Basic Principles of GMP

Basic Principles of GMP
World Health Organization Basic Principles of GMP 21 April, 2017 Documentation Part 2 This is part 2 of the module on Documentation. 15

World Health Organization
21 April, 2017 Documentation Labels What must be labelled? Containers, equipment, premises Label information? Clear, unambiguous, company format Intermediates and bulk products Colours can be used, e.g. green (accepted), red (rejected) There are different types of documents. Let's look at "labels" as one set of documents. What must be labelled in the factory? (Let the participants name items to be labelled and then expand on why labels are needed, what should be reflected on the labels and so on. These include labels on containers, equipment, rooms (including the product processed, stage of production, cleanliness status, "under maintenance" or "out of order"). The information appearing on labels should be clear, easily readable, and not leave any confusion. Labels should be in the company's format. Often companies prefer to have the name of the company on the label, the use of colour codes for some status, dates, signatures and other relevant information depending on what the label indicates. 15.10

World Health Organization 21 April, 2017 Different types of labels, e.g. cleaning status, production stage, status of materials Other types of labels? Here are some examples of labels used, including the use of colours (see "to be cleaned" in a red colour (warning), opposed to the "cleaned" label (in green).

World Health Organization 21 April, 2017 Labels can indicate the status of materials such as "quarantine" This is an example of a label indicating that the materials are under "quarantine" and cannot be used until released by QC. In addition, a chain is used to prevent access to the material under quarantine.

21 April, 2017 Documentation Finished Product Label National legislation, but includes: Name Active ingredients and amounts Batch number Expiry date Storage conditions, precautions if necessary Directions for use, earnings Name and address of manufacturer Finished products should also be labelled. The information to appear on the label is normally prescribed in the national legislation. Normally, at least the following information should appear on the label: Name Active ingredients and amounts Batch number Expiry date Storage conditions, precautions if necessary Directions for use, earnings Name and address of manufacturer 15.11

21 April, 2017 Documentation Reference standards Label to include: Name Potency or concentration Date of manufacture Expiry date Date the closure is first opened Storage condition Control number Reference materials have very specific use in the quality control laboratory. You should also read the information in the additional guidelines for QC laboratories. Reference materials should be properly labelled to ensure the correct use and use within the prescribed requirements, conditions and date. The container should be labelled with information such as: The Name Potency or concentration Date of manufacture Expiry date Date the closure is first opened Storage condition Control number Other information could also appear on the label to ensure proper use and traceability 15.12

Documentation 21 April, 2017 Specifications Specifications: Authorized, approved, signed and dated Starting materials and packaging materials include tests on identity, content, purity, quality Finished products Intermediates and bulk Water, solvents and reagents QC, QA or documentation centre Besides labels, there are also other types of documents. One specific type of document that is important to ensure quality and compliance with a quality standard, is a "specification". Different materials, components and other items may have specifications that indicate the standard to which it should comply. Think of equipment components such as filter bags, sieves, punches and dies. Materials including starting materials, packaging materials, intermediates and bulk should also have specifications. These materials should eb tested for compliance against the specifications. All specifications should be authorized (that means approved by responsible persons, signed and dated) before use. Specifications are normally prepared and kept, maintained (reviewed and updated) by QC or QA and are stored in the documentation centre. 15.14, 15.15

