Basic Principles of GMP

Basic Principles of GMP
World Health Organization Basic Principles of GMP 25 November, 2017 Materials In this module we shall be looking at the GMP guidelines for all aspects relating to the handling and processing and storage of materials. This includes guidance on the purchasing, receiving, storage and distribution of materials, finished product and waste materials. We will be looking at the different types of materials, and materials at different stages in production processes. The programme is as follows: Presentation minutes Group session 60 minutes Plenary session 30 minutes Test minutes All timings are approximate 14

World Health Organization
Materials World Health Organization 25 November, 2017 Objectives To review specific requirements for each type of material: Starting materials Packaging materials Intermediate and bulk products Finished products Rejected and recovered materials Recalled products Returned goods Reagents and culture media Reference standards Waste materials Miscellaneous materials To examine (in groups) the problems associated with materials, and how to overcome them Our main objective in this session is to review with you all the key issues relating to materials mentioned in the WHO GMP text, Part One. First of all, we will be discussing the general principles of GMP for materials. We will then review in turn different materials including: Starting materials Packaging materials Intermediate and bulk products Finished products Rejected and recovered materials Recalled products Returned goods Reagents and culture media Reference standards Waste materials Miscellaneous materials. We will then have a group discussion where we will be looking at specific issues and problems relating to materials, that you may encounter during your inspections.

Materials 25 November, 2017 Principle Objective of the pharmaceutical manufacturer produce finished products for patient's use from a combination of materials Materials combined Active pharmaceutical ingredients and Excipients (auxiliary materials) Packaging materials Materials include also Gases, solvents, reagents, process aids, etc. Special attention 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. 14.1, 14.2

Materials 25 November, 2017 General requirements for materials Materials for cleaning, lubrication, and pest control Not in direct contact with product Suitable grade, e.g. food grade if possible All incoming materials and finished products quarantined after receipt or processing until released for use or distribution stored under appropriate conditions orderly fashion (batch segregation) materials management stock rotation (FEFO) Water – suitable for use 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). 14.3–14.6

Materials 25 November, 2017 Starting Materials – I Purchasing – important operation From approved suppliers – if possible, direct from the manufacturer Specifications for materials Consignment checks Integrity of package Seal intact Corresponds with the purchase order Delivery note Supplier’s labels Cleaned and labelled with information 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). 14.7 – 14.10

Materials 25 November, 2017 Starting Materials – II Different batches in one delivery/consignment Starting materials labelled name and internal code Supplier's batch number(s) and manufacturer's on receipt Status (e.g. quarantine, on test, etc.) expiry date or retest date Role of validated computer systems "Sampled" containers identified Make sure that the manufacturer checks the containers for any damage and possible contamination and cross-contamination. You should also assess how the manufacturer deals with a consignment of material, that is made up of different batches of the same material. It is required that the different batches be considered separate for sampling, testing and release. You should verify this by recording any materials with different batches that had been received in one consignment (by checking the shelf, or the goods received register), and comparing the sampling, testing and release results in the laboratory. Starting materials in the storage area should be properly labelled. The label should bear at least: - the name of the material and an internal reference code - batch number given by the supplier, and manufacturer’s batch or receiving number - the status of the material (e.g. quarantine, released, rejected) - expiry date of the material, or a re-test date. (See also point of the WHO Text, GMP for Active Pharmaceutical Ingredients (bulk drug substances)). Some manufacturers make use of computerized systems. In such cases, the above-mentioned information is not always on the label. However, in such cases, you have to inspect the computer system and ensure that the system has been validated. As the materials normally have to be sampled and tested against the specification, a procedure has to be followed for sampling the material. The containers from which samples were taken, should be identified (e.g. a label). 14.11 – 14.14

World Health Organization 25 November, 2017 There should be appropriate procedures or measures to ensure the identity of the contents of each container of starting material. Bulk containers from which samples have been drawn should be identified. Only starting materials released by the quality control department and within their shelf-life should be used. Sampling tools/equipment/utencils should be used to ensure that representative samples are taken for testing.

