GMP Lecture 1 & 2 PDF

GMP What are the aims of Pharmaceutical Industry ? 1- Manufacturing1 and marketing2 of safe and effective drug products, biological products and medical devices used for the acute/chronic treatment and diagnosis of disease of the highest quality. 2- Conducting research in the pharmaceutical field....

GMP What are the aims of Pharmaceutical Industry ? 1- Manufacturing1 and marketing2 of safe and effective drug products, biological products and medical devices used for the acute/chronic treatment and diagnosis of disease of the highest quality. 2- Conducting research in the pharmaceutical field. "Good Medicine is a Human Right, not a Privilege. Testing drug qualities is the responsibility of: 1. Ministry of health Now Egyptian Drug 2. National health authority Authority 3. National organization for drug control & research There are some objects that ensure homogeneity and good manufacturing practice such as building1, production process2, equipment3 used, personnel4 and documentation5. Definitions: Authorized person: A person Air Lock: An enclosed space with responsible for release of batches two or more doors, only one of the and ingredients. doors should be opened at any Batch or Lot: A defined quantity of time for controlling the air flow drug product (dosage form) or between them. other material that intended to Air Curtain: present at any door of have uniform characters and air lock to avoid dust accumulation quality and produced according to and cross contamination. single manufacturing order during the same cycle of manufacturing. It should have the same conditions of preparation, packaging,……...and no difference occurs. Batch number: A distinctive combination of numbers and/or Batch Record: All documents letters which identify the batch, associated with manufacturing of from which the complete history a batch of finished product which of manufacture, processing, provides a history of each batch packaging and distribution can be and all circumstances affecting determined. the quality of the finished product. All materials forming the Bulk Product: A product that has batch and their quantities must be undergoes all stages of production written in the batch record. It also not including packaging and contains information about: labeling. - Complete description of Finished Product: A product that manufacture procedures. has undergoes all stages of production including packaging - Quality control investigations. and labeling. - Acceptance criteria. In-process Control: Checks Clean Area: an area with defined performance during production to environmental control of monitor and if necessary to adjust the particulate and microbial process to ensure that the product contamination. This area is confirms to its specifications. constructed and used in such way to reduce introduction, generation Calibration ‫معايرة‬: a set of operations and retention of contamination. that establish under specified Critical process: a process that may conditions the relationship between cause variation in the quality of a values indicated by an instrument or pharmaceutical product system and values obtained from a (granulation, drying, mixing). reference standard. Validation ‫فاعلية‬: Validated Cross Contamination: manufacturing process is one which contamination of starting material has proved to do what is required or (raw material), intermediated expected to do. product or finished product with other materials of other line of production during manufacture. Documentation: all written Expiration date: means the date placed on procedures, instructions, description, the immediate container label of a drug specifications and records involved in product that designate the date through the product is expected to remain within the manufacture of drug product. specifications. Kinetically, it is the time Infra structure of factory: It feeds required for 10% of the material to most departments with superheated disappear (degraded). If it only includes a month and year, it is expected that the steam, electricity, air, gases, deionized product will meet specifications through water and sterile water. the last day of the month. Stability: The ability of a Shelf life: the interval of time that a drug pharmaceutical product, in a specific product is expected to remain within specifications as determined from stability container/closure system, to retain study. the defined physical, chemical, Utilization period: the period of time therapeutic, and toxicological during which a reconstituted preparation specifications till the end of the stated or the finished dosage form in an opened dating, under defined storage multi-dose container can be used. conditions. ISO: International organization for Overage: the excess quantity of drug standardization. It is a worldwide that must be added to the preparation federation of national standards. It was to maintain at least 90% of the active started by regulations of the use of raw ingredients expected during the shelf materials in drug manufacturing and life. now it becomes a system of regulative Quarantine: Physical isolation of any procedure to regulate the product including raw material, manufacturing process. packaging material, intermediate, bulk ISO 9003: A standard for companies or finished product and yellow label is that assemble and test product added on its package (under test) till it designed and manufactured elsewhere. will undergo quality control procedures. ISO 9002: A standard for companies The decision may be: released (green that manufacture, but do not design label) or refused (red label). what they manufacture. SOP (Standard Operation Procedure): ISO 9001: A standard for companies an authorized written procedure giving that design and service what they instructions for performing operations, manufacture. not necessary specific to a given product or a material but of a more general nature. Returned product: Finished product sent back to the manufacturer. Recovery: In case of non conformed dosage form but the active ingredient is still having its properties. Recovery includes introduction of all or part of this batch to another new batch at a definite stage of production. Reprocessing: Where a batch of unacceptable quality is rendered acceptable by one or more additional operations.  