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Presentation on theme: "GMP ORIENTATION SESSION"— Presentation transcript:

Good Manufacturing Practices Good Manufacturing Practices Practices Manufacturing Good Practices Manufacturing Good GMP ORIENTATION SESSION

4/11/2017 GMP ORIENTATION Introduction Quality Management Terminology Premises Equipment Personnel Sanitation & Hygiene Material Testing This presentation is just only a orientation of the Good Manufacturing Practices. However each one of you has to read the individual GMP’s and understand their importance further and enable yourself in implementing them to your work atmosphere. The main sections or topics apart from the introduction to GMP’s that covered under GMP’s are Quality Management Terminology and other Definitions that are used in Pharmaceutical Industry. Premises Equipment Personnel Sanitation & Hygiene Material Testing – Raw Material, Intermediate, Packing & Labelling and Finished Product. Manufacturing Control Quality Control Documentation Samples & Stability Sterile Production and Inspection. GMP ORIENTATION SESSION

9. Manufacturing Control QC Documentation Samples & Stability Sterile Production GMP ORIENTATION SESSION

1. Introduction Purpose of GMP Good Manufacturing Practice (GMP) regulations were introduced as a means to ensure that a given product is processed reliably, repeatedly, consistently, safely and to a high quality. In the pharmaceutical processing industry GMP is an essential part of the production process. GMP ORIENTATION SESSION

4/11/2017 1. Introduction Why GMP is established? Just prior to start of the 2nd World War there was a serious poisoning incident in the USA. This prompted the introduction of the “Food, Drugs and Cosmetics Act 1938”, by US Food and Drugs Administration (FDA). The intention of the new act was to ensure that food, drugs, cosmetics and biological products were safe for human contact. Hence the need to establish Good Manufacturing Practice (GMP). It is very interesting to know how these regulations have been generated to satisfy the needs of the public. A Brief History FDA is one of US oldest public health agencies. 1800’s: Federal control over the US drug supply began in 1848 with the Drug Importation Act, which required US Customs to stop the importation of adulterated drugs. Due to the growing necessity for safe food and drug products, in 1862 President Abraham Lincoln appointed chemist Charles M Wetherill to head the chemical division in the newly created Department of Agriculture. This division conducted numerous food adulteration studies. Late in the 2800s, more than 100 food and drug bills were introduced in Congress. 1900s: In 1902, the Biologics Control Act was passed to ensure purity and safety of serums, vaccines, and similar products used to prevent or treat diseases in humans. Shcoking disclosures of insanitary conditions in meat packing plants, the use of poisonous preservatives and dyes in foods, and cure-all claims for worthless and dangerous patent medicines prompted Congress to pass the Food and Drugs Act in This federal law prohibited interstate commerce in misbranded and adulterated foods, drinks, and drugs. In 1930, what had become the Food, Drug, and Insecticide Administration was renamed the Food and Drug Administration (FDA). 1938: FDA was involved in a five-year legislative struggle to completely revise the Food and Drugs Act. Following the death of 107 persons mostly children, who took a poisonous Elixir of Sulfanilamide, Congress greatly strengthened the public health protection by passing the Federal Food, Drug, and Cosmetic Act (FD&C Act). This new Act: extended FDA’s control to cosmetics and therapeutic devices; required new drugs to be proven safe before marketing; authorized standards of identity, quality, and fill-of-container for foods; authorized factory inspections; and increased the legal tools available to enforce provisions of the Act. Mid 1900s After the passage of the FD&C Act, numerous amendments, standards, and laws were passed, and court cases set precedents to further define FDA’s role in protecting the public health. These covered areas such as food sanitation standards, prosecution for violations, drug labeling and effectiveness, pesticide residues, biologics, food additives, packaging and labeling, low –acid canned foods, medical devices, infant formula, nutrition labeling, and dietary supplements. In 1949, FDA published its first guidance to industry. 1997 The Food and Drug Administration Modernization Act (FDAMA) mandated the most wide-ranging reforms in Agency practices since In FDAMA, Congress recognized that the protection of public health is a responsibility shared by the entire health care community. The law directs the Agency to carry out its mission in consultation and cooperation with all FDA stakeholders, including consumer and patient groups, the regulated industry, healthcare professionals, and FDA’s regulatory counterparts abroad. Provisions of FDAMA include measures to accelerate review of devices, regulate advertising of unapproved uses of approved drugs and devices, and regulate health claims for foods. Today With a more than 80% favourable rating in public opinion polls, the Agency is cooperating with its stakeholders in the US and abroad to continue protecting consumers and the public health in the new era of technological and scientific advances. In the wake of the terrorist attacks on September 11, 2001, FDA has also been entrusted with two critical functions in the nation’s war on terrorism: To prevent the willful contamination of all regulated products. To Improve the availability of medications to prevent or treat injuries caused by biological, chemical, or nuclear agents. Regulated Products Products regulated by FDA include: all foods except for meat and poultry [regulated by the US Department of Agriculture (USDA)]; prescription and non-prescription drugs; blood products, vaccines, and tissues for transplantation; medic al devices and radiological products, including cellular telephones; animal drugs and feed; and cosmetics Areas that FDA does not handle include restaurant food and sa nitation, air or water pollution, alcoholic beverages, and drug abuse. Although FDA doesn’t directly regulate restaurant food and sanitation, it develops the policies (model code) that local authorities use. FDA also plays a strong role in the training of local investigators conducting restaurant inspections. Although FDA does not regulate pesticides, it does regulate products that are contaminated with pesticides. FDA doesn’t regulate the practice of pharmacies or medical practitioners either, but there are certain sales and distribution practices of pharmacies and doctors that it does regulate. Does FDA regulate Product Labeling In addition to setting product standards, FDA regulates the labeling of products under its jurisdiction. This information, which must be valid, well documented, and not misleading, plays a major role in protecting consumers and the public health. The FDA-regulated food label helps shoppers eat a healthy diet, and the labeling of drugs and medical devices gives prescribers and patients reliable guidance about the safety and effectiveness of healthcare products. The next time you are in a grocery store, compare the nutritional information labels on three different foods or drinks. You will notice that the format and content of the labels are the same. FDA requires food producers to provide this specific information in the exact format that you see. So whether you are buying bottled water or a package of cupcakes, you — the consumer — are provided with nutritional information that can help you determine how that product fits into your dietary needs. Reporting: FDA welcomes consumer reports and complaints about regulated products. Timely reporting by consumers, health professionals, and FDA-regulated companies allows the Agency to take prompt action. Information concerning ways for the public to report problems to FDA can be found on the FDA’s Web site at: A collection of FDA-enforced laws and related statutes can be found at: GMP ORIENTATION SESSION

4/11/2017 1. Introduction Where to find GMP Regulations/Guidelines? US – 21 CFR Part 210 & 211 ( Canada - Europe - WHO - Australia - US- FDA guidelines – The 21 CFR Part 210 & While Part 210 gives regulations on Current Good Manufacturing Practice in Manufacturing, Processing, Packaging or Holding of Drugs in general, Part 211 gives regulations on Current Good Manufacturing Practice for Finished Pharmaceuticals. These regulations are written in legal language and are some times difficult to decipher. These guidelines are taken from the Food Drug and Cosmetics Act. Canada-The Canadian GMP guidelines represent more or less the FDA regulations and are taken from Food and Drug Act, Canada. In these guidelines, rationale approach is given and it is more easy to understand and decipher. All of the GMP guidelines US, Canada, Europe or WHO deals on the same aspects: Quality Management Premises Personnel Sanitation & Hygiene Material Testing (Raw material, intermediate and Finished Product) Quality Control Documentation Stability and Sterility GMP ORIENTATION SESSION

4/11/2017 Section Regulation F P/L I (non-MRA) I (MRA) D W T 1. Premises C X 2. Equipment C 3. Personnel C 4. Sanitation C C 5. Raw Material Testing C C 6. Manufacturing Control C C 7. Quality Control C C C 8. Packaging Material Testing C C 9. Finished Product Testing C C 10. Records C C C C C 11. Samples C C 12. Stability C C 13. Sterile Products C This is a typical chart that gives details of the various regulations and its concern with different departments and marketing features - Canadian GMP F = Fabricator P/L = Packager/Labeller I = Importer D = Distributor W = Wholesaler T = Tester GMP ORIENTATION SESSION