World Health Organization 25 November, 2017 Damage to and problems with containers Recorded and reported to QC Investigated Any damage to containers received (that could possibly have an adverse effect on the quality of the material), should be recorded on receipt and reported to the quality control section. It should also be investigated before a decision is made regarding the release or rejection of the material.

Materials World Health Organization 25 November, 2017 Examples of Labelling of Starting Materials This is an example of a status label

Materials 25 November, 2017 Starting Materials – III Use only QC released material if within shelf-life Dispensing designated persons written procedure Correct materials accurately weighed clean, properly labelled containers Independent checks and record material and weight or volume Dispensed material kept together and labelled The quality control department is responsible for sampling, testing, release and rejection of materials. It is important to verify that the manufacturer only uses materials in production that had been released by the quality control section. The materials must also be within their shelf-life. The process of weighing or dispensing materials for production, should be done in accordance with an approved procedure. Only designated persons, who are qualified and trained, should dispense materials for production. Dispensing is a critical stage in the manufacturing process and should be properly controlled. It is important that the correct material, and the correct quantity of material is dispensed (accurately weighed) for the product to be manufactured. As the materials are taken from labelled containers when dispensed, it should be weighed out into clean, labelled containers to ensure that the identification of the material isn’t lost. The label should reflect all the relevant information. There should be a second person who performs an independent check of the dispensing activity, to ensure that correct material and the correct weight (or volume) of the material had been dispensed. This check should be recorded e.g. on the batch manufacturing document or weighing ticket (label). You can evaluate the SOP for dispensing, and assess whether the SOP is complete and will ensure that the dispensing activity complies with GMP requirements to prevent contamination, cross-contamination and mix-ups. Materials dispensed for a particular batch of product, should be kept together (e.g. on a pallet) and properly labeled to identify the product and batch it was weighed out for. 14.15 – 14.18

World Health Organization 25 November, 2017 Discuss dispensing of materials

Materials 25 November, 2017 Packaging materials - I Primary and printed packaging materials purchasing, handling and control as for starting materials Printed packaging materials: particular attention Stored in secure conditions with authorized access Roll labels where possible in place of cut labels Loose materials stored and transported in separate, closed containers - to avoid mix-ups Issued by designated personnel SOP for issue and returns Packaging materials should also be controlled by the manufacturer. Specific attention should be given, and controls exercised for primary packaging materials, and printed packaging materials. The product will come into direct contact with the primary packaging materials. Special care should be given to the quality of these materials such as ampoules, bottles and foil used in blister or strip packing. The prevention of mix-ups of printed packaging materials such as leaflets, labels and cartons is of great importance. The guidelines recommend that the purchase, handling and control of primary and printed packaging materials should be as for starting materials. (There should thus be approved suppliers and specifications for these materials. They should be quarantined on receipt, sampled and tested before release or rejection). The access to printed packaging material should be controlled to prevent any unauthorized access. Cut labels and other loose printed packaging materials should be stored and transported in separate, closed (sealed) containers to prevent possible mix-ups. Only designated personnel should issue printed packaging materials to production. The issue (and return when allowed) of printed packaging materials should be done in accordance with written SOPs. 14.25–14.20

World Health Organization 25 November, 2017 Discuss the: issuing of materials, reconciliation, storage and transport in closed containers to prevent mix-ups

Materials 25 November, 2017 Printed and primary packaging materials - II Each delivery or batch: specific reference number or identification mark Delivery to packaging department Check quantity, identity and conformity to packaging instructions Outdated or obsolete material Destroyed Disposal record It is recommended that manufacturers allocate reference numbers to materials. These reference numbers are unique for each batch or consignment of material and assist in the traceability of material. Personnel in the packaging department should check materials delivered to the department to ensure that the correct quantity of the correct material, complying with the packaging instructions, had been issued. All outdated or obsolete primary packaging material and printed packaging material should be destroyed in accordance with an SOP. The destruction should be recorded. 14.21 – 14.23

World Health Organization Basic Principles of GMP 25 November, 2017 Intermediate and bulk products Kept under appropriate conditions If purchased as such Handled on receipt as though these are starting materials Kept under appropriate conditions If purchased as such: Handled on receipt as though these are starting materials 14.24 – 14.25