Documentation 21 April, 2017 Specifications and Test Procedures Test Procedures: Validated (facility and equipment) before routinely used Specifications: Periodic review In compliance with current pharmacopoeia Pharmacopoeia, reference standards and spectra should be available Specifications should be reviewed at regular intervals to ensure that these are current. The company should ensure, that where appropriate, the specifications are in compliance with the recommendations in current or latest pharmacopoeia. Test procedures must be validated or verified for the available facilities before they are used for routine testing. Compendial methods need to be verified. This means that the method is demonstrated to give correct results in the laboratory facilities available. Specifications will include tests for identity, content purity and quality. Specifications should be dated and authorized. The responsibility for their issue and maintenance rests with the QC department. It may be necessary to update the documents occasionally in line with national compendiums or the company's requirements. Written specifications are required for all starting and packaging materials including water in all its various standards. The minimum requirements for these documents are: INN name and internal code reference Reference to pharmacopoeia monograph if appropriate Test parameters and acceptance criteria Other information may include: Details of supply, testing methodology and storage conditions. For packaging materials, there should be reference to compatibility with the drug. For all materials, the frequency of retest should be specified. If intermediates or bulk products are either purchased or dispatched, then they will need a specification. One will also be required if the data obtained from these materials are going to be used in the assessment of the finished product. They will be similar to the specification for the starting material or finished product, as appropriate. For finished products, the specification should include the following information: Name and internal code reference Name of the active ingredients The formula (or a reference to it) Description of dosage form and packaging Sampling and testing methodology Storage conditions Shelf-life. Specifications and test procedures will be used by the QC department and are generally located in the laboratories. 15.13,

Documentation 21 April, 2017 Specifications: Starting and packaging materials Include: Name (e.g. INN) and internal code Pharmacopoeia (if applicable) Qualitative and quantitative requirements and limits Other data may include: Supplier Sampling procedure or reference Storage conditions, precautions Retest date There are specific recommendations in GMP as to what should be included in specifications. In general, the documents should be properly designed to contain the relevant information. Starting and packaging material specifications should include information such as: Name (e.g. INN) and internal code Pharmacopoeia (if applicable) reference Qualitative and quantitative requirements and limits Other data may include: Supplier name and address Sampling procedure or reference e.g. to the SOP Storage conditions, Precautions (e.g. to be observed during storage or sampling) A Re-test date

World Health Organization 21 April, 2017 Can you list which documents are associated with / needed for sampling of starting materials? And for packaging materials? Let the participants list some documents associated with sampling of starting materials. These may include: SOP for sampling Checklist Labels (under test, sample label. "sampled" label). Cleanliness status label of sampling utensils SOP for cleaning etc

Documentation 21 April, 2017 Specifications: Finished products Include: Name and code reference Names of actives (e.g. INN) Formula Dosage form, package details Reference to sampling Qualitative and quantitative requirements and limits Storage conditions and precautions Shelf life Specifications for finished products should include: Name and code reference for the product Names of actives (e.g. INN) Formula Dosage form, package details Reference to sampling Qualitative and quantitative requirements and limits Storage conditions and precautions Shelf life 15.21

Documentation 21 April, 2017 Master Formulae - I Master formula for each product and batch size Manufacturing instructions include: Name of product with product reference code Dosage form, strength and batch size List of starting materials including quantities and unique reference code Expected final yield with acceptable limits (and intermediate yields) Processing location and principal equipment There must be a formally approved master formula for each product that is manufactured, in each batch size. The information that it should contain includes the following: Name of the product with product reference code Dosage form, strength and batch size A full list of materials including quantities and unique reference code for each Expected final yield with acceptable limits (plus intermediate yields) Processing location and principle equipment 15.22 – 15.23

Documentation 21 April, 2017 Master Formulae - II Manufacturing instructions - continued Equipment preparation (e.g. cleaning, assembling, calibrating, etc.) Detailed stepwise processing instructions and checks, pre-treatments, sequence of additions, times, temperatures, etc. In-process control instructions and their limits Storage requirements and special precautions Any special precautions if needed There must be a formally approved master formula for each product that is manufactured, in each batch size. The information that it should contain includes the following: Methodology for equipment preparation (cleaning, calibration, etc......) Stepwise processing instructions (space for operator to sign, check signature, recording of times, quantities, temperatures, etc......) Details of in-process controls with instructions for sampling and acceptance limits Storage requirements and any special precautions. 15.22 – 15.23

Documentation 21 April, 2017 Master Formulae - III Authorized packaging instructions for each product, pack size and type, and to include: Name of the product Dosage form, strength and method of application Pack size (number, weight or volume of product in final container) List of all packaging materials (quantities, size, types and code number) The packaging instruction is the similar to the master formula, but covers packaging rather than manufacturing. There should be one document for each product and pack size. The information that it should contain includes: Name of the product Dosage form, strength and method of administration Pack size (number, weight or volume of product in finished pack) List of all packaging materials (quantities, size and code number). (Continued on next slide) 15.24

