Basic Principles of GMP

Basic Principles of GMP
Documentation This module deals with the very important topic of documentation. It is a half to one-day session (depending on the participants ability and experience) divided into 2 roughly equal parts: In each half, there will be minutes of presentation, 45 minutes discussion in groups and 30 minutes feedback to the whole group. There will be one test and discussion (40 minutes) covering the whole module that will be taken at the end.

Documentation General Principles – I
Documentation is an essential part of QA and relates to all aspects of GMP 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.

Documentation What is being made?
Most of us when attempting a task need some sort of documentation What is being made? Most of us when attempting a task need some sort of documentation.

And if the documentation is wrong or you worked „by heart”…
The drawing was wrong!

Documentation Why are documents so important? 1
Communication How can I know what to do? Cost Audit trail Communication - "How can I know what I think until I see what I say: " E M Forster. Communicate ideas to a remote audience. Documentation fixes in time physical expressions to vaguely formed concepts, structured far more rigorously then when they are going around in someone’s head. Cost - the cost of poor quality documentation is hard to measure. But think of the time wasted through misinterpretation, recovering from errors, resubmitting to regulatory authorities, failing regulatory audits, etc Audit trail - footprints in the snow. Write what you do, do what you write and if you didn't write what you did...you didn't do it!!

Communication “Communicate ideas to a remote audience. Documentation fixes in time physical expressions to vaguely formed concepts, structured far more rigorously then when they are going around in someone’s head” E.M. Foster Communication - "How can I know what I think until I see what I say: " E M Forster. Communicate ideas to a remote audience. Documentation fixes in time physical expressions to vaguely formed concepts, structured far more rigorously then when they are going around in someone’s head. Cost - the cost of poor quality documentation is hard to measure. But think of the time wasted through misinterpretation, recovering from errors, resubmitting to regulatory authorities, failing regulatory audits, etc Audit trail - footprints in the snow. Write what you do, do what you write and if you didn't write what you did...you didn't do it!!

Cost of poor quality documents is hard to measure… But think of the time wasted through misinterpretation, recovering from errors, resubmitting to regulatory authorities, failing regulatory inspections… Audit trail like footprints in the snow. Write what you do, do what you write and if you did not write what you did – you did not do it! Communication - "How can I know what I think until I see what I say: " E M Forster. Communicate ideas to a remote audience. Documentation fixes in time physical expressions to vaguely formed concepts, structured far more rigorously then when they are going around in someone’s head. Cost - the cost of poor quality documentation is hard to measure. But think of the time wasted through misinterpretation, recovering from errors, resubmitting to regulatory authorities, failing regulatory audits, etc Audit trail - footprints in the snow. Write what you do, do what you write and if you didn't write what you did...you didn't do it!!

Two basic forms of documents
Master formulae e.g. instructions to prepare batches (batch size specific, e.g. different Master Formulae for 10,000 and 1 Mio tablets batch sizes), or its label Records e.g. processing records: during the preparation of every batch: records are kept (boxes filled in, temperature-time records, etc.)

Documentation General Principles – I Documents should be
designed prepared reviewed distributed with care Design of documentation Documents should be designed, prepared, reviewed and distributed with care. In terms of design, there is no single right answer – the one thing you can be sure about is that every company will come up with a different design. However, it is better for the operators if a consistent approach is taken. It is possible for some of the documents to be combined, but generally they should be separate. They must comply with the relevant part of the manufacturing and marketing authorizations. All documents should be unambiguous with a title and a clear statement of purpose. They should contain clear, numbered references to each activity. They should have sufficient space to record relevant data. They should be easy to check and all relevant activities should be recorded on them.

General Principles – II
Documentation General Principles – II Inspectors should look at the “Style” of the document Instructions in the imperative Short sentences Not long sentences Instructions must be in the imperative – Go , Do, Stop, Mix, Blend, Wash, etc...... Look for short sentences. Long sentences do not allow the reader time to grasp messages. A florid, roseate style over endowed with polysyllabic phraseology confuses the reader.

General Principles – III
Documentation General Principles – III Approval of documentation Approved, signed and dated by appropriate authorized persons No document should be changed without authorization Documents should be designed, prepared, reviewed and dated by appropriate authorized persons. No document should be changed without authorization. Any alteration made to a document should be signed and dated; the alternation should permit the reading of the original information. Where appropriate the reason for the alternation should be recorded.