World Health Organization Basic Principles of GMP 25 November, 2017 Finished products Held in quarantine until their final release Then stored as usable stock under suitable storage conditions Evaluation and documentation necessary for release Product release procedure Batch record review and related procedure Held in quarantine until their final released Then stored as usable stock under suitable storage conditions Evaluation and documentation necessary for release Product release procedure Batch record review and related procedur 14.26 – 14.27

Materials 25 November, 2017 Rejected, reworked and recovered materials Rejected materials and products Clearly marked Stored separately in restricted areas Action – returned to supplier/destroyed, etc. in timely manner Action approved by authorized personnel – records maintained Rejected materials When materials are rejected, they should be clearly marked as such. Rejected materials should be stored separately and access to the area should be controlled. This is to prevent the accidental use or distribution of rejected materials. Manufacturers can return rejected materials to the suppliers, destroy the materials or reprocess the rejected materials. The action the manufacturer initiates, should however be described and defined in a procedure. The action to be taken should be approved by authorized personnel. The action and approval must be recorded. Reprocessing Reprocessing of rejected materials should only be done in exceptional cases. It should only be allowed if the quality of the product is not negatively affected. The product must still comply with the specifications. During your inspections, you should assess the SOP to ensure that it clearly describes the manufacturer’s policy and procedure for reprocessing, as well as who will be responsible for evaluating the risks that are involved in reprocessing rejected material. Remember, proper and complete records should be maintained for reprocessed materials. A reprocessed batch should be given a new batch number. The manufacturer should also consider additional testing of reprocessed materials, e.g. stability testing of the batch. 14.28

Materials 25 November, 2017 Rejected, reworked and recovered materials Rework and recovery Should be exceptional cases Only if: Risks involved have been evaluated and the quality of final product will not be affected Specifications are met Defined procedure Records maintained New batch number additional testing to be considered by QC Rejected materials When materials are rejected, they should be clearly marked as such. Rejected materials should be stored separately and access to the area should be controlled. This is to prevent the accidental use or distribution of rejected materials. Manufacturers can return rejected materials to the suppliers, destroy the materials or reprocess the rejected materials. The action the manufacturer initiates, should however be described and defined in a procedure. The action to be taken should be approved by authorized personnel. The action and approval must be recorded. Reprocessing Reprocessing of rejected materials should only be done in exceptional cases. It should only be allowed if the quality of the product is not negatively affected. The product must still comply with the specifications. During your inspections, you should assess the SOP to ensure that it clearly describes the manufacturer’s policy and procedure for reprocessing, as well as who will be responsible for evaluating the risks that are involved in reprocessing rejected material. Remember, proper and complete records should be maintained for reprocessed materials. A reprocessed batch should be given a new batch number. The manufacturer should also consider additional testing of reprocessed materials, e.g. stability testing of the batch. 14.29 – 14.30

Materials 25 November, 2017 Recalled products and returned goods Recalled products Identified Stored separately Secure area - access controlled Decision taken on their fate Returned goods Destroyed unless suitable quality SOP: decision regarding their fate (relabelling, resale, etc.) Consider: nature of product, special storage conditions, condition, history, time elapsed since issue Action taken to be recorded Recalled products There may be occasions when a manufacturer has to recall a product or a batch of a product from the market. There could be various reasons for the recall, such as a quality defect. Products that have been recalled from the market, should be identified (labelled). It is recommended that recalled products be stored separately in areas where access is controlled. This is to ensure that recalled products are not issued or sold again by accident. Recalled products should be kept in this controlled area, until a final decision is made by a designated or responsible person regarding the fate of the product. The decision regarding the fate of recalled products should be taken as soon as possible. The process of handling, and storage of recalled products should be in compliance with the company’s standard operating procedure. (See also the module on recalls). Returned goods Products that have left the premises of the manufacturer, can be returned to the manufacturer for various reasons. Products returned to the supplier must be handled in accordance with an SOP. Returned goods should preferably be destroyed. The quality control department can critically assess the product to determine whether the quality of the product is still satisfactory, and recommend that the product be sold again, relabeled or reprocessed. In considering this, the nature of the product must be considered (e.g. dosage form), storage condition requirements (e.g. fridge storage), the condition and history of the product, as well as the time lapse since sale to return to the manufacturer. If the product was supposed to be stored between 2 and 8 degrees Celsius, and it had been in the distribution chain for a long time, the manufacturer could have difficulty in assessing whether the product had not been exposed to conditions that could have adversely affected the product. 14.32 – 14.33