8 2. Quality Management Purpose of Quality Management
GMP ORIENTATION 4/11/2017 2. Quality Management Purpose of Quality Management To Determine and implement the “quality policy” The basic elements are: A well defined “quality system” encompassing the Procedures, Processes, and Resources Systematic actions necessary to ensure adequate confidence that a product (or service) will meet given requirements for “Quality” The holistic view of all these aspects is termed as “Quality Assurance” The definition given here is in conformance with the definition contained in the international standard ISO 9000, standard established by the International Standards Organization, aimed at ensuring that an organization has a quality management system and that it complies with all aspects of that system. Quality management is defined as the aspect of management function that determines and implements the quality policy. The quality policy is a statement by the top management of the company of its overall intentions and direction relating to quality, formally expressed as a corporate policy. The top management of a company usually includes the board of directors or general manager of the company, the plant or factory managers together with the senior managers. There are two basic elements of this aspect of the management function of a pharmaceutical company: A working infrastructure = quality system. This includes: Organizational structure Procedures Processes Resources A company needs to have a plan to develop all these items and a statement of its intent to carry out that plan. It is only when all the elements of the plan have been carried out that there is a system of quality management in place. Any company or organization making pharmaceuticals should show that there is a structure – an organization dedicated to making the products correctly. This structure must have the backing of the most senior management of the company to be sure that it will succeed. Systematic actions to bring the quality policy to life. The totality of these actions is termed quality assurance (QA). Inside an organization, QA is a management tool. In contractual situations, it provides confidence in the supplier. An important part of the systematic actions is the availability of a complete system of standard operating procedures. These are normally known as SOPs. They describe all the actions that need to be taken in a standardized way. This means that everyone involved in pharmaceutical manufacturing has a book of procedures that guides them in the way that they should do their job. It provides a standardized way of working. GMP ORIENTATION SESSION

4/11/2017 2. Quality Management Quality Management QA – Quality Assurance GMP QC - Quality Control The concepts of QA, GMP and Quality Control are interrelated aspects of Quality Management “Quality System” is increasingly being used in drug manufacturing and is on the increase because of the influence of ISO 9000, a model for a Quality System. Quality Management covers three main divisions under its umbrella and these are Quality Assurance, Good Manufacturing Practice and Quality Control. Even though QC is under QA, because of its importance it is treated as one of the main wings under quality management. The concepts of QA, GMP and Quality Control are interrelated aspects of Quality Management. GMP ORIENTATION SESSION

4/11/2017 2. Quality Management Quality Assurance Wide ranging concept Total organized System QA incorporates GMP Quality assurance is a wide-ranging concept that covers all matters that individually or collectively influence the quality of a drug. It is the total of the organized arrangements made with the objective of ensuring that drugs are of the quality required for their intended use. Quality assurance therefore incorporates Good Manufacturing Practices, along with other factors that are outside the scope of these guidelines. GMP ORIENTATION SESSION

4/11/2017 2. Quality Management Quality Assurance Aim Ensure that GMP requirements are met in production of the drug product. Clarity in Responsibilities Adequate resources Adopted clear and specified procedures. Arrangements for correct usage of material Control on all aspects of production process Proper processing, packaging/labeling and verification of Drug Product. Sale of only quality drug products. Proper procedures for Storage of drug products. Self-inspection procedures and quality audit. A system of quality assurance appropriate for the manufacture of drugs should ensure that: Drugs are designed and developed in a way that takes into account the GMP requirements; Managerial responsibilities are clearly specified; Systems, facilities and procedures are adequate; Production and control operations are clearly specified, and GMP are adopted; Arrangements are made for the supply and use of the correct raw and packaging materials; Control on intermediates, in-process monitoring, and validation activities are carried out; The finished product is processed, packaged/labelled, verified, and tested according to defined procedures; Drugs are not sold or supplied before the quality control department has indicated that each batch has been produced and controlled in accordance with the requirements of the marketing authorization and of any other regulations relevant to the production, control and release of drugs; Satisfactory arrangements exist for ensuring that the drugs are stored, distributed, and subsequently handled in such a way that quality is maintained throughout their shelf life; There is a procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the quality assurance system; GMP ORIENTATION SESSION

4/11/2017 2. Quality Management GMP for Drugs Clear, defined, controlled and validated manufacturing procedures. All key elements are provided for manufacturing process. Clear, unambiguous written procedures. Trained operators. Proper documentation. Distribution of drugs with minimum or zero risk to quality. System available for recall of the product from market. All complaints examined and corrective & preventive measures taken. Good Manufacturing Practices (GMP) for Drugs Good Manufacturing Practices (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 are concerned with both production and quality control. Their basic requirements are as follows: Manufacturing processes are clearly defined and controlled. All critical processes are validated to ensure consistency and compliance with specifications. Manufacturing processes are controlled, and any changes to the process are evaluated. Changes that have an impact on the quality of the drug are validated as necessary. 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 unambiguous language; Operators are trained to carry out and document procedures; Records are made, manually or by instruments, 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 manufacture (including distribution) that enable the complete history of a batch to be traced are retained in a comprehensible and accessible form; The distribution of the drugs minimizes any risk to their quality; A system is available for recalling any batch of drug from sale or supply; Complaints about marketed 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. GMP ORIENTATION SESSION

4/11/2017 2. Quality Management Quality Control Adequate facilities Trained personnel Approved procedures are available for sampling, inspecting and testing of raw materials, packaging materials, intermediate bulk and finished products. Monitoring environmental conditions for GMP purposes Quality Control Quality control is the part of GMP that is concerned with sampling, specifications, testing, documentation and release procedures. This approach ensures that materials are not released for use, and that drugs released for sale or supply, until their quality has been deemed satisfactory. The basic requirements of quality control are as follows: Adequate facilities, trained personnel, and approved procedures are available for sampling, inspecting and testing of raw materials, packaging materials, intermediate bulk and finished products, and, where appropriate monitoring environmental conditions for GMP purposes; 1.1 Samples of raw materials, packaging materials, and intermediate, bulk, and finished products are taken according to procedures approved by the quality control department; 1.2 Test methods are validated; 1.3 Records are made that demonstrate that all the required sampling, inspecting, and testing procedures were actually carried out, and any deviations are recorded and investigated; 1.4 The finished products contain active ingredients that comply with the qualitative and quantitative composition requirements of the marketing authorization, have the purity required, are enclosed within their proper container and are correctly labelled; 1.5 Records are made of the results of inspection, and to show that testing of materials, and of intermediate, bulk, and finished products is formally assessed against specification; 1.6 Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures; 1.7 No batch of drug is released for sale or supply prior to approval by the quality control department, in accordance with the requirements of the marketing authorization (Notice of Compliance (NOC), Drug Identification Number (DIN)); 1.8 Sufficient reference samples of raw materials and drugs are retained to permit future examination of the drug if necessary, and the drug is retained in its final pack unless exceptionally large packs are produced. GMP ORIENTATION SESSION