Documentation 21 April, 2017 Master Formulae – IV Packing instructions - continued Examples of printed packaging materials, with location of batching information Special precautions, including area clearance checks (before and after operations) Description of the packaging operation including equipment to be used In-process controls, with sampling instructions and acceptance limits The packaging instruction - continued: Examples of printed packaging materials, with location of batching information Special precautions, including area clearance checks Description of the packaging operation In-process control checks, with sampling instructions and acceptance criteria. Both these documents are used as references in the development of processing records. They should be located in development, quality control and production departments. The master formula is frequently used as the master batch-processing document. It is often photocopied to provide the individual batch-processing document. Whatever method is used, it must ensure that there can be no transcription error. The batch-processing document is never a hand-written copy. The same method can be used to prepare the batch packaging document. 15.24

21 April, 2017 This is an example of a batch manufacturing instruction sheet.

Documentation 21 April, 2017 Batch Processing Record – I Record kept for each batch processed Based on the master or specifications (e.g. copied to avoid errors) Before start of process - check suitability of area and equipment clear of previous products, documents, materials Checks recorded A batch processing record is required for each batch of material produced. The review of this document is a critical part of the batch release process. A master document should be prepared for each batch size that will be manufactured. It will be taken from the relevant parts of the master formula as discussed previously. The first step in this document must be the area clearance check. This is a record of the previous product and batch processed in the area and a confirmation that all the material and documentation relating to that batch has been removed. It is also confirmation that all the cleaning has been carried out correctly. This check must always be documented. The batch processing record is both a detailed instruction to the operator of the activities that must be carried out during manufacturing and a record that these activities have been carried out. It should be filled in at the time that processing takes place. Critical activities require a check signature from a second person (either from production or QC as appropriate) to confirm that the information recorded is accurate. 15.25 – 15.26

Documentation 21 April, 2017 Batch Processing Records – II Information recorded during processing include: Name of the product, batch number Dates and times (e.g. start, major steps, completion) Name of person responsible for each stage of production Name of operators carrying out each step (check signatures) Theoretical quantities for materials in the batch Reference number and quantity of materials used in the batch The information required in the batch processing record includes: Name of the product Batch number Dates and times for major steps in the process Name of person responsible for each stage of production Name of operators carrying out each step and check signatures if required Theoretical quantities for materials in the batch Reference number and quantity of materials used in the batch 15.27

Documentation 21 April, 2017 Batch Processing Records – III Information recorded during processing include (cont.): Main processing steps and key equipment In-process controls carried out, person's initials, and results obtained Yield at each stage with comments on deviations Expected final yield with acceptable limits Comments on any deviations from process Area clearance check Instructions to operators A batch processing record (continued): The information required in the batch processing record includes: Main processing steps and key equipment In-process controls carried out, and the results obtained Yield at each stage with comments on deviations Expected final yield with acceptable limits Comments on any deviations from the process Area clearance check, instructions to operators Record of activities Information that does not change, such as the product name, process steps and theoretical quantities of material, can be printed on the master copy. Variables, such as actual quantities of materials used and yields are entered by the operators during the manufacturing process. 15.27

21 April, 2017 Documentation This is an example of a batch record. The elements to look for here are easy reading, by careful setting out blocks of information so that the reader is able to go through the complicated information easily, and a systematic approach to the sequence of information.