General Principles – IV
Documentation General Principles – IV Distribution of documentation carefully controlled to ensure that up-to-date documents used – according to an SOP Document register is needed Electronically or photographically recorded data only by authorised persons. Older copies never deleted Distribution of documents needs to be carefully controlled in order to ensure that the most up-to-date version is always being used. There should be a distribution list, if appropriate, attached to the document. Unauthorized photocopying of original documents should be actively discouraged. Some companies manage this by having part of the front page printed in colour, or by using an official stamp or other means of identification. There should be an SOP for distribution, retrieval and preparation of documentation. A document register is required. This ensures that change control over all documents is properly managed. Some documents may be stored electronically. Special controls have to be developed. If documentation is handled by electronic data-processing methods, only authorized persons should be able to enter or modify data in the computer, and there should be a record of changes and deletions; access should be restricted by passwords or other means, and the entry of critical data should be independently checked. Whichever way the master is stored, it is important that clear copies are reproduced for use with individual batches.

Documentation General Principles – V Review
system for regular revision master copies: date of the next review Review (even if no changes are needed) should be documented If changes, the change history attached If the document is a process record: completion (filled in legibly) during the process (not later!) by pen, no pecil (indelible!) If alteration: cross out and explain the alteration no empty boksz should remain Documents should be reviewed regularly; however, the definition of “regular” will vary from company to company and with the document in question. Although not a WHO GMP text requirement, it is useful for all master copies to have a review-by date. Alternative methods of identifying the need for review include diaries or electronic reminders. The key is to have a system. Once the review date is reached, if no changes are required, the document should be annotated to show that it has been reviewed and the review-by date amended. If amendment of the document is required, there should be a history of the changes attached at the end. In the case of changes being made, it is important that all old copies are withdrawn and replaced by the new ones. (This confirms the previous point about the need for controlled distribution). If the document is a process record, it should be filled in clearly and legibly. The writing should be indelible, i.e. in pen, not pencil. Any alterations must be made by putting a single line through the incorrect information, signing it and putting in the new information. There should be no use of correcting fluid or similar products. If an alteration is made, then the reason for the alteration should also be given. This is particularly important where a laboratory test result is changed – the reason for the change must be given. There should be no blank spaces left on a document. If a box is provided for inputting information it should either be filled in or marked as not applicable. To leave it empty causes problems for people auditing the documents – they won't know whether it should be blank or not. All associated charts and other materials, such as sterilization records and copies of printed packaging materials should be included with process records and stored with them. It is essential that documents are completed as the process proceeds. Inspectors should examine documents in progress for signs of either pre-process completion or post-process completion. For example, the error of signing the documentation for LVP sterilization before the product went into the autoclave.

Types of documentation
Labels, specifications and master formulae Batch processing and batch packaging records Standard operating procedures (for any operation which is not product-specific) Stock control and distribution records Water quality manual Other types This slide summarizes all the types of documents that are listed in the WHO GMP text, plus three additional ones. We will review each one in detail later in the session, but at this point, we will run through the list to make sure we are aware of all the requirements (Note for the trainer: that makes a good group session for audience participation rather than just reading the list to the seminar. One can also ask what must go on the e.g. Release label, or cleaning label, etc......) Labels are required for all containers, equipment and premises. Specifications and testing procedures are required for all starting materials, packaging materials, intermediates, bulk and finished products. There must be a master formulation for all manufacturing processes and a packaging instruction for each stock-keeping unit that is produced. Batch processing documents and records are required for all manufacturing processes. Batch packaging documents and records are required for packaging operations. Standard operating procedures (SOPs) are required for all operations that are not product-specific, whether related directly to manufacturing or to operation of the facility. The following are three examples of other documents that are useful and frequently found: Stock control records are usually used for all materials that are stored in the warehouse. Distribution records are usually used for all batches of material that are dispatched from the warehouse. A water quality manual describes all aspects of the water system design, operation, maintenance and water quality testing.

Documentation of premises
Plans can be considered to be documents.

Documentation Photographs can be documents and part of a herbal identification; provided they are properly authorised and controlled Photographs of herbal specimens can be very useful documents if properly authorized and controlled. The photograph shows a pollen grain, unique to the botanical genus and species, being compared with the authenticated reference photograph. The gentleman on the right is serving a 5 year apprenticeship to the lady in the centre who is a qualified Traditional Chinese Herbal Medicine specialist.

