and continuing training of quality control personnel is carried out and adapted according to need  How to implement the regulations of GMP VII-Personnel Key personnel c) The authorized person The authorized person is responsible for a) Compliance with technical or regulatory requirements related to the quality of finished products. b) The approval of the release of the finished product for sale. c) Implementation (and, when needed, establishment) of the quality system. d) Participation in the development of the company’s quality manual. e) Supervision of the regular internal audits or self-inspections. f) Oversight of the quality control department. g) Participation in external audit (vendor audit). h) Participation in validation programmes.  How to implement the regulations of GMP Key personnel - Shared responsibilities between the heads of the production and quality control: (a) Authorization of written procedures and other documents, including amendments (b) Monitoring and control of the manufacturing environment; (c) Plant hygiene. (d) Process validation and calibration of analytical apparatus. (e) Training, including the application and principles of quality assurance. (f) Approval and monitoring of suppliers of materials. (g) Approval and monitoring of contract manufacturers. (h) Designation and monitoring of storage conditions for materials and products. (i) Performance and evaluation of in-process controls. (j) Retention of records; (k) Monitoring of compliance with GMP requirements. (l) Inspection, investigation and taking of samples in order to monitor factors that may affect product quality.  The requirements for approving Howa batch by responsible to implement theperson for release: regulations of GMP (a) The marketing and the manufacturing authorization requirements for the product have been met for the batch concerned. (b) The principles and guidelines of GMP, as laid down in the guidelines published by WHO, have been followed. (c) The principal manufacturing and testing processes have been validated. (d) All the necessary checks and tests have been performed and account taken of the production conditions and manufacturing records. (e) any planned changes or deviations in manufacturing or quality control have been notified in accordance with a well defined reporting system before any product is released. Such changes may need notification to, and approval by, the drug regulatory authority. (f) any additional sampling, inspection, tests and checks have been carried out or initiated, as appropriate, to cover planned changes and deviations. (g) all necessary production and quality control documentation has been completed and endorsed by supervisors trained in appropriate disciplines. (h) appropriate audits, self-inspections and spot-checks are carried out by experienced and trained staff. (i) approval has been given by the head of quality control. (j) all relevant factors have been considered, including any not specifically associated with the output batch directly under review (e.g. subdivision of output batches from a common input, factors associated with continuous production runs).  How to implement the regulations of GMP VIII. Training: - The manufacturer should provide training in accordance with a written programme for all personnel whose duties take them into manufacturing areas or into control laboratories. - Besides basic training on the theory and practice of GMP, newly recruited personnel should receive training. Training - Approved and Continuing training programmes should be available. Training records should be kept. - Personnel working in areas where contamination is a hazard, e.g. clean areas or areas where highly active, toxic, infectious or sensitizing materials are handled, should be given specific training. - The concept of quality assurance should be fully discussed during the training sessions. - Visitors or untrained personnel should not be taken into the production and quality control areas. If this is unavoidable, they should be given relevant information in advance (particularly about personal hygiene) and the prescribed protective clothing. - Consultant and contract staff should be qualified for the services they provide. Evidence of this should be included in the training records. VIIII. Personal hygiene How to implement the regulations of GMP - All personnel, prior to and during employment, should undergo health examinations. - Personnel conducting visual inspections should also undergo periodic eye examinations - All personnel should be trained in the practices of personal hygiene All personnel should be trained in the practices of personal hygiene e.g wash their hands before entering production areas. Signs to this effect should be posted and instructions observed. - Any person shown an apparent illness or open lesions should not be allowed to handle starting materials, packaging materials, in-process materials or drug products until the condition is no longer judged to be a risk. - Direct contact should be avoided between the operator’s hands and starting materials, primary packaging materials and intermediate or bulk product. - personnel should wear clean body coverings appropriate to the duties they perform, including appropriate hair covering - Smoking, eating, drinking, chewing, and keeping plants, food, drink, smoking material and personal medicines should not be permitted in production, laboratory and storage areas. - Personal hygiene procedures including the use of protective clothing should apply to all persons entering production areas. , e.g. contractors’ employees, visitors, senior managers, and inspectors.  How to implement the regulations of GMP X- Premises Principle. Premises must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out. General :The layout and design of premises must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt, and any adverse effect on the quality of products. - Premises used for the manufacture of finished products should be suitably designed and constructed to facilitate good sanitation. - Premises should be carefully maintained, and it should be ensured that repair and maintenance operations do not present any hazard to the quality of products. - Premises should be cleaned and, where applicable, disinfected according to detailed written procedures. Records should be maintained. - Electrical supply, lighting, temperature, humidity and ventilation should be appropriate - Premises should be designed and equipped to prevent entry of insects, birds or animals. a certain procedure for rodent and pest control - Premises should be designed to ensure the logical flow of materials and personnel  How to implement the regulations of GMP Ancillary areas - Rest and refreshment rooms should be separate from manufacturing and control areas. - Facilities for changing and storing clothes and for washing and toilet purposes should be suitable for the number of users. - Toilets should not communicate directly with production or storage areas. - Maintenance workshops should be separated from production areas - Animal houses should be well isolated from other areas, with separate entrance. Storage areas Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products with proper separation and segregation: Ensure good storage conditions ,clean, dry, sufficiently lit and acceptable temperature limits quarantine status is ensured by storage in separate areas, which clearly