4/11/2017 3. Terminology API: Active Pharmaceutical Ingredient DIN: Drug Identification Number GLP: Good Laboratory Practices ICH: International Conference on Harmonization HPFBI: Health Products and Food Branch Inspectorate NOC: Notice of Compliance MRA: Mutual Recognition Agreement PIC/S: Pharmaceutical Inspection Cooperation/Scheme WHO: World Health Organization Here some frequent terminology used is given. But for other terms that are used in Pharmaceutical Industry one hast to refer the Glossary given below. Glossary of Terms The definitions given below apply to the terms used in these guidelines, they also apply to the terms used in the annexes unless otherwise specified therein. Definitions quoted from other documents are identified in brackets at the end of the definition. Active Pharmaceutical Ingredient (ingrédient pharmaceutique actif) - Any substance or mixture of substances that is intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body. (ICH, Q7A, step 5) Airlock (sas) - An enclosed space with two or more doors, that is interposed between two or more rooms, usually of differing classes of cleanliness, for the purpose of controlling the airflow between those rooms when either people or goods need to enter or leave them. Aseptic Area (aire aseptique) - A zone or zones within a clean area where Grade A or B (see table in Section C of these guidelines) conditions are maintained. Aseptic Process (procédé aseptique) - A method of producing a sterile product in which sterile bulk drug or sterile raw materials are compounded and assembled with sterile packaging components under Grade A or B conditions (see table in Section C of these guidelines). Batch (lot de fabrication) - A quantity of drug in dosage form, a raw material, or a packaging material, homogeneous within specified limits, produced according to a single production order and as attested by the signatories to the order. In the case of continuous manufacture, a batch corresponds to a defined fraction of the production, that is characterized by its intended homogeneity. 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. Batch Certificate (certificat de lot) - A certificate issued by the fabricator of a lot or batch of a drug that is exported within the framework of a mutual recognition agreement and in which the fabricator identifies the master production document for the drug and certifies that the lot or batch has been fabricated, packaged/labelled and tested in accordance with the procedures described in that document; provides a detailed description of the drug, including a statement of all properties and qualities of the drug, including the identity, potency and purity of the drug, and a statement of tolerances for the properties and qualities of the drug; identifies the analytical methods used in testing the lot or batch and provides details of the analytical results obtained; sets out the addresses of the buildings at which the lot or batch was fabricated, packaged/labelled and tested; and certifies that the lot or batch was fabricated, packaged/labelled and tested in accordance with the good manufacturing practices of the regulatory authority that has recognized those buildings as meeting its good manufacturing practices standard. (C.01A.001) BATCH NUMBER (numéro de lot de fabrication) - A distinctive combination of numbers and/or letters that specifically identifies a batch. The batch number appears on the batch records, certificates of analysis, etc. Bracketing (méthode des extrêmes) - The design of a stability schedule such that only samples on the extremes of certain design factors (e.g., strength, package size) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested. Where a range of strengths is to be tested, bracketing is applicable if the strengths are identical or very closely related in composition (e.g., for a tablet range made with different compression weights of a similar basic granulation, or a capsule range made by filling different plug fill weights of the same basic composition into different sized capsule shells). Bracketing can be applied to different container sizes or to different fills in the same container closure system. (ICH, Q1A(R)) Bulk Drug (drogue en vrac) - Unpackaged dosage form, usually in quantities larger than the largest commercially available package size. Certificate of Manufacture (certificat de fabrication) - A document issued by a vendor to a distributor or importer that attests that a specific lot or batch of drug has been produced in accordance with its master production document. Such certificates include a detailed summary of current batch documentation, with reference to respective dates of revision, manufacture, and packaging, and are signed and dated by the vendor's quality control department. Change Control (contrôle des changements) - A written procedure that describes the action to be taken if a change is proposed (a) to facilities, materials, equipment, and/or processes used in the fabrication, packaging, and testing of drugs, or (b) that may affect the operation of the quality or support system. Changeover Procedure (procédure de conversion) - A logical series of validated steps that ensures the proper cleaning of suites and equipment before the processing of a different product begins. Clean Area (aire propre) - A room or suite of rooms where Grade C or D conditions (see table in Section C of these guidelines) are required. The rooms have a defined environmental control of particulate and microbial contamination and are constructed, maintained, and used in such a way as to minimize the introduction, generation, and retention of contaminants. Critical Process (procédé critique) - A process that may cause significant variation in the quality of the finished product. Date of Fabrication (date de fabrication) - Unless otherwise defined in the Food and Drug Regulations, this is the date when any active ingredient, anti-oxidant, preservative, or air/oxygen scavenger is first added to the lot being processed. Director (directeur) - The Assistant Deputy Minister, Health Products and Food Branch, of the Department of Health. (A ) Distributor (distributeur) - A person, including an association or partnership, who under their own name, or under a trade, design or word mark, trade name or other name, word, or mark controlled by them, sells a food or drug. (A ) Divisions 1A and 2 to 4 apply to the following distributors (C.01A.003): a distributor of a drug listed in Schedule C or D to the Act or in Schedule F to these Regulations, a controlled drug as defined in subsection G (1) or a narcotic as defined in the Narcotic Control Regulations who does not hold the drug identification number for the drug or narcotic; and a distributor of a drug for which that distributor holds the drug identification number. Dosage Form (forme posologique) - A drug product that has been processed to the point where it is now in a form in which it may be administered in individual doses. Drug (drogue) - Any substance or mixture of substances manufactured, sold, or represented for use in (a) the diagnosis, treatment, mitigation, or prevention of a disease, a disorder, an abnormal physical state, or the symptoms thereof, in humans or animals, (b) restoring, correcting, or modifying organic functions in humans or animals, or ©) "disinfection" in premises in which food is manufactured, prepared, or kept. (Section 2 of the Act) In Division 1A and Division 2 of the Food and Drug Regulations, "drug" means a drug in dosage form, or a drug that is a bulk process intermediate that can be used in the preparation of a drug listed in Schedule C to the Act or in Schedule D to the Act that is of biological origin. It does not include a dilute drug premix, a medicated feed as defined in Section 2 of the Feeds Regulations, 1983, a drug that is used only for the purposes of an experimental study in accordance with a certificate issued under Section C or a drug listed in Schedule H to the Act. (C.01A.001(2)) Fabricate (manufacturer) - To prepare and preserve a drug for the purpose of sale. (C.01A.001) Fabricator's Batch Certificate (Certificat de fabrication d'un lot) - A certificate delivered under the scope of a mutual recognition agreement for a lot or batch of a drug. (The certificate's content is described in Annex A). Please refer to regulation C.01A.001 (1) for a complete definition of "batch certificate". Filling (remplissage) - Transferring a bulk drug into its final container and enclosing it in the container. Finished Product (produit fini) - A product that has undergone all stages of production, including packaging in its final container and labelling. Formulating (transformation) - Preparing components and combining raw materials into a bulk drug. For sterile products, this includes such steps as cleaning, rinsing, sterilizing, aerating, flushing, and filtering. Group 2 Products (produits du groupe 2) - Drugs listed in Schedule D to the Act and subject to Health Canada's lot release programme which require the highest level assessment after the notice of compliance (NOC) has been issued. This assessment includes targeted testing, protocol review, and written approval for sale of each lot in Canada in the form of a release letter. Importer (importateur) - A person who imports into Canada a drug for the purpose of sale. In-Process Control (contrôle en cours de fabrication) - Checks performed during production in order to monitor and, if necessary, to adjust the process to ensure that the finished product conforms to its specifications. The control of the production environment or equipment may also be regarded as a part of in-process control. In-Process Drug (drogue semi-finie) - Any material or mixture of materials that must, to become a drug in dosage form, undergo further processing. In-Process Testing (analyse en cours de fabrication) - The examination or testing of any material or mixture of materials during the manufacturing process. Installation Qualification (qualification d'installation) - The documented act of demonstrating that process equipment and ancillary systems are appropriately selected and correctly installed. Label (étiquette) - Any legend, word, or mark attached to, included in, belonging to, or accompanying any food, drug, cosmetic, device, or package. (Section 2 of the Act) Long Term Testing (analyses à long terme) - Stability studies under the recommended storage condition, for the re-test period or shelf life proposed (or approved) for labelling. (ICH, Q1A(R)) Lot (lot) - A quantity of any drug in dosage form, a raw material, or a packaging material, homogeneous within specified limits, constituting all or part of a single batch and identified by a distinctive lot number that appears on the label of the finished product. Lot Failure (lot défectueux) - A lot or batch that has been rejected due to failure to meet in process or final product release specifications. Lot Number (numéro de lot) - Any combination of letters, figures, or both, by which any food or drug can be traced in manufacture and identified in distribution. (A ) Manufacturing Batch Document (fiche de lot de fabrication) - Instructions that outline in detail the materials and procedures required to fabricate, prepare, and preserve a single lot or batch of a drug in dosage form. Marketing Authorization (autorisation de mise en marché) - A legal document issued by Health Canada, authorizing the sale of a drug product in Canada; it includes a Notice of Compliance (NOC) or a Drug Identification Number (DIN). Mass Balance (somme des masses) - The process of adding together the assay value and levels of degradation products to see how closely these add up to 100% of the initial value, with due consideration of the margin of analytical error. (ICH, Q1A(R)) Master Formula (formule-type) - A document or set of documents specifying the raw materials with their quantities and the packaging materials, together with a detailed 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. Master Production Document (document-type de production) - a document that includes specifications for raw material, for packaging material and for packaged dosage form, master formula, sampling procedures, and critical processing related SOPs, whether or not these SOPs are specifically referenced in the master formula. Matrixing (méthode de la matrice) - The design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations is tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations is tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same container closure system, and possibly in some cases, different container closure systems. (ICH, Q1A(R)) MRA Country (pays participant) - A country that is a participant in a mutual recognition agreement with Canada.(C.01A.001) Mutual Recognition Agreement (accord de reconnaissance mutuelle) - An international agreement that provides for the mutual recognition of compliance certification for Good Manufacturing Practices for drugs. (C.01A.001) Operational Qualification (qualification opérationelle) - The documented action of demonstrating that process equipment and ancillary systems work correctly and operate consistently in accordance with established specifications. Package/Label (emballer/étiqueter) - To put a drug in its immediate container or to affix the inner or outer label to the drug. (C.01A.001) Packaging (emballage) - Operations required to package and label a single lot or batch of a drug in dosage form. Packaging Material (matériel d'emballage) - Labels, printed packaging materials and those components in direct contact with the dosage form. (refer to C ) Packaging Batch Document (fiche d'emballage de lot de fabrication) - Instructions that outline in detail the materials and special procedures required to package and label a single lot or batch of a drug in dosage form. Parenteral Use (usage parentéral) - Administration of a drug by means of hypodermic syringe, needle or other instrument through or into the skin or mucous membrane. (C ) Pharmaceutical (produit pharmaceutique) - A drug other than a drug listed in Schedule C or D to the Act. (C.01A.001) Potency (teneur) - The activity or amount of active moiety, or any form thereof, indicated by l abel claim to be present. Process Qualification (qualification de procédé) - The phase of validation dealing with sampling and testing at various stages of the manufacturing process to ensure that product specifications are met. Production (production) - All operations involved in the preparation of a finished product, from receipt of materials, through processing and packaging, to completion of the finished product, including storage. Purified Water (eau purifiée) - As defined in any standard listed in Schedule B to the Food and Drugs Act. Purity (pureté) - The extent to which a raw material or a drug in dosage form is free from undesirable or adulterating chemical, biological, or physical entities as defined by specification. Qualified Personnel (personnel qualifié) - Individuals who have the appropriate education, training and experience to perform their duties. Qualified Authority (autorité qualifiée) - An authority member of the Pharmaceutical Inspection Cooperation/Scheme (PIC/S) or the United States Food and Drug Administration (USFDA). Quality Control Department (service du contrôle de la qualité) - A separate and distinct operation, maintained by a manufacturer or an importer, that is responsible only to management, and that monitors the quality of production operations and exercises control over the quality of materials required for and resulting from those operations. Quarantine (quarantaine) - Effective restriction of the availability of material or product for use (physically or by system), until released by the quality control department. Raw Material (matière première) - Any substance, other than in-process drug or packaging material, intended to be used in the manufacture of drugs, including those that appear in the master formula but that do not appear in the drug such as solvents and processing aids. Recognized Building (bâtiment reconnu) - In respect of the fabrication, packaging/labelling or testing of a drug, a building that a regulatory authority that is designated under subsection C.01A.019(1) in respect of that activity has recognized as meeting its Good Manufacturing Practices standards in respect of that activity for that drug.(C.01A.001) Reconciliation (bilan comparatif) - A comparison, making due allowance for normal variation, between the amount of product or materials theoretically produced or used and the amount actually produced or used. Recovery (récupération) - The introduction of all or part of previous batches of the required quality into another batch at a defined stage of manufacture. Regulatory Authority (autorité réglementaire) - A government agency or other entity in an MRA country that has a legal right to control the use or sale of drugs within that country and that may take enforcement action to ensure that drugs marketed within its jurisdiction comply with legal requirements. Reprocessing (retraitement) - Subjecting all or part of a batch or lot of an in-process drug, a bulk process intermediate (final biological bulk intermediate) or a bulk drug 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 and are validated and pre-approved by the quality control department or as part of the marketing authorization. Re-Test Date (date de ré-analyse) - The date when samples of a drug substance are re-examined to ensure that the material is still suitable for use. Re-Test Period (période de ré-analyse) - The period of time during which a drug substance can be considered to remain within the specifications and therefore acceptable for use in the fabrication of a given drug product, provided that it has been stored under defined conditions; after this period, the batch is re-tested for compliance with specifications and then used immediately. (ICH, Q1A(R)) Returned Product (produit retourné) - Bulk drug or finished product sent back to the manufacturer or importer. Reworking (reprise) - Subjecting an in-process drug, a bulk process intermediate (final biological bulk intermediate), or final product of a single batch/lot 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. (WHO GMP) Self-Contained Facility - (installation confinée) - means premises that provide complete and total separation of all aspects of the operation, including personnel and equipment movement, with well established procedures, controls and monitoring. This includes physical barriers as well as separate air handling systems. Self-contained facilities does not necessarily imply two distinct and separate buildings. Sell (vendre) - Offer for sale, expose for sale, have in possession for sale, and distribute, regardless of whether the distribution is made for consideration. (Section 2 of the Act) Shelf Life / Expiration Dating Period - (durée de conservation/période de péremption) - The time interval during which a drug product is expected to remain within the approved specification provided that it is stored under the conditions defined on the label and in the proposed containers and closure. Standard Operating Procedure (SOP) - (procédure opératoire normalisée) - A written procedure giving instructions for performing operations not necessarily specific to a given product or material but of a more general nature (e.g., equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific master and batch production documents. Sterile (stérile) - Free from viable microorganisms. System (système) - A regulated pattern of interacting activities and techniques that are united to form an organized whole. Terminal Sterilization (stérilisation en phase terminale) - Sterilizing a drug in its final closed container. Validation (validation) - The documented act of demonstrating that any procedure, process, and activity will consistently lead to the expected results. Includes the qualification of systems and equipment. Vendor (vendeur) - The fabricator of the item. Wholesale (vendre en gros) - To sell any of the following drugs, other than at retail sale, where the seller's name does not appear on the label of the drugs: a drug listed in Schedule C or D to the Act or in Schedule F to these Regulations or a controlled drug as defined in subsection G (1); or a narcotic as defined in the Narcotic Control Regulations. (C.01A.001) GMP ORIENTATION SESSION