Documentation 21 April, 2017 Batch Packaging Records – I For every batch or part of a batch Based on approved packaging instructions Can be copied or computer generated Before start – checks that equipment and work station suitable and clean, no previous product Line clearance (opening) Recorded The batch packaging record is required for every batch or part batch that is packaged. It is developed from the relevant part of the packaging instructions and, once again, its review is an important part of the batch release process. Depending on company practice and the design of the document, it may be specific to a particular batch size or may be used for a variety of sizes. Before the start of the packaging process – checks that equipment and work station are suitable and clean should be provided. It should be checked that there is no previous product that remained on the packaging line. A formal line clearance (opening) should be done in accordance with an SOP and this should be recorded in the BPR or checklist. 15.28, 15.29

Documentation 21 April, 2017 Batch Packaging Records – II Contents: Name of the product, batch number and quantity to be packed Batch number, theoretical quantity and actual quantity of finished product Actual quantity obtained – reconciliation Dates and times of operation Name of person responsible for packaging, initials of operators carrying out each step Checks, and in-process results The batch packaging record. The information required for the completed batch packaging record, once again, consists of a combination of pre-printed material and data that are added by the operators during the process: Name of the product, batch number and quantity to be packed Batch number, theoretical quantity and actual quantity of finished product Reconciliation calculations Dates and times of operation Name of person responsible for packaging Initials of operators carrying out each step Checks made and results obtained 15.30

Documentation 21 April, 2017 Batch Packaging Records – III Contents: Details of packaging operation, including equipment and line used Returns to store Specimen of printed packaging materials, with batch coding approval (batch number and expiry date) Deviations and actions taken; and authorization Reconciliation of packaging materials, including issues, use, returns and destruction The batch packaging record - continued: Details of packaging operation, including equipment and line used Returns to store Specimen of printed packaging materials, with batch coding Comments on deviations from the process and actions taken Reconciliation of packaging materials, including returns and destruction. If returns to the stores are permitted for printed packaging materials, they should first be checked to make sure that they have not been batch coded. A QC signature is required as part of this process, either on leaving the packing hall or on being received in the stores. If excess materials are destroyed, there must be a record of the quantities on the batch documentation. There should also be a procedure covering destruction, including methods and responsibilities. Reconciliation is of vital importance since it helps to confirm that the batch has been processed correctly. Any significant variation in materials should be taken as an indication that there could be a problem. Inspectors should check for investigation of these variations before the batch is signed off. Finally, area clearance checks should show no foreign materials are carried over from one operation to the next. 15.30

21 April, 2017 Documentation Batch packaging document and line clearance Discuss the SOP, checklist, checks for the correct batch number and expiry date, correct printed packaging material, correct primary and secondary packaging material

Documentation 21 April, 2017 Standard Operating Procedures (SOP) - I What is an SOP? Who is responsible for preparing SOPs? What is the format for an SOP? Which activities require SOPs? Where should SOPs be stored? Are SOPs associated with records? Although useful reference documents for inspectors, Standard Operating Procedures (SOPs) are written for the benefit of the persons carrying out the operation in question. They should be written so that the user can easily understand them. If possible, they should be written by or with the operators, to ensure that they accurately reflect what happens in practice. They will be written by the department responsible for carrying them out, but should also be approved by the QA department, if appropriate. Master copies of procedures should be stored by the responsible department or centralized in the document control department. Authorized copies of each procedure should be stored adjacent to the place where the operation will be carried out, as a reference document that can be consulted at will. All critical equipment should have logbooks in which maintenance and cleaning are recorded. A record should also be kept of the use of this equipment. The procedures for sanitation should include methods, equipment, materials, responsibilities and the schedule for carrying them out. 15.31

21 April, 2017 This is an example of an SOP sheet. Elements to look for are the set out (all upper case can be difficult to read), accountability of the document, traceability, purpose, scope and instructions in the imperative.

Documentation 21 April, 2017 Standard Operating Procedures - II Which activities require SOPs? Equipment and analytical apparatus: Assembly, validation Calibration Internal labelling, quarantine and storage of materials Operation Maintenance and cleaning Personnel matters: Qualification Training Clothing Hygiene SOPs are required for a whole range of activities within the facility and may include the following: Receipt of all material deliveries Internal labelling, quarantine and storage of materials Operation, maintenance and cleaning of all instruments and equipment Sampling of materials Batch numbering systems Material testing at all stages of production 15.31