Materials 25 November, 2017 Reagents and culture media Records for receipt or preparation Reagents Preparation in accordance with SOP Appropriately labelled: concentration, standardization factor, shelf-life, date that restandardization is due, storage conditions signed and dated Culture media positive and negative controls each time prepared and used Inoculum size appropriate All reagents and culture media should be recorded upon receipt or preparation. Some manufacturers record the relevant information in registers, others record the information in computer systems. Reagents Written standard operating procedures should be followed for the preparation of reagents, when these are not purchased from suppliers. All reagents and volumetric solutions should be appropriately labelled. Ensure that the labels indicate at least the concentration, the standardization factor, the shelf-life, the due date for re-standardization and the storage conditions of the reagent. It is also necessary to check whether the analyst that prepared the reagent had signed and dated the label. You can use this information to verify who prepared the reagent, and whether the SOP was followed by verifying the calculations in the analyst log book. Culture media Manufacturers have to ensure that the culture media they will use is suitable for the intended use. However, false results indicating micro contamination, are also not desired. Verify whether the manufacturer applies both positive and negative controls on culture media. The size of the inoculum used in positive controls should be appropriate to the sensitivity required. 14.34 – 14.36

Materials 25 November, 2017 Reference standards - I Official reference standards Use preferable whenever these exist Only for the purpose as per monograph Storage conditions Reference standards prepared by the producer Tested, released and stored in the same way as official standards In a secure area A responsible person Secondary or working standards Appropriate checks and tests at regular intervals Standardized against official reference standards – initially and at regular intervals Manufacturers make use of reference standards to test products and materials. An important part of the inspection in the laboratory, will be to assess hoe the laboratory handles, stores and uses reference standards. Manufacturers should make use of reference standards, available as official reference standards. Official reference standards should be used only for the purpose described in the monograph (e.g. pharmacopoeia). Official reference standards should be stored under conditions as specified by the supplier to ensure that the conditions will not adversely affect their quality, resulting in inaccurate or unreliable results. Reference standards prepared by the producer should be tested, released (or rejected) and stored in the same way as official standards. The standards should be stored in a secure area and a responsible person should be designated to control the reference standards. The manufacturer may establish secondary or working standards by applying appropriate checks and tests on materials to be used as reference standards. These tests and checks must be performed on a regular basis to ensure standardization (and suitability of use of the secondary or working standard). All working standards should be based on official reference standards (when available). (The trainer should refer the attendees to Annex 3 of the WHO Technical Report Series, No 885 (fifty-fifth report, published in 2599, regarding “General guidelines for the establishment, maintenance and distribution of chemical reference standards”). 14.37 – 14.40, 14.42

Materials 25 November, 2017 Reference standards - II Reference standards labelled with information including Name Batch, lot or control number Date of preparation Shelf-life Potency Storage conditions Stored and used in an appropriate manner Manufacturers make use of reference standards to test products and materials. An important part of the inspection in the laboratory, will be to assess hoe the laboratory handles, stores and uses reference standards. Manufacturers should make use of reference standards, available as official reference standards. Official reference standards should be used only for the purpose described in the monograph (e.g. pharmacopoeia). Official reference standards should be stored under conditions as specified by the supplier to ensure that the conditions will not adversely affect their quality, resulting in inaccurate or unreliable results. Reference standards prepared by the producer should be tested, released (or rejected) and stored in the same way as official standards. The standards should be stored in a secure area and a responsible person should be designated to control the reference standards. The manufacturer may establish secondary or working standards by applying appropriate checks and tests on materials to be used as reference standards. These tests and checks must be performed on a regular basis to ensure standardization (and suitability of use of the secondary or working standard). All working standards should be based on official reference standards (when available). (The trainer should refer the attendees to Annex 3 of the WHO Technical Report Series, No 885 (fifty-fifth report, published in 2599, regarding “General guidelines for the establishment, maintenance and distribution of chemical reference standards”). 14.41, 14.43