4/11/2017 4. Premises C The premises in which a lot or batch of a drug is fabricated or packaged/labelled shall be designed, constructed and maintained in a manner that; Permits the operations therein to be performed under clean, sanitary and orderly conditions; Permits the effective cleaning of all surfaces therein; Prevents the contamination of the drug and the addition of extraneous material to the drug. The pharmaceutical establishment should be designed and constructed in a manner such that it permits cleanliness and orderliness while preventing contamination. Regular maintenance is required to prevent deterioration of the premises. The ultimate objective of all endeavours is product quality. The land and buildings where the manufacturing operations are located must contribute towards the quality of the products. They do this by avoiding the risks of contamination, permitting effective cleaning and maintenance, minimizing the build-up of dirt and dust and preventing quality defects. The geography of the chosen location can have a considerable impact upon the design of facilities. Is the location subject to earthquake hazards? Does it experience flooding regularly – during the monsoon season for example? What precautions need to be taken regarding continuity of supply of services? The climate of the area is also important. If the company will be handling, for example, gelatin capsules then humidity is of great concern. If the company has a lot of goods requiring temperature or humidity controls in transport, and the goods have to sit on the dockside for weeks waiting for a boat to arrive, there may be a problem with the quality of the products. The company may need to rent temperature-controlled storage. If it does, how will it check the quality of that storage? The factory may have to seek some expensive design solutions to overcome the problems that arise. Does the process make a lot of noise, for example? If it does and the location is close to neighbours, then the company may be forced into expensive soundproofing. The neighbourhood is also important. If the company is to be located next to a steel mill then the design precautions that it will have to take, and the level of maintenance that it will have to undertake, will be very different than if it is in a rural setting. If the neighbours change, the company will need to take appropriate measures to handle the situation correctly. The company is also required to take measures that prevent the factory polluting the surrounding area with product or by-products from its manufacturing processes. A site inspection is useful before building commences to ensure that the area is suitable for the construction of a pharmaceutical factory. The design should make sanitation easier. Here we are looking for surfaces that will be resistant to the cleaning methods and materials that are going to be used. We are also looking for designs of surfaces to ensure easy cleaning. This means paying attention to the joints of all surfaces, the detailed designs of windows and the way that they fit into the frames. Are ceiling and wall joints coved in to provide a smooth surface between the two flat surfaces? Premises have to be carefully maintained so that they continue to provide the environment that they were designed for. Many designs now provide for a service corridor at the rear or side of every manufacturing area. Wherever possible, all equipment, particularly moving and maintainable parts, should be located against this service corridor. This enables the mechanics to undertake their maintenance without entering the manufacturing area. This reduces the threat to product quality from maintenance to an absolute minimum. All maintenance should be carried out using a planned maintenance programme. All cleaning and disinfection of areas should be undertaken in accordance with a written procedure. All such procedures should be designed and operated to ensure that cross-contamination and contamination are eliminated. The area is then of the required cleanliness standard for the production being undertaken. The company must be able to maintain the services for factory operation at the level of quality required for production. If a sterile area is to be operated in a location, where the electricity supply is very unreliable, then the permanent use of an auxiliary generator may be essential. Lighting, temperature, humidity and ventilation control systems should all be designed and operated to ensure that product quality is safeguarded. These systems can affect product quality not only during manufacture but also during storage and packaging too. Poor quality electrical supply can also affect the ability of equipment to operate. Quality control is reliant on a good electricity supply in order to perform a variety of tests and obtain reliable results. Water treatment plants need to be given special attention. Poor quality water can cause many manufacturing problems, including the obvious microbiological problems associated with biofilm formation. Finally, the premises need to be designed and operated to prevent the ingress of insects and animals. Rest and refreshment rooms will be required for the staff. These must be located apart from all other areas involved in manufacturing, packaging, storage or quality control. The type of activity going on will determine the degree of segregation. If all that is to be allowed is consumption of drinks then a separate room will probably be enough. If smoking and eating is to be allowed then the segregation will need to be much more extensive. The smells of cooking and smoking must be kept away from the products. This will require special ventilation systems for the kitchens and the cafeteria. Facilities must be provided for operators and all visitors to change their clothes and footwear. Storage will be needed for outdoor clothing and a system provided to assist correct entry to the manufacturing areas. Many companies are now designing the entry to manufacturing areas as a one-way system with double-sided lockers. This means that all personnel entering a manufacturing area must pass through the change procedure in one direction. People exit the factory and gain access to their outdoor clothes from the other side of the locker. This prevents any possibility of cross-contamination. Toilet and other wash facilities should not be directly accessible from manufacturing, storage or quality control areas. Hand-washing facilities must be provided and their use encouraged with the provision of toilet paper, soap and towels or other types of hand-drying facilities. Maintenance workshops should be separated from production areas. If tools are to be kept in a manufacturing area, then they should be placed in a container or cupboard specific for that purpose. Animal houses should be isolated from all other areas with separate entry and air-handling facilities to prevent any risk of cross-contamination. So on so forth. GMP ORIENTATION SESSION