Documentation 21 April, 2017 Standard Operating Procedures - III Which activities require SOPs? Environmental monitoring Pest control Complaints Recalls Returned goods Other SOPs include: Environmental monitoring Pest control Complaints Recalls Returned goods 15.31

Documentation 21 April, 2017 Standard Operating Procedures - IV SOP and records for receiving materials Name of material as on delivery note Name and in-house code Date of receipt Supplier's and manufacturer's name Batch number Quantity and number of containers received State of container and other information The SOP for receiving material is an important SOP. The company should ensure that the correct materials are received from the correct supplier and manufacturer, the correct quantity and other relative quality parameters. The SOP and records for receiving materials should reflect at least: Name of material as on delivery note Name and in-house code Date of receipt Supplier's and manufacturer's name Batch number Quantity and number of containers received State of container and other information 15.33

Documentation 21 April, 2017 Standard Operating Procedures - V Other SOPs include: Internal labelling, quarantine and storage of materials Operation, maintenance, calibration and cleaning of all instruments and equipment – production and QC Sampling of materials Batch numbering systems Material testing at all stages of production Complaints, recalls To ensure that activities are performed in an organized, and consistent manner, procedures can help to ensure that an operation is carried out in a standardized manner. SOPs are used to train people, and if different people follow the same SOP in a consistent manner, then there can be a level of assurance that the process or activity will be done in a standardized manner. Therefore SOPs for most (if not all) activities are recommended. Other SOPs include: Internal labelling, quarantine and storage of materials Operation, maintenance, calibration and cleaning of all instruments and equipment – production and QC Sampling of materials Batch numbering systems Material testing at all stages of production 15.31, 15.32

Documentation 21 April, 2017 Standard Operating Procedures - VI Which activities require SOPs? (Continued) Batch release or rejection Maintenance of distribution records Equipment assembly and validation Maintenance, cleaning and sanitation Personnel recruitment, training, clothing and hygiene Environmental monitoring Pest control …and many more… Batch release or rejection. Maintenance of distribution records Equipment assembly and validation Calibration and operation of analytical apparatus Maintenance, cleaning and sanitation Personnel recruitment, training, clothing and hygiene Environmental monitoring Pest control Additionally, deviation and fault analysis and investigation procedures for out-of-specification results are very significant. For further details on SOP requirements, refer to the WHO GMP text. 15.31

Documentation 21 April, 2017 Standard Operating Procedures - VII SOP for sampling: the method of sampling and the sampling plan equipment to be used precautions to avoid contamination amount(s) of sample(s) to be taken instructions for any required subdivision of the sample type of sample container(s) to be used specific precautions …and many more… Standard Operating Procedures - VII SOP for sampling: the method of sampling and the sampling plan equipment to be used precautions to avoid contamination amount(s) of sample(s) to be taken instructions for any required subdivision of the sample type of sample container(s) to be used specific precautions …and many more… 15.37

Documentation 21 April, 2017 Records What should be recorded? Where should records be stored? Why are the records important?

Documentation 21 April, 2017 Records Different types of records should be kept For defined periods of time Production records and packaging records Quality control records Distribution records Equipment records Records Different types of records should be kept For defined periods of time Production records and packaging records Quality control records Distribution records Equipment records 15.32

Documentation 21 April, 2017 Records Records of receipt of materials Name of material, “In-house” name and/or code of material Date of receipt, supplier’s and manufacturer’s name Batch or reference number, quantity, and number of containers received; Comment (e.g. state of the containers). 15.33 The records of the receipts should include: (a) the name of the material on the delivery note and the containers; (b) the “in-house” name and/or code of material if different from (a); (c) the date of receipt; (d) the supplier’s name and, if possible, manufacturer’s name; (e) the manufacturer’s batch or reference number; (f) the total quantity, and number of containers received; (g) the batch number assigned after receipt; 15.33