Good Manufacturing Practice (GMP) What is GMP? GMP is that part of Quality assurance which ensures that the products are consistently manufactured and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. A set of principles and procedures which when followed by manufacturer for therapeutic goods, helps to ensure that the products manufactured will have the required quality. Definition of Quality: Quality is also defined as excellence in the product or service that fulfills or exceeds the expectations of the customer. Quality is not fine-tuning your product at the final stage of manufacturing, before packaging and shipping. Quality is built into the product at every stage from conceiving specification & design stages to prototyping testing and manufacturing stages. Some of the main risk Unexpected contamination of products, causing damage to health or even death. Mix-up caused by false/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. So GMP is important ------  GMP prevent poor quality medicine.  GMP helps to ensure perfect medicines for intended therapeutic use. Why GMP is important? GMP is the government requirement GMP provides a high level assurance that medicines are manufactured in a way that ensures their safety, efficacy and quality. GMP reduces rejection, complaint, recall. GMP satisfies customers GMP maintain manufacturing consistency. GMP ensures quality medicines to comply with their marketing authorization. GMP provides company image and reputation. GMP Covers… 1. ALL aspects of production; from the starting materials, premises and equipment to the training and personal hygiene of staff. 2. Detailed, written procedures are essential for each process that could affect the quality of the finished product. 3. 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.  QC and QA QC is that part of GMP which is QA is the sum total of organized concerned with sampling, arrangements made with the specifications, testing and within object of ensuring that product the organization, will be of the Quality required by documentation, and release their intended use. procedures which ensure that All those planned or systematic the necessary and relevant tests actions necessary to provide are carried out. adequate confidence that a Operational laboratory product will satisfy the techniques and activities used to requirements for quality. fulfill the requirement of Quality QA is company based QC is lab based QA, GMP & QC inter-relationship QA, GMP & QC inter-relationship QA, GMP & QC inter-relationship QA, GMP & QC inter-relationship Components of GMP:  1. Quality management Quality management is usually defined as the aspect of management function that The basic elements of quality determines and implements the management are: an appropriate “quality policy”, i.e. the overall infrastructure or “quality system”, intention and direction of an encompassing the organizational organization regarding quality, as structure, procedures, processes formally expressed and and resources; and systematic authorized by top management. actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for quality.  2. Quality Assurance (QA) It is the sum total of the organized arrangements made with the objective of ensuring that medicinal products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practice plus other factors outside the scope of this Guide. The system of Quality Assurance appropriate for the manufacture of medicinal Products should ensure that: i. Medicinal products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice; ii. Production and control operations are clearly specified and Good Manufacturing Practice adopted; iii. Managerial responsibilities are clearly specified; iv. Arrangements are made for the manufacture, supply and use of the correct starting and packaging materials from approved vendor; v. All necessary controls on intermediate products, and any other in process controls and validations are carried out; vi. The finished product is correctly processed and checked, according to the defined procedures; vii. Medicinal products are not sold or supplied before the QC/QA operation has certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization. viii. Satisfactory arrangements exist to ensure, that the medicinal products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life; ix. There is a procedure for self inspection and/or quality audit, which regularly appraises the effectiveness and applicability of the quality assurance system. 3. Good Manufacturing Practice (GMP) for medicinal products GMP is that part of QA which ensures that products are GMP is aimed primarily at diminishing consistently produced and the risks inherent in any controlled to the quality pharmaceutical production. Such risks standards appropriate to their are essentially of two types: intended use and as required by 1. cross-contamination (in particular the marketing authorizations or of unexpected contaminants) and product specification. 2. mix ups (confusion) caused by, for example, false labels being put on containers. The basic requirements of GMP are that: a) All manufacturing processes are clearly defined, systematically reviewed in the light of experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their specifications; b) Qualification and validation are performed; c) All necessary resources are provided; d) Instructions and procedures are written in clear language, specifically applicable to the facilities provided; e) Operators are trained to carry out procedures correctly; f) Records are made during manufacture to show that all the steps required by the defined procedures and instructions have in fact been taken and that the quantity and quality of the product are as expected; any significant deviations are fully recorded and investigated; g) Records covering manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form; h) The proper storage and distribution of the products minimizes any risk to their quality; i) A system is available to recall any batch of product from sale or supply; and j) Complaints about marketed products are examined; the causes of quality defects investigated, and appropriate measures taken in respect of the defective products to prevent recurrence.  