4/11/2017 5. Equipment C 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: permits the effective cleaning of its surfaces; prevents the contamination of the drug and the addition of extraneous material to the drug; permits it to function in accordance with its intended use. The equipment used should be located in areas of production or testing in such a way as to support the operators in ensuring that the manufacturing process or testing procedure is followed correctly. The location can prevent omission of steps in the process and avoid possible cross-contamination and mix-ups of products and materials. The design can also assist in easy cleaning and maintenance of equipment. Proper design can prevent operation errors. An example of this is the way in which batch numbers can be changed in the machine. If the labelling machine has a solid block which has to be removed to enable a new batch number to be set up - then physical checks can be done. However, new devices are available that permit changes of batch numbers using a keyboard. In this case there needs to be some form of safeguard to prevent inadvertent batch number changes. Equipment should be constructed of materials that suit the operation and use of the equipment for the range of products manufactured and tested on site. The construction materials should not corrode or deteriorate and thus influence the manufacturing or testing procedure. In cases where manufacturers adapt existing equipment to serve intended needs, inspectors should evaluate that the adaptation will not result in a negative or adverse effect in respect of the quality of the product. Suitable materials should be used when equipment is adapted. Prevention of cross-contamination and error is of great importance to the factory's operations. There must be no possibility of cross-contamination. The layout, design and location of equipment can result in possible cross-contamination of products. Cross-contamination in tablet compression and packaging machines is a common problem area. Most inspectors can give examples of tablets being found in a packaging machine after cleaning. If the design of a tablet inspection belt is such that it is difficult to clean the belt,the risk of tablets remaining in the equipment becomes greater. Inspectors should ask the company questions about the way in which equipment is cleaned to remove all of the materials from the previous batch. Another problem for cross-contamination is a tablet that rolls freely along the floor. Another source of cross-contamination is dust. What happens to the dust created at critical points, such as hopper loading for compressing machines or tablet-counting machines? Are there signs of dust on top of cupboards in the area? Complex-designed equipment could also result in maintenance not being performed as recommended by the supplier of the equipment. Equipment must be maintained to ensure that it performs in the way that it is supposed to. The company should be able to show to you that it has maintenance schedules for major pieces of equipment and that it has people who are capable of maintaining the equipment. Alternatively, it should be able to show that it uses contract maintenance people who understand the equipment, and the use to which it is to be put. You should thus verify whether the company has logbooks in which it records the use of the equipment and when planned preventative maintenance and regular maintenance had been performed. Assess whether there is a programme for maintenance, and whether this programme is followed. The operation of the equipment must not lead to adverse quality problems developing unnoticed. Again, old tablet presses are a common source of problems particularly at start up and shut down. The problem is that as the tablet machine starts to speed up or slow down - the tablet weight changes. It can easily produce out-of-specification tablets during start-up or shut-down. Inspectors can evaluate the company’s action in relation to this problem. Does the company reject first and last tablets from a machine session? What does the company do if tablets are found to be out-of-specification during a periodic check? Does it reject all the tablets made since the last good check? What does the company do if the compressing machine hopper gets low on granules. Another important aspect to inspect is that of transfer of product and materials through pipelines, and services supplied to the factory. It is important that all pipelines are clearly labelled, indicating the contents and the direction of flow. This is important, whether it be pipelines transferring product from storage tanks to the filling line, or whether it be service pipings containing water, compressed air or other materials. Pipe connections should be of the right standard and specification for the material and pipeline to prevent any wrong connections and mix-ups. Some services, particularly compressed gases, have statutory standards of connection. The connectors are thus designed to prevent any connection other than to a pipe containing the same gas. The use of adaptors is not recommended. The quality and quantity of material delivered through pipelines are normally monitored and tested at regular intervals, e.g. the supply of distilled or purified water . Pressure regulators are also often required to meet standards legislated elsewhere. Many processes and items of equipment these days are reliant on the quality of services. If incorrect pressures or incorrect quality standards are available, the factory and equipment may not perform to the validated standard. Product produced in this way could be borderline in quality or, periodically, substandard. The problem is that, in large-volume production, quality control may not identify a problem with parts of the batch because the sample required to be taken is too small. This is particularly true of sterile production. Often balances and other measuring equipment are the simplest and also sadly the most neglected of equipment. If the appropriate balance or measuring equipment is not used then a good quality product will not be produced. This is so fundamental to a successful operation, but how many times have we seen operators struggling with inappropriate or non-functioning measuring equipment? All balances and measuring equipment must be capable of weighing or measuring the materials over the desired range required for production and testing. You should verify what the range of weights are to be weighed in production, and assess whether the balance can in fact weigh the required range of weights. The balances and measuring equipment must further be precise. Proof of the range and accuracy of balances can be evaluated by the inspector as part of the validation report results for balances, which should indicate the results for accuracy, precision, range and linearity. It is important that the appropriate weighing and measuring equipment is available in the relevant areas, including production and quality control laboratories. If equipment is not readily available, the temptation will be for operators to use something that is not suitable - but more convenient. Balances and measuring equipment must be calibrated regularly for its ability to work within the specification. Proper records of calibration, check weighing and use must be maintained. Although calibration is done at regular intervals, check weighing has to be done on a daily basis. The inspector has to check the SOPs and records showing compliance with the procedure. The records should show that the check was done, by whom, and the actual results obtained. Such checks are of crucial importance in the laboratory, in tablet check weighing, and dispensing. They are also critical in any area where materials are weighed. Weighing and measuring equipment must only be used within the limits set for it. These limits may be set within the pharmacopoeia or by the supplier. The company should have SOPs to describe the ranges of acceptability of different weigh scales. Production equipment must be suitably designed for the intended use of the equipment. Manufacturers will experience difficulty in obtaining the consistent results required, when they use equipment for purposes it had not been designed for. An example of this is where manufacturers use a small compressing machine to make tablets larger than the design specification. The machine will perhaps be unable to compress the tablets correctly or it will be unable to supply sufficient granules to each die. Using liquid-filling equipment to fill larger or smaller volumes than specified will lead to inaccurate volumes being dispensed. This applies to quality control equipment as much as it does to production equipment. Quality control equipment must be suitable for the tests to be carried out on it. The equipment must be designed to be cleaned easily even if it is dedicated to one product. This is even more important if the equipment is to be used on a number of different products. This means that the equipment should be easy to take apart. It should have all crevices designed out to enable easy cleaning and make visual inspection simple. If the equipment is used to produce a variety of products, a specific written cleaning procedure will be needed. Separate cleaning procedures may be needed for products requiring different cleaning processes. Inspectors should ensure that the manufacturer has an SOP for cleaning of each major piece of equipment. Verification of compliance with the SOP by reviewing the schedule for cleaning and records of cleaning is very important during the inspection. The manufacturer should have taken the design of the piece of equipment in consideration when the cleaning procedure was designed and validated. Production equipment should be placed or located in such a way that it can be used for the intended purpose. Think of the placement of granulators, ossilators and fluidized bed driers in the manufacture of orals solid dosage forms. Proper maintenance of equipment is important to ensure that the equipment will operate or perform in accordance with its specifications. Equipment must be made of materials that will not react with the product to be made. That often means very high quality stainless steel or other suitable material. The construction materials should not present any hazard to the product being manufactured, it should not react with the materials or product and should not absorb any substance in the product of material being processed. Some materials and products react or are absorbed by plastic, and some plastic contains plastisizers that may leach into products. Therefor, it also means that the product should not absorb anything from the equipment nor reacts with it. A frequent source of black spots in and on tablets is excessive lubrication of punches and dies on tablet compressing machines or insufficient lubrication. Grey contamination of creams or ointments can come from bearings or plastic scraper blades incorrectly adjusted. The equipment must be correctly labelled at all times. This is to show whether it is clean or dirty, and ready for use with the next batch or a new product. When a piece of equipment becomes defective for any reason, then it must be removed from the area or clearly labelled (status label). This is to prevent it from being used when it is no longer capable of producing a good quality product. Where a piece of equipment is installed in a line of equipment and it is defective, then its connection with other machines in the line should be interrupted. If this is not done, it may be possible that it could be operated inadvertently. Accurate results for materials and products tested are of vital importance in a quality control environment. To ensure this, all equipment and instruments used for quality control testing must be suitable for the tests to be performed. When a testing instrument or piece of equipment becomes defective in the laboratory, then the accuracy of results can not be guaranteed. Defective instruments and equipment should be removed from the area or clearly labelled (status label). This is to prevent analysts from using equipment for testing when the equipment should no longer be used. All equipment should be cleaned from time to time, even if it is dedicated to one product. The cleaning method should be validated so that it will routinely achieve the desired result. As discussed earlier, it should be designed to permit effective cleaning. During inspections, you should verify that cleaning is done as required in terms of the SOP for cleaning (especially the frequency of cleaning, between batches of the same product, between different products being manufactured on the same piece of equipment, as well as the records or logs maintained for the cleaning). The method chosen for cleaning must not be the source or cause of contamination. The location, layout and design of the wash area for equipment must be evaluated. In some companies, equipment is transported to a cleaning area equipped with all the services required for effective cleaning. In this case, inspectors should check the route that the equipment follows to get to the cleaning area. Assess what precautions are taken by the manufacturer to prevent cross-contamination on the way. In others, the equipment is cleaned where it is located. In this case, what precautions are taken to prevent cross-contamination during cleaning? Inspectors should also investigate where and how equipment is stored after cleaning to prevent contamination of clean equipment while other pieces are being cleaned. The manner of drying of equipment after cleaning, can also be a source of contamination. Another problem associated with cleaning, could be the use of compressed air and the use of brushes and brooms. The company’s attitude towards the use of compressed air and brushes for cleaning is a useful pointer. The use of compressed air is common for moving dust and dirt from inaccessible places on machines. Unfortunately it can then settle in an uncontrolled way on all the equipment and processes in the vicinity. The same is true of the use of brushes and brooms for cleaning. The methods chosen should be easy for all operators to use and should be designed for use with the particular piece of equipment concerned. They should be validated for effectiveness and described in written procedures. Validated and checked written cleaning procedures are essential. There may be considerable advantages in involving the operators in the preparations of these procedures. This is to ensure that, at all stages, they are practical and include all the steps required for ensuring that cleaning has been correctly completed. The procedures should be readily available, and the cleaning materials used must not damage the equipment. When vacuum cleaners are used, inspectors should check to ensure that they are working properly, and that the dust collection device is working effectively. Vacuum cleaners should not be the cause of cross-contamination. GMP ORIENTATION SESSION