marked and their access restricted to authorized personnel. Segregation between the storage of rejected, recalled, or returned materials or products Highly active and radioactive materials, narcotics, and other dangerous drugs should be stored in safe and secure areas. A separate sampling area for starting materials to avoid cross contamination  How to implement the regulations of GMP Weighing areas - The weighing of starting materials and the estimation of yield by weighing should be carried out in separate weighing areas designed for that use, for example with provisions for dust control. Production areas Highly sensitizing materials (e.g. penicillins) , biological preparations, hormones and cytotoxic substances should be manufactured in special production rea to control cross contamination. The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of pharmaceutical products. Premises constructed to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels. Walls, floors and ceilings should be smooth and free from cracks and open joints, should not shed particulate matter, and should permit easy and effective cleaning and disinfection. Pipework, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses that are difficult to clean. Drains should be of adequate size and designed and equipped to prevent back-flow. Production areas should be effectively ventilated, with air-control facilities (including filtration of air to a sufficient level to prevent contamination and cross-contamination also control of temperature and humidity. Premises for the packaging of pharmaceutical products should be specifically designed to avoid mix-ups or cross- contamination.  How to implement the regulations of GMP Quality control areas Quality control laboratories should be separated from production areas Quality control laboratories should be designed to have suitable storage space for samples, reference standards , solvents, reagents and records. There should be separate air supply to laboratories and production areas A separate room may be needed for instruments to protect them against Electrical interference, vibration, contact with excessive moisture and other external factors  How to implement the regulations of GMP XI- Equipment: - Equipment must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out - The layout and design of equipment must permit effective cleaning and maintenance to avoid cross- contamination, build-up of dust or dirt. - Fixed pipework should be clearly labelled to indicate the contents and the direction of flow. - All service pipings and devices should be adequately marked and special attention paid to the provision of non-interchangeable connections or adaptors for dangerous gases and liquids. - Balances and other measuring equipment should be available for production and control operations and should be calibrated on a scheduled basis.. - Washing, cleaning and drying equipment should be chosen and used so as not to be a source of contamination. - The production equipment that come into contact with the product must not be reactive, additive, or absorptive. - Defective equipment should be removed from production and quality control areas. it should be clearly labelled as defective to prevent use. - Current drawings of critical equipment and support systems should be maintained.  How to implement the regulations of GMP XII-Materials Principle. The main objective of a pharmaceutical plant is to produce finished products for patients’ use from a combination of materials (starting and packaging). Materials include starting materials, packaging materials, gases, solvents, process aids, reagents and labelling materials. General : No materials used for operations such as cleaning, lubrication of equipment and pest control, should come into direct contact with the product. Where possible, such materials should be of a suitable grade (e.g. food grade) to minimize health risks. Starting materials Starting materials should be purchased only from approved suppliers with the required specifications All incoming materials should be checked to ensure that the consignment corresponds to the order Starting materials in the storage area should be labelled by all require information. Appropriate procedures or measures to ensure the identity of the contents of each container of starting material Starting materials should be dispensed only by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labelled containers.  How to implement the regulations of GMP Packaging materials The purchase, handling and control of primary and printed packaging materials should be as for starting materials Packaging materials should be issued for use only by designated personnel following an approved and documented procedure Outdated or obsolete primary packaging material or printed packaging material should be destroyed and its disposal recorded. All products and packaging materials to be used should be checked on delivery to the packaging department for quantity, identity and conformity with the packaging instructions Intermediate and bulk products: - Intermediate and bulk products should be kept under appropriate conditions. - Intermediate and bulk products purchased as such should be handled on receipt as though they were starting materials.  How to implement the regulations of GMP Finished products Finished products should be held in quarantine until their final release The evaluation and the documentation is necessary for sale , Rejection , recovering, reprocessing or reworking. Rejected materials and products should be stored separately in restricted areas to be returned to the suppliers or reprocessed or destroyed. The introduction of all or part of earlier batches should be authorized and carried out in accordance with a defined authorized procedure Additional testing of any finished product should be considered by the quality control department. Recalled products Recalled products should be identified and stored separately in a secure area until a decision is taken on their fate Returned goods Products returned from the market should be destroyed unless it is certain that their quality is satisfactory after critical assessment by QC.  How to implement the regulations of GMP Reagents and culture media There should be records for the receipt and preparation of reagents and culture media. Reagents made up in the laboratory should be prepared according to written procedures and appropriately labelled by all details. Reference standards Official reference standards should be used only for the purpose described in the appropriate monograph. Reference standards prepared by the producer should be tested, released and stored in the same way as official standards. All reference standards should be labelled stored and used in a manner that will not adversely affect their quality  How to implement the regulations of GMP Waste materials Provision should be made for the proper and safe storage of waste materials awaiting disposal. Toxic substances and flammable materials should be stored in suitably designed, separate, enclosed cupboards, as required by national legislation. It should be disposed of safely and in a sanitary manner at regular and frequent intervals. Miscellaneous Rodenticides, insecticides, fumigating agents and sanitizing materials should not be permitted to contaminate equipment, starting materials, packaging materials, in-process materials or finished products