Documentation 21 April, 2017 Records Analysis records to include: Name of material / product Batch number Reference to specification and test procedures Test results Dates Equipment references for traceability Initials / names of analysts and supervisors who checked the data Statement of release or rejection 15.43 Analysis records should include at least the following data: (a) the name of the material or product and, where applicable, dosage form; (b) the batch number and, where appropriate, the manufacturer and/or supplier; (c) references to the relevant specifi cations and testing procedures; (d) test results, including observations and calculations, and reference to any specifi cations (limits); (e) date(s) and reference number(s) of testing; (f) the initials of the persons who performed the testing; (g) the date and initials of the persons who verifi ed the testing and the calculations, where appropriate; (h) a clear statement of release or rejection (or other status decision) and the dated signature of the designated responsible person. 15.43

Documentation 21 April, 2017 Records Include also: Cleaning and use Qualification and validation Calibration Maintenance Preventive maintenance etc… 15.35

Documentation World Health Organization 21 April, 2017 Group Session I Group session We are now going to have our first group task which is to build a small toy of building bricks, first with no documentation and then with some very simple documentation. We will then measure the improvement that even simple documents can bring to a process. (Depending on the participants’ ability and experience there is an alternative Group session at the end of this module.)

21 April, 2017 Documentation Part 1 - Trainer’s Notes (use overhead) Time required: Allow 1 hour or a little longer Materials required: One per team of a piece kit for building toy models from bricks, such as a racing car or truck. The Lego® brand of product or equivalent is ideal. The 50 piece models may be too complicated to allow teams to complete the building required within the short space of time you will give them. Avoid helicopters, boats and other complicated models. Make sure the model comes with building instructions using only illustrations – no text. The group session also demonstrates the power of illustration when trying to describe complicated items (such as the different sorts of blocks) and the sequence of assembly. The analogy is that illustration (photographs or drawings) or flow charts in standard operating procedures are a very powerful means of communication. Instructions: Prior to the group session, put all the blocks for the models into one clear plastic bag per model. Label with e.g. “Racing Car”. Provide no other information on the bag. Keep the assembly instructions and the box separately. Form the groups into teams of about Lower numbers than this is satisfactory but do not go above 6. A maximum of about 4 teams seems to work best. The teams will be naturally competitive but do not let this get out of hand – rather make it as fun as possible. Before handing out the plastic bags of blocks, instruct the teams not to open the bags until instructed to do so. Explain that they are to assembly a model toy with no training and no operating instructions. Compare this with a pharmaceutical factory which asks an untrained employee to clean a complicated piece of machinery with no instructions. Score the teams efforts using the specifications and score card attached. Make this into an overhead and write on it with White Board marker to allow the O/head to be used again. You will be the sole judge awarding the points but this can be made fun, especially the aesthetic test and the robustness test. The teams will then have the manufacturer’s instructions given to them together with the box the model came in. Explain that even an illustration on a box conveys a powerful message. Tell them you will allow them exactly one minute to look at the bags, then on the command “Start” they can have 3 Minutes exactly (for a 30 piece model) to assembly the model without any operating procedures. Allow 4-5 minutes for more complicated 50 piece kits. Monitor the time closely. At the end of the time say Stop and warn the teams you will deduct points if any pieces are touched after the time is up. Score the results in front of everyone. Award a small prize if appropriate to the winning team. Total all points to check for improvement in the next phase. Get the teams to pull the model apart, hand out the model assembly instructions provided by the manufacturer and repeat the construction. Give exactly the same time as before. Repeat the scoring and calculate the grand total and improvement. Improvements typically range from %

Documentation World Health Organization 21 April, 2017 Group Session II From your own experience of factory inspections, how do documentation systems in this country compare with the WHO model? Identify gaps and reasons What will help and/or hinder the process of eliminating these gaps? We are now going to have a group discussion. Use your own experience from inspection visits that you have made to draw up a picture of the documentation systems that are in place in most companies in this country (Alternative text if training inexperienced persons). List the main gaps that you are likely to find and try to identify the reasons for them. When you have done that, discuss the process of eliminating those gaps. What will help companies to eliminate the gaps and what will hinder them? Finally, what sort of responses will you insist on companies achieving when you visit them in the future and find problems.

Basic Principles of GMP

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