4. Quality Control (QC) Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organization, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory The basic requirements of Quality Control are that: I. adequate facilities, trained personnel and approved procedures are available for sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes; II. samples of starting materials, packaging materials, intermediate products, bulk products and finished products are taken by personnel and by methods approved by Quality Control; III. Test methods are validated; IV. Records are made, manually and/or by recording instruments. Any deviations are fully recorded and investigated; V. the finished products contain active ingredients complying with the qualitative and quantitative composition of the marketing authorization, are of the purity required, and are enclosed within their proper containers and correctly labeled; VI. No batch of product is released for sale or supply prior to certification by an authorized person that it is in accordance with the requirements of the relevant authorizations; VII. Sufficient reference samples of starting materials and products are retained to permit future examination of the product if necessary and that the product is retained in its final pack unless exceptionally large packs are produced.  5. Sanitation and hygiene The scope of sanitation and There shall be written hygiene covers personnel, procedures assigning premises, equipment and responsibility for sanitation and apparatus, production materials describing in sufficient detail and containers, products for the cleaning schedules, cleaning and disinfection, and methods, equipment, and materials to be used in cleaning anything that could become a the buildings and facilities; such source of contamination to the written procedures shall be product. followed. Records should be maintained.  6. Qualification and validation (a) The premises, supporting utilities, The key elements of a equipment and processes have been designed qualification and validation in accordance with the requirements for GMP program of a company should (design qualification, or DQ); be clearly defined and (b) The premises, supporting utilities and documented in a validation equipment have been built and installed in master plan. compliance with their design specifications (installation qualification, or IQ); Qualification relates to (c) The premises, supporting utilities and instruments and equipment. equipment operate in accordance with their Validation relates to processes. design specifications (operational qualification, or OQ); Qualification and validation (d) A specific process will consistently produce a should establish and provide product meeting its predetermined documentary evidence that specifications and quality attributes (process validation, or PV, also called performance qualification, or PQ). A protocol is a written set of instructions broader in scope than a Standard Operating Procedure Validation Master Plan (VMP) is a (SOP). high-level document which A protocol describes the details of establishes an umbrella validation a comprehensive planned study to plan for the entire project. investigate the consistent VMP describes which equipment, operation of new systems, methods and processes system/equipment, a new will be validated and when they procedure, or the acceptability of will be validated. a new process before it is implemented  Method validation is the process used to confirm that the analytical procedure employed for a specific test is suitable for its intended use. Results from method validation can be used to judge the quality, reliability and consistency of analytical results; it is an integral part of any good analytical practice. Analytical methods need to be validated or revalidated before their introduction into routine use; whenever the conditions change for which the method has been validated (e.g., an instrument with different characteristics or samples with a different matrix). 7. Complaints and product recalls QA and GMP are about preventing errors. If errors occur, QA system should have a plan to deal with complaints. Each complaint or inquiry be evaluated by knowledgeable and responsible personnel. The records of production, packaging, and distribution of drug and the retained samples provide the basis for assessing the validity and seriousness of the deviations that caused the complaint. The complaint file itself also plays an important role in determining whether any other similar complaints have been received on the lot in question, or on any other lots of the same product. First, there is the urgent need to confirm whether consumers are potentially at risk and to initiate any appropriate action. A second value is the review of the product and its production process to establish whether any modifications are required. Third is the need to rapidly respond to the customer, thereby attempting to maintain confidence in the product and company. Manufacturers should have a written recall procedure, with nominated persons responsible for implementing it as necessary, within, or outside of, normal working hours.  8. Contract production and analysis Principle. Contract production and The simplest way to avoid such analysis must be correctly defined, agreed and controlled in order to misunderstandings is to have a avoid misunderstandings that written contract, setting out the could result in a product or work or duties of all parties to the analysis of unsatisfactory quality. contract and the standards that The contract should permit the must be met. contract giver to audit the facilities of the contract accepter. In the case of contract analysis, the final approval for release must be given by the authorized person. 9. Self-inspection, quality audits and supplier’s audits/approval Principle: The purpose of self-inspection is to evaluate the manufacturer’s compliance with GMP in all aspects of production and quality control. The self inspection program should be designed to detect any shortcomings in the implementation of GMP and to recommend the necessary corrective actions. Self-inspections should be performed routinely, and may be, in addition, performed on special occasions, e.g. in the case of product recalls or repeated rejections, or when an inspection by the health authorities is announced. The team responsible for self-inspection should consist of personnel who can evaluate the implementation of GMP objectively. All recommendations for corrective action should be implemented. The procedure for self-inspection should be documented, and there should be an effective follow-up program. Written instructions for self-inspection should be established to provide a minimum and uniform standard of requirements. These may include questionnaires on GMP requirements covering at least the following items: Items for self-inspection (a) personnel; (i) sanitation and hygiene; (b) premises including personnel facilities; (j) validation and revalidation programs; (c) maintenance of buildings and (k) calibration of instruments or equipment; measurement systems; (d) storage of starting materials and (l) recall procedures; finished products; (m) complaints management; (e) equipment; (n) labels control; (f ) production and in-process controls; (o) results of previous self-inspections and (g) quality control; any corrective steps taken. (h) documentation;  Quality audit It may be useful to supplement self-inspections with a quality audit. A quality audit consists of an examination and assessment of all or part of a quality system with the specific purpose of improving it. A quality audit is usually conducted by outside or independent specialists or a team designated by the management for this purpose. Such audits may also be extended to suppliers and contractors. 