GMP Lecture Notes PDF

GMP Prepared by: Mohamed S. Elafify, Ph.D By Dr. Mohamed Elafify 1 Contents  What is GMP.  GMP evolution.  Importance of GMP.  GMP-associated glossary. By Dr. Mohamed Elafify 2 What is GMP ? One of a drug developer’s greatest responsibilities is to ensu...

GMP Prepared by: Mohamed S. Elafify, Ph.D By Dr. Mohamed Elafify 1 Contents  What is GMP.  GMP evolution.  Importance of GMP.  GMP-associated glossary. By Dr. Mohamed Elafify 2 What is GMP ? One of a drug developer’s greatest responsibilities is to ensure that the products they provide are safe for use in humans. No matter how a medicinal product is delivered – through injection or any other way – it must be manufactured in a way that meets rigorous quality and regulatory standards. GMP is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. By Dr. Mohamed Elafify 3 What is GMP ? GMP are aimed primarily at diminishing the risks inherent in any pharmaceutical production. Such risks are essentially of two types: cross-contamination (in particular of unexpected contaminants) and mix-ups (confusion) caused by, for example, false labels being put on containers The most common standards that guide how drug products are manufactured are Good Manufacturing Practices (GMP) and Current Good Manufacturing Practices (cGMP). "GMP" - A set of principles and procedures which, when followed by manufacturers for therapeutic goods, ensure that the products manufactured will have the required quality. “cGMP” – where c = current, to emphasize that the expectations are dynamic (Promoting continual advancement) By Dr. Mohamed Elafify 4 GMP versus cGMP By Dr. Mohamed Elafify 5 GMP evolution The first GMP text published by WHO was developed during 1967–69 upon request by WHO’s Member States and was revised in 1975. Since 1978, the FDA has referred to the GMP guidelines as cGMP to emphasize that the regulations are constantly evolving to reflect the latest developments in the industry. Revised and expanded GMP guidelines were prepared during 1989–90. In 1996, GMP guidelines were published by WHO for the validation of manufacturing processes. These concepts were integrated in its revised text in 2003. Volume 1 of Quality Assurance of Pharmaceuticals: a compendium of guidelines and related materials was published by WHO in 1997. By Dr. Mohamed Elafify 6 Why GMP is important Poor quality medicine may contain toxic substances that have been unintentionally added. A medicine that contains little or none of the claimed ingredients will not have the intended therapeutic effect. GMP helps boost pharmaceutical export opportunities. A- Most countries will only accept import and sale of medicines that have been manufactured according to internationally recognized GMP. B- Governments seeking to promote their countries export of pharmaceuticals can do so by making GMP mandatory for all pharmaceutical production and by training their inspectors on GMP requirements. By Dr. Mohamed Elafify 7 Under GMP (a) All manufacturing processes are clearly defined, and 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, including: (i) appropriately qualified and trained personnel; (ii) adequate premises and space; (iii) suitable equipment and services; (iv) appropriate materials, containers, and labels; (v) approved procedures and instructions; (vi) suitable storage and transport; (vii) adequate personnel, laboratories, and equipment for in- process controls (d) Operators are trained to carry out procedures correctly. By Dr. Mohamed Elafify 8 Under GMP (e) Instructions and procedures are written in clear language, specifically applicable to the facilities provided. (f) Records are made (manually and/or by recording instruments) during manufacture to show that all the steps required by the defined procedures and instructions have been; 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. (j) Complaints about marketed products are examined, the causes of quality defects investigated, and appropriate measures taken with respect of the defective products to prevent recurrence. By Dr. Mohamed Elafify 9 Glossary Pharmaceutical product: Any material or product intended for human or veterinary use presented in its finished dosage form, that is subject to control by pharmaceutical legislation in the exporting state and/or the importing state. Active pharmaceutical ingredient (API): Any substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when so used, becomes an active ingredient of that pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, treatment, or prevention of disease or to affect the structure and function of the body. By Dr. Mohamed Elafify 10 Starting material: Any substance of a defined quality used in the production of a pharmaceutical product, but excluding packaging materials. Intermediate product: Partly-processed product that must undergo further manufacturing steps before it becomes a bulk product. Bulk product: Any product that has completed all processing stages up to, but not including, final packaging. Finished product: A finished dosage form that has undergone all stages of manufacture, including packaging in its final container and labelling. By Dr. Mohamed Elafify 11 Quarantine: The status of starting or packaging materials, intermediates, or bulk or finished products isolated physically or by other effective means while a decision is awaited on their release, rejection or reprocessing. Batch (or lot): A defined quantity of starting material, packaging material, or product processed in a single process or series of processes so that it is expected to be homogeneous. It may sometimes be necessary to divide a batch into a number of sub-batches, which are later brought together to form a final homogeneous batch. e.g. In the case of terminal sterilization, the batch size is determined by the capacity of the autoclave. The batch size can be defined either as a fixed quantity or as the amount produced in a fixed time interval. By Dr. Mohamed Elafify 12 Batch records: All documents associated with manufacturing a batch of bulk or finished products. They provide a history of each batch of product and all circumstances pertinent to the quality of the final product. Batch number (or lot number): A distinctive combination of numbers and/or letters that uniquely identifies a batch on the labels, its batch records, and corresponding certificates of analysis, etc. Master record: A document or set of documents that serve as a basis for the batch documentation (blank batch record). Master formula: A document or set of documents specifying the starting materials with their quantities and the packaging materials, together with a description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process