4/11/2017 6. Personnel C 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. People are the most important element in any pharmaceutical operation, without the proper personnel with the right attitude and the right 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 vigilance, 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. The personnel is the most important asset of a company, and the easiest to neglect. The establishment and maintenance of a satisfactory system of quality assurance and GMP relies upon people who develop the system, the people who use the system and the people who examine the system to see if it has worked. People are involved, no matter how automated the process or how capital intensive the operation. The behaviour of the people is fundamental to any system of GMP. Personnel policies must reflect this. In our first group session we will be looking at those policies that encourage compliance with GMP. Sufficient number of staff must be available to carry out the work for which the manufacturer is responsible. These people must have the level of training and experience that will enable them to do their work. The staff must have written job descriptions to ensure that they understand clearly what it is that they have to do, and what they are responsible for. Finally these staff must have a knowledge and understanding of GMP to enable them to carry out their duties in accordance with GMP. Staff must have a clear job description which tells them and the rest of the company what their role is, what their responsibilities are and what authority they have to carry out their tasks. The company should also have a written organization chart. The combination of organization chart and written job descriptions enables the company to see quickly whether there are any gaps or whether there are any areas of overlap, owing to too many people being involved. The organisation chart should make clear and ensure the independence of QA/QC from production. Personnel involved in QA/QC must have the authority to carry out their responsibilities. This is very easy to say and sometimes not so easy to ensure. Problems can emerge in every size of company, from small private companies to very large multinational enterprises. They arise because of a combination of human interactions, and the pressures placed on people by the business considerations. All personnel involved with materials and products should receive GMP training. This training should commence upon recruitment and continue throughout employment. The training should be appropriate to their needs and position within the company, and should include training in hygiene standards. Personnel policies should be designed to encourage people to support the development and maintenance of high quality standards in all work performed. The company should prevent people who have not been properly trained from entering any production, storage or quality control area without strict supervision. For example: it should not be the case that people from accounts are allowed to walk through the factory to get to the warehouse to pick up or deliver invoices. Access to all other areas of the company should be organized so that no entry to production, storage or laboratory areas is necessary (see Premises). GMP ORIENTATION SESSION

4/11/2017 7. Sanitation & Hygiene C & C C 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: 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 instructions on the sanitary fabrication and packaging/labelling of drugs and the handling of materials used in the fabrication and packaging/labelling of drugs. Sanitation in a pharmaceutical plant influences the quality of drug products as well as employee attitude. 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 Food and Drugs Act are satisfied. GMP ORIENTATION SESSION

4/11/2017 7. Sanitation & Hygiene C & C C 1. Every person who fabricates or packages/labels a drug shall have in writing, minimum requirements for the health and the hygienic behaviour and clothing of personnel to ensure the clean and sanitary fabrication and packaging/labelling of the drug. 2. No person shall have access to any area where a drug is exposed during its fabrication or packaging/labelling if the person is affected with or is a carrier of a disease in a communicable form, or has an open lesion on any exposed surface of the body Employee's health, behaviour, and clothing may contribute to the contamination of the product. Poor personal hygiene will nullify the best sanitation program and greatly increase the risk of product contamination. GMP ORIENTATION SESSION

4/11/2017 8. Material Testing 1. Raw Material Testing – C to C 2. Packaging Material Testing – C to C 3. Finished Product Testing – C to C GMP ORIENTATION SESSION