10. Personnel, training and personal hygiene To apply GMP there must be sufficient qualified personnel to carry out all the tasks for which the manufacturer is responsible. Individual responsibilities should be clearly defined and understood by the persons concerned and recorded as written job descriptions. Personnel should be aware of the principles of GMP that affect them and receive initial and continuing training, including hygiene instructions, relevant to their need.  11. Premises Premises must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out. 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, in general, any adverse effect on the quality of products. Electrical supply Lighting, temperature, humidity and ventilation should be appropriate. Premises should be designed and equipped so as to afford maximum protection against the entry of insects or other animals. Steps should be taken in order to prevent the entry of unauthorized people. Premises should be designed to ensure the logical flow of materials and personnel. Premises used for the manufacture of finished products should be suitably designed and constructed to facilitate good sanitation.  12. Equipment Manufacturing equipment should be Equipment must also be capable of capable of producing products, withstanding repeated, thorough materials, and intermediates that cleaning. Traces of previous product, at are intended and that conform to levels that might be acceptable in other the required or specified quality industries, are totally unacceptable in characteristics. the manufacture of medicines. As far as the properties of the materials of Furthermore, the equipment must construction of the equipment are be designed and built so that it is concerned, there are two major possible (and relatively easily concerns: possible) to clean it thoroughly. 1. The possibility of contamination, or Surfaces that come into contact with degradation, of the product by the products should have smooth and material from which the equipment is polished finishes to harbor constructed contamination or make cleaning 2. The action of the product, or material difficult. in-process, on the material from which the equipment is constructed.  13. Materials The main objective of a pharmaceutical Provision should be made for the plant is to produce finished products for proper and safe storage of waste patients’ use from a combination of materials awaiting disposal. materials (starting and packaging). Toxic substances and flammable Materials include starting materials, materials should be stored in packaging materials, gases, solvents, suitably designed, separate, enclosed process aids, reagents and labeling cupboards, as required by national materials. legislation. No materials used for operations such Waste material should not be as cleaning, lubrication of equipment allowed to accumulate. It should be and pest control, should come into collected in suitable receptacles for direct contact with the product. Where removal to collection points outside possible, such materials should be of a the buildings and disposed of safely suitable grade (e.g. food grade) to and in a sanitary manner at regular minimize health risks. and frequent intervals.  14. Documentation The various types of documents used should be fully defined in the manufacturer's quality management system Good documentation is an essential part of (QMS). the QA system and, as such, should exist for all aspects of GMP. Documentation may exist in a variety of forms, including paper-based, electronic or Its aims are to define the specifications and photographic media. The main objective of procedures for all materials and methods of the system of documentation utilized must manufacture and control; to ensure that all be to establish, control, monitor and record personnel concerned with manufacture all activities which directly or indirectly know what to do and when to do it; to impact on all aspects of the quality of ensure that authorized persons have all the medicinal products. information necessary to decide whether or not to release a batch of a medicine for The QMS should include sufficient sale, to ensure the existence of instructional detail to facilitate a common documented evidence, traceability, and to understanding of the requirements, in provide records and an audit trail that will addition to providing for sufficient permit investigation. recording of the various processes and evaluation of any observations, so that It ensures the availability of the data ongoing application of the requirements needed for validation, review and statistical may be demonstrated. analysis. The design and use of documents depend upon the manufacturer.  15. Holding and distribution The goods hold stage is where it is necessary to ensure that the goods remain in good condition, and do not become harmed or damaged through incorrect or unsuitable storage conditions or bad handling. That is, it is important to ensure that quality goods are not reduced to rubbish. All goods must be stored in a clean, neat, orderly way, in conditions that will not affect their quality or cause them to deteriorate in any way. Untidy stores increase the possibility of mix-up and confusion — mix- up of different types of goods, mix-up of different batches (or lots), mix-up of goods of different status. It is very difficult to have effective stock rotation unless goods are stored in an orderly fashion.  Thank you Dr. Amira Boseila E-mail: [email protected] Office room: NG50