controls. By Dr. Mohamed Elafify 13 Manufacture: All operations of purchase of materials and products, production, quality control, release, storage and distribution of pharmaceutical products, and the related controls. Manufacturer: A company that carries out operations such as; production, packaging, repackaging, labeling, and re-labelling of pharmaceuticals. Authorized person: The person recognized by the national regulatory authority as having the responsibility for ensuring that each batch of finished product has been manufactured, tested and approved for release in compliance with the laws and regulations in force in that country. Critical operation: An operation in the manufacturing process that may cause variation in the quality of the pharmaceutical product. By Dr. Mohamed Elafify 14 Airlock: An enclosed space with two or more doors, which is interposed between two or more rooms, e.g. of differing classes of cleanliness, for the purpose of controlling the airflow between those rooms when they need to be entered. An airlock is designed for use either by people or for goods and/or equipment. Clean area: An area with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce the introduction, generation, and retention of contaminants within the area. Contamination: The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or on to a starting material or intermediate during production, sampling, packaging or repackaging, storage or transport. Cross-contamination: Contamination of a starting material, intermediate product or finished product with another starting material or product during production. By Dr. Mohamed Elafify 15 Production: All operations involved in the preparation of a pharmaceutical product, from receipt of materials, through processing, packaging and repackaging, labeling and re-labeling, to completion of the finished product. In-process control: Checks performed during production to monitor and, if necessary, to adjust the process to ensure that the product conforms to its specifications. The control of the environment or equipment may also be regarded as a part of in- process control. Specification A list of detailed requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation. Reconciliation: A comparison between the theoretical quantity and the actual quantity. By Dr. Mohamed Elafify 16 Standard operating procedure (SOP): An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material (e.g. equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Validation: Action of proving, under the principles of GMP, that any procedure, process, equipment, material, activity, or system leads to the expected results. Calibration: The set of operations that establish the relationship between values indicated by an instrument or system for measuring (especially weighing), recording, and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established. By Dr. Mohamed Elafify 17 Reprocessing: Subjecting all or part of a batch or lot of an in- process drug, bulk process intermediate (final biological bulk intermediate) or bulk product of a single batch/ lot to a previous step in the validated manufacturing process due to failure to meet predetermined specifications. Reprocessing procedures are foreseen as occasionally necessary for biological drugs and, in such cases, are validated and pre-approved (i.e. SOP) as part of the marketing authorization. Reworking: Subjecting an in-process or bulk process intermediate (final biological bulk intermediate) or final product of a single batch to an alternate manufacturing process due to a failure to meet predetermined specifications. Reworking is an unexpected occurrence and is not pre-approved as part of the marketing authorization. By Dr. Mohamed Elafify 18 Packaging: All operations, including filling and labeling, that a bulk product has to undergo to become a finished product. Filling of a sterile product under aseptic conditions or a product intended to be terminally sterilized, would not normally be regarded as part of packaging. Packaging material: Any material, including printed material, employed in the packaging of a pharmaceutical, but excluding any outer packaging used for transportation or shipment. Packaging materials are referred to as primary or secondary according to whether or not they are intended to be in direct contact with the product. Large-volume parenterals: Sterile solutions intended for parenteral application with a volume of 100 ml or more in one container of the finished dosage form. By Dr. Mohamed Elafify 19  Quality assurance (QA): is a wide-ranging concept covering all matters that influence the quality of a product. QA therefore incorporates GMP and other factors, including those outside the scope of this guide such as product design and development The system of quality assurance appropriate to the manufacture of pharmaceutical products should ensure that: Pharmaceutical products are designed and developed in a way that takes account of the requirements of GMP and other associated codes such as those of good laboratory practice (GLP) and good clinical practice (GCP). Production and control operations are specified in a written form and GMP requirements are adopted. Managerial responsibilities are specified in job descriptions. By Dr. Mohamed Elafify 20 The QA system should ensure that Arrangements are made for use of the correct starting and packaging materials. All necessary controls on starting materials, intermediate products, bulk products, and other in-process controls, calibrations, and validations are carried out. The finished product is correctly processed and checked, according to the defined procedures. Pharmaceutical products are not sold or supplied before the authorized persons have certified that each production batch has been produced and controlled following the requirements of the marketing authorization and any other regulations relevant to the production, control, and release of pharmaceutical products. Deviations are reported, investigated, and recorded. By Dr. Mohamed Elafify 21 The QA system should ensure that There is a procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the quality assurance system. Satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical products are stored by the manufacturer, distributed, and subsequently handled so that quality is maintained throughout their shelf-life. There is a system for approving changes that may have an impact on product quality. Regular evaluations of the quality of pharmaceutical products should be conducted with the objective of verifying the consistency of the process and ensuring its continuous improvement. By Dr. Mohamed Elafify 22