4/11/2017 8. Material Testing Material Testing – C , 010, 016, 017, 018 & 019 Lot-to-lot Testing No release of material without proper testing and compliance. Water may, prior to the completion of tests be used in the production of the drug Proper documentation C Each lot or batch of raw material shall be tested against the specifications for the raw material prior to its use in the production of a drug. No lot or batch of raw material shall be used in the production of a drug unless that lot or batch of raw material complies with the specifications for that raw material. Notwithstanding subsection (1), water may, prior to the completion of its tests under that subsection, be used in the production of a drug. Where any property of a raw material is subject to change on storage, no lot or batch of that raw material shall be used in the production of a drug after its storage unless the raw material is retested after an appropriate interval and complies with its specifications for that property. Where the specifications referred to in subsections (1), (2) and (4) are not prescribed, they shall be in writing; be acceptable to the Director, who shall take into account the specifications contained in any publication mentioned in Schedule B to the Act; and be approved by the person in charge of the quality control department. In raw material testing mainly it involves the identity tests etc. The main objective of a pharmaceutical factory is to produce finished products from a combination of materials. The way in which the factory is organised to look after all the materials is therefore of vital importance to the quality of the finished product. Special attention must be given to the requirements and guidelines regarding GMP for materials, all stages of production and quality control testing. It includes: Specifying the materials (specifications) Purchasing materials Receiving materials Storing materials Dispensing Using materials for production Storing the finished product Distributing the finished product Dealing with all the reagents and standards used in testing Dealing with the waste materials that arise from the processes. Non-compliance with GMP guidelines could result in manufacturing products not containing the right materials, or the right quality of materials. This is turn can result in products being rejected or recalled from the market. In general, all incoming materials and finished products should be quarantined immediately after receipt for processing, until they are released for use or for distribution. The manufacturer of starting materials normally specifies the storage conditions for raw materials. The manufacturer of the finished product must be aware of the storage conditions for the materials used in the factory, and must ensure that the materials are stored under appropriate conditions. Inspectors should check that the storage areas are maintained at the correct temperature and relative humidity specifications. The conditions should thus be controlled, monitored and recorded. Review the SOP and records for these parameters and ensure that the materials are stored in the correct environment by verifying the label information and environment control records All containers of materials should be stored in an orderly way to prevent cross-contamination and mix-ups. Segregation between products is necessary to prevent possible cross-contamination. Segregation of different batches of the same product is also recommended to promote stock rotation. Ensure that the manufacturer also has a system of controlling stock. Different systems exist for materials management, including a bin card system and bin locations, and computerized stock control. It is important to look at the process of issuing of material as well as the return of unused material back to the store. During the inspection, also ensure that materials that have the shortest expiry date, are used first (First-in-first-out (FIFO) or EEFO (Earliest Expiry, First Out). The purchasing of starting or raw materials is an important activity of the manufacturer. It is not considered as merely an administrative activity. The inspector should ensure that the staff that are responsible for purchasing of materials, have sufficient knowledge of the materials, products and suppliers of the materials. During your inspection, you should also verify that the materials are only bought from the specified suppliers. This is normally specified in the registration dossiers, or approved suppliers list, or specification of the material. To ensure that the correct materials are supplied, manufacturers are advised to rather purchase materials direct from the manufacturer of the material, and, where possible, not from an agent or broker. It is advisable that the manufacturer discusses the specification for the raw materials with the manufacturer. This could ensure that the correct quality of material is supplied to the manufacturer of the finished products. All aspects relating to the production and control of the starting material, including the handling, labelling and packaging requirements can be agreed upon. Aspects relating to complaints and rejection procedures can also be discussed. During your inspection, you will assess how the manufacturer receives materials from the suppliers. The procedure followed (check written SOP against actual procedure), should include checking the consignment for integrity of the containers or package, that the seals are intact, and that the information on the order, delivery note and label on the containers correspond with each other. All containers should be cleaned when necessary before these are taken into the premises, and should be properly labelled with relevant information (e.g. status, name of the material, reference code etc). GMP ORIENTATION SESSION

22 9. Manufacturing Control
GMP ORIENTATION 4/11/2017 9. Manufacturing Control Manufacturing control – C to C C Every fabricator, packager/labeller, distributor referred to in paragraph C.01A.003(b) and importer of a drug shall have written procedures, prepared by qualified personnel, in respect of the drug to ensure that the drug meets the specifications for use of that drug. Every person required to have written procedures referred to in subsection (1) shall ensure that each lot or batch of the drug is fabricated, packaged/labelled and tested in compliance with those procedures. This Regulation requires that a number of measures be taken to maintain the integrity of a drug product from the moment the various raw materials enter the plant to the time the finished dosage form is released for sale. These measures seek to ensure that all manufacturing processes are clearly defined, systematically reviewed in light of experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their established specifications. GMP ORIENTATION SESSION

23 9. Manufacturing Control
GMP ORIENTATION 4/11/2017 9. Manufacturing Control Manufacturing control – C to C C Every fabricator, packager/labeller or distributor referred to in section C.01A.003, importer, and wholesaler of a drug shall maintain a system of control that permits complete and rapid recall of any lot or batch of the drug that is on the market; and a program of self-inspection. The purpose of a recall is to remove from the market, a drug that represents an undue health risk. Drugs that have left the premises of a fabricator, packager/labeller, distributor, wholesaler and importer can be found in a variety of locations. Depending on the severity of the health risk, it may be necessary to recall a product to one level or another. Fabricators, packagers/labellers, distributors, wholesalers, and importers are expected to be able to recall to the consumer level if necessary. Additional guidance on recalls can be found in the Heath Canada document titled "Product Recall Procedures". This Regulation also requires fabricators, packagers/labellers, distributors, wholesalers, and importers to maintain a program of self-inspection. The purpose of self-inspection is to evaluate the compliance with GMP in all aspects of production and quality control. The self-inspection program is designed to detect any shortcomings in the implementation of GMP and to recommend the necessary corrective actions. Drugs offered for sale in Canada, regardless of whether they are domestically produced or are imported, must meet the requirements of the GMP Division of the Food and Drug Regulations. Contract production and analysis must be correctly defined, agreed on, and controlled in order to avoid misunderstandings that could result in a product or work or analysis of unsatisfactory quality. Normally, a contract or other written agreement exists between the parties involved, and that document clearly establishes the duties of each party. GMP ORIENTATION SESSION

24 9. Manufacturing Control
GMP ORIENTATION 4/11/2017 9. Manufacturing Control Manufacturing control – C to C C Every fabricator and packager/labeller and subject to subsections (3) and (4), every distributor referred to in section C.01A.003(b) and importer of a drug shall maintain a system designed to ensure that any lot or batch of the drug fabricated and packaged/labelled on premises other than their own is fabricated and packaged/labelled in accordance with the requirements of this Division. The distributor referred to in paragraph C.01A.003(b) of a drug that is fabricated, packaged/labelled, and tested in Canada by a person who holds an establishment licence that authorizes those activities is not required to comply with the requirements of subsection (2) in respect of that drug. GMP ORIENTATION SESSION

25 9. Manufacturing Control
GMP ORIENTATION 4/11/2017 9. Manufacturing Control Manufacturing control – C to C C If a drug is fabricated or packaged/labelled in an MRA country at a recognized building, the distributor referred to in paragraph C.01A.003(b) or importer of the drug is not required to comply with the requirements of subsection (2) in respect of that activity for that drug if the address of the building is set out in that person's establishment licence; and b that person retains a copy of the batch certificate for each lot or batch of the drug received by that person. GMP ORIENTATION SESSION

4/11/2017 10. Quality Control Quality control – C to C C Every fabricator, packager/labeller, distributor referred to in paragraph C.01A.003(b) and importer shall have on their premises in Canada a quality control department that is supervised by personnel described in section C The quality control department referred to in subsection (1) shall be a distinct organizational unit that functions and reports to management independently of any other functional units including the manufacturing, processing, packaging or sales unit. Quality control is the part of GMP concerned with sampling, specifications, and testing and with the organization, documentation, and release procedures. This Regulation ensures that the necessary and relevant tests are actually carried out and that raw materials and packaging materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. Quality control is not confined to laboratory operations but must be incorporated into all activities and decisions concerning the quality of the product. Although manufacturing and quality control personnel share the common goal of assuring that high-quality drugs are fabricated, their interests may sometimes conflict in the short run as decisions are made that will affect a company's output. For this reason, an objective and accountable quality control process can be achieved most effectively by establishing an independent quality control department. The independence of quality control from manufacturing is considered fundamental. The rationale for the requirement that the quality control department be supervised by qualified personnel is outlined under Regulation C GMP ORIENTATION SESSION