Materials 25 November, 2017 Waste materials proper and safe storage when awaiting disposal toxic substances and flammable materials: in suitably designed, separate, enclosed areas as per national legislation not to be allowed to accumulate collected in suitable containers for removal to collection points safe and sanitary disposal regular and frequent intervals Waste materials In any manufacturing environment, there is a considerable amount of waste materials. This includes waste materials resulting from testing in laboratories. Waste materials can not always be taken away from the premises, or destroyed immediately. The manufacturer should therefor make provision for proper and safe storage of waste material. Some waste can contain toxic substances. Toxic substances and flammable materials should be stored in suitably designed, separate, enclosed cupboards. You should also assess whether these materials are stored in compliance with the legislation where you are inspecting. It is important to make sure that waste materials are not allowed to accumulate. Waste materials should be removed at regular and frequent intervals. You can inspect the receptacles and assess the SOP for storage and disposal of waste to verify whether the manufacturer has policy regarding the removal and safe disposal of waste. Verify whether the manufacturer complies with its own policy and SOP. You should also make sure that the process of disposal is done safely and in a sanitary manner. Miscellaneous There are also several other miscellaneous materials used in the manufacturing site. These include rodenticides, insecticides, fumigating agents, and sanitizing materials. These materials are used for specific purposes and are often toxic or hazardous. Ensure that there is no possibility that these materials can contaminate equipment, starting materials, intermediate or bulk products when these materials are used or stored on the premises. 14.44

Materials 25 November, 2017 Miscellaneous materials Miscellaneous Rodenticides, insecticides, fumigating agents Sanitizing material No contamination risk to equipment, starting materials, packaging materials, in-process materials, finished products Waste materials In any manufacturing environment, there is a considerable amount of waste materials. This includes waste materials resulting from testing in laboratories. Waste materials can not always be taken away from the premises, or destroyed immediately. The manufacturer should therefor make provision for proper and safe storage of waste material. Some waste can contain toxic substances. Toxic substances and flammable materials should be stored in suitably designed, separate, enclosed cupboards. You should also assess whether these materials are stored in compliance with the legislation where you are inspecting. It is important to make sure that waste materials are not allowed to accumulate. Waste materials should be removed at regular and frequent intervals. You can inspect the receptacles and assess the SOP for storage and disposal of waste to verify whether the manufacturer has policy regarding the removal and safe disposal of waste. Verify whether the manufacturer complies with its own policy and SOP. You should also make sure that the process of disposal is done safely and in a sanitary manner. Miscellaneous There are also several other miscellaneous materials used in the manufacturing site. These include rodenticides, insecticides, fumigating agents, and sanitizing materials. These materials are used for specific purposes and are often toxic or hazardous. Ensure that there is no possibility that these materials can contaminate equipment, starting materials, intermediate or bulk products when these materials are used or stored on the premises. 14.45

Materials World Health Organization 25 November, 2017 Group session List specific aspects of GMP requirements, in relation to the groups of materials listed below, that you would assess when inspecting a manufacturer Printed packaging materials Thermolabile materials Water Sterile materials Identify three materials that present problems in your experience What are some of the problems that you have experienced before and during inspection of materials? Possible issues: Printed packaging material: Purchasing, Specifications, Receiving, Sampling, Mix-ups, Batch integrity, Storage and transport, issue and returns to production and stores. Thermolabile materials Purchasing, Specifications, Receiving, Sampling, Storage and transport. Water: Quality of water, types of water. Water purification system (DI, RO, WFI) Sterile materials Purchasing, Specifications, Receiving, Sampling, Prevention of contamination and cross-contamination, Batch integrity, Storage, dispensing, bio-burden control and determination.

Basic Principles of GMP

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