4/11/2017 10. Quality Control Quality control – C to C C No lot or batch of drug shall be made available for sale unless the sale of that lot or batch is approved by the person in charge of the quality control department. A drug that is returned to the fabricator, packager/labeller, distributor referred to in paragraph C.01A.003(b) or importer thereof shall not be made available for further sale unless the sale of that drug is approved by the person in charge of the quality control department. The responsibility for the approval of all raw materials, packaging materials and finished products is vested in the quality control department. It is very important that adequate controls be exercised by this department in order to guarantee the quality of the end product. To maintain this level of quality, it is also important to examine all returned drugs and to give special attention to reprocessed drugs. GMP ORIENTATION SESSION

4/11/2017 10. Quality Control Quality control – C to C C No lot or batch of raw material or of packaging/labelling material shall be used in the fabrication or packaging/labelling of a drug, unless that material is approved for that use by the person in charge of the quality control department. No lot or batch of a drug shall be reprocessed without the approval of the person in charge of the quality control department. GMP ORIENTATION SESSION

4/11/2017 10. Quality Control Quality control – C to C C All fabrication, packaging/labelling, testing, storage, and transportation methods and procedures that may affect the quality of a drug shall be examined and approved by the person in charge of the quality control department before their implementation. Pharmaceutical processes and products must be designed and developed taking GMP requirements into account. Production procedures and other control operations are independently examined by the quality control department. Proper storage, transportation, and distribution of materials and products minimize any risk to their quality. Complaints may indicate problems related to quality. By tracing their causes, one can determine which corrective measures should be taken to prevent recurrence. Having tests carried out by a competent laboratory provides assurance that test results are genuine and accurate. Written contracts for consultants and contract laboratories describe the education, training, and experience of their personnel and the type of services provided and are available for examination and inspection. Records of the activities contracted are maintained. GMP ORIENTATION SESSION

4/11/2017 10. Quality Control Quality control – C to C C The person in charge of the quality control department shall cause to be investigated every complaint on quality that is received and cause corrective action to be taken where necessary. The person in charge of the quality control department shall cause all tests or examinations required pursuant to this Division to be performed by a competent laboratory. GMP ORIENTATION SESSION

4/11/2017 11. Documentation Documentation – C to C Purpose of Documentation to ensure that there are specifications for all materials and methods of manufacture and control ensure all personnel know what to do and when to do it ensure that authorized persons have all information necessary for release provide audit trail Documentation is an essential part of QA and relates to all aspects of GMP. The pharmaceutical industry must have a good document framework (infrastructure). It is important for a manufacturer to get the documentation right in order to get the product right. There are a number of purposes for documents: They are used to define specifications for materials and for methods of manufacture and control. They ensure that everyone concerned with manufacture and QC knows what to do, how and when to do it. They allow decisions to be taken on batch release. They provide an audit trail, which is particularly important in the case of suspect batches. GMP ORIENTATION SESSION

4/11/2017 12. Samples & Stability Samples – C to C Importance of Samples To ensure that responsible officials at fabricating, distributing, or importing establishments and at Health Centers have ready access to those samples that are essential for re-examination should a product quality concern arise. C Every distributor referred to in paragraph C.01A.003(b) and importer of a drug shall retain in Canada a sample of each lot or batch of the packaged/labelled drug for a period of at least one year after the expiration date on the label of the drug unless otherwise specified in the distributor's or importer's establishment licence. The fabricator shall retain a sample of each lot or batch of raw materials used in the fabrication of a drug for a period of at least two years after the materials were last used in the fabrication of the drug unless otherwise specified in the fabricator's establishment licence. C The samples referred to in section C shall be in an amount that is sufficient to determine whether the drug or raw material complies with the specifications for that drug or raw material. GMP ORIENTATION SESSION

4/11/2017 12. Samples & Stability Stability – C to C Importance of Stability To establish a time period during which drug product in the package in which it is sold comply with the specifications. To monitor by means of a continuing program , the stability of the drug in the package in which it is sold. Tests carried out mainly are: Potency Tests, Physical Characteristics and Purity tests. The purpose of the written stability program is to ascertain the normal shelf life of the products that is to determine how long the products can be expected to remain within specifications under recommended storage conditions. The requirements for the formal stability studies (primary and commitment batches) are outlined in the various Health Canada and ICH Guidelines. Each packaged dosage form must be covered by a sufficient amount of data to support its asserted shelf life in its trade package. The purpose of the written continuing stability program is to monitor the shelf life of the product. It also serves to determine how long the product can be expected to remain within specifications under recommended storage conditions. Each packaged dosage form must be covered by a sufficient amount of data to support its labelled expiry date in its trade package. Any significant change that may have an impact on the quality of the product should be assessed and may require further stability studies. GMP ORIENTATION SESSION

4/11/2017 13. Sterile Production Sterile Production – C To ensure that a drug that is intended to be sterile shall be fabricated and packaged/labelled In separate and enclosed containers Under the supervision of personnel trained in microbiology and By a method scientifically proven to ensure sterility Sterile drugs are susceptible to particulate, pyrogenic and microbiological contamination. Due to the health hazard associated with the use of contaminated sterile products, special precautions are required in the production of these products. The skill, training, and competency of all personnel involved are critical. Quality assurance is important and the production must follow carefully established and validated methods of preparation and sterilization. GMP ORIENTATION SESSION

35 GMP ORIENTATION 4/11/2017 13. Sterile Production Basic Environmental Standards for the Manufacture of Sterile Products at rest (5) in operation Grade Maximum permitted number of particles / m3 equal to or above (3) 0,5 µm 5 µm A (1) 3 500 1 (6) B (2) 2 000 C (2) 20 000 D (2) not defined (4) Unidirectional (laminar) airflow systems provide a homogeneous air speed of 0.45 m/s +/- 20% (guidance value) at the working position. Precise air speeds will depend on the type of equipment. In order to attain air Grades B, C, and D, the number of air changes will be related to the size of the area and to the equipment and personnel present in the area. Low values for contaminants are reliable only when a large number of air samples are taken. The requirement and limits for this area will depend on the nature of the operations carried out. The particulate conditions given in the "at rest" column are to be achieved after a short clean-up period (20 minutes) after the operation has been completed. It is expected to get these areas completely free from particles sized equal or greater than 5 µm. As it is impossible to demonstrate absence of particles with any statistical significance the limits are set to 1 particle / m3. During the qualification of classified rooms it should be shown that the areas could be maintained within the defined limits. GMP ORIENTATION SESSION

36 GMP ORIENTATION 4/11/2017 13. Sterile Production Recommended limits for microbial contamination (a) (e) Grade air sample cfu/m3 settle plates (diameter 90mm), cfu/4 hours (b) contact plates (diameter 55 mm), cfu/plate (c) glove print 5 fingers cfu/glove (d) A < 1 B 10 5 C 100 50 25 - D 200 These are average values. For a Grade A area, no individual result should exceed 3 without investigation. Individual settle plates may be exposed for less than 4 hours. The surface sampled with a contact plate is subject to appropriate cleaning immediately after use. Monitoring is conducted after critical operations are complete. All indicated sampling methods are required unless alternative methods demonstrate equivalency. GMP ORIENTATION SESSION

GMP ORIENTATION 4/11/2017 Warehouse (Raw Material, Packaging Material, Intermediate, Bulk Drug, etc.) C C C PHARMACEUTICAL PRODUCTION PROCESS FLOW-CHART BASED UPON GMP GUIDELINES QC Lab FOR ANALYSIS C C C C C C Yes Quarantine Waiting for QC ANALYSIS FINISHED PRODUCT SHIPPED TO MARKET QC Reject Can be Re-analyzed Return Material to Vendor No QC Pass Samples Retained for Stability Testing C C PRODUCTION C C C , C This is a flow chart for a Pharmaceutical Production Process, based upon the GMP guidelines. Yes Yes QC Testing C C C QC Reject Can be re-processed Send To Scrap No Can be re-processed No QC Pass QC Reject QC Reject Labeling & Packaging C C FINISHED PRODUCT C C QC Pass QC Testing C C QC Pass QC Testing C C Documentation/Records C C GMP ORIENTATION SESSION Ravi K Muddha




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