Documentation Flow charts provide substantial information at a glance
This is an example of a flow chart - another useful documentation tool

Labels What must be labelled? Finished products – country-specific regulatory requirements and within-factory labels. Labels on every container and even process equipment! What must be on the label? Status (colour) + identification data Who has responsibility for labelling? QC staff for status labels, production or store staff for another types There are two classes of labels. There are the finished product labels, which must meet national drug regulatory authority requirements as specified in the marketing authorization. Then there are the labels used within the factory to control processes. Labels are required for all containers of materials, whether for starting materials, intermediates or finished products; there must be sample labels and labels that are applied to materials that have been sampled; there must also be labels for all process equipment and for premises that are in use for manufacturing. The labels should be clear and unambiguous. Where possible, it is advisable for companies to use colours to indicate status (quarantine, accepted, rejected, cleaned or dirty). Companies generally have their own systems for internal labelling that define what information is carried, but for finished products, there is a national requirement. Responsibility for labelling varies with company practice, but the process is generally overseen and controlled by the QC department. QC staff are responsible for issuing status labelling when a material has been approved or rejected. The responsible production and/or QC staff should sign labels stating that equipment is clean and available for use. Reference standards (both primary and secondary) must be appropriately labelled and the issue of these must be controlled.

Documentation: how to prepare culture media for sterility testing
This is an example of the documentation required for preparation of microbiological test media according to Good Quality Control Laboratory Practices”. The important elements to look for in this type of document are circled: a) traceability and document pedigree b) pagination - how many pages are there in this document and what page is this page? c)Headings - the purpose of the document, the scope, where is applicable. d) Instructions in the imperative, that is, action words - mix, blend, weigh, check and so on.

Specifications and test procedures
Validated before used (identity, purity, assay). Dated and authorised. Responsibility: QC staff Starting and packaging materials name, reference to the Pharmacopoeia,, testing methods and acceptance criteria, supplyer, storage conditions, retest date Intermediates and bulk products similar but internal specifications, shelf-life Finished products 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.

Example: manufacturing Batch Record
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.

Manufacturing instructions
Master Formulae 1 Manufacturing instructions Name of product with product reference code Dosage form, strength and batch size Full list of materials including quantities; unique reference code Expected final yield with acceptable limits (+intermediate yields) Processing location and principle 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

Manufacturing instructions - continued
Master Formulae 2 Manufacturing instructions - continued Equipment preparation methodology Stepwise processing instructions space for operator to sign, write exact quantities, temperature Details of in-process controls with instructions for sampling and acceptance limits Storage requirements and special precautions 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.

Packaging instructions
Master Formulae 3 Packaging instructions 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) 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)

Packing instructions - continued
Master Formulae 4 Packing instructions - 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 All Master Formulae are references in records. They are available in both Production and QC 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.

Documentation: Master Formula for tabletting
This is an example of a batch manufacturing instruction sheet.

Batch Processing Records 1
For each batch! Its review is critical for the release! First step: area clearance check: confirm cleaning and no remaining materials from the previous production Name of the product, batch number Dates and times for major steps in process 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 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. 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

Batch Processing Records 2
(continued) Main processing steps and key equipment In-process controls carried out, 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 Record of activities A batch processing record (continued): The information required in the batch processing record includes: Reference number and quantity of materials used in the batch 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. 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.

Batch Packaging Records
Also part of the batch release 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 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. 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

Batch Packaging Records 2
Details of packaging operation, including equipment and line used Returns to store (if there is no batch code/batch number on them!) If destroyed: record! 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 Area clearance check Product variables Record of activities and check signatures 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.

Example: SOP 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, pedigree, purpose, scope and instructions in the imperative.

Standard Operating Procedures 1
Written by the Division responsible for carrying them out, but also approved by QA Who is responsible for SOPs? Where should SOPs be stored? There should be one master copy in a central place plus authorised (photo?)copies adjacent to the place where the operation is carried out. Critical equipment: logbooks (use, maintenance, cleaning) 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.

Which activities require SOPs? 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 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

Which activities require SOPs? - continued 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 Complaints, recalls, returned goods SOPs are required for a whole range of activities - continued: 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 Complaints Recalls Returned goods. 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.

Stock Control and Distribution Records
What should be recorded? Raw materials, packaging materials, finished products – Batch no, status, quantities, exp. date. Manual or electronic. Ensures proper rotation such as FIFO or FEFO. Distribution record per batch. Batch No, quantity and destination of each delivery Where should records be stored? Why are the records important? Finally, we turn to three types of documents that are not directly mentioned in the WHO GMP texts: stock control records, distribution records and water quality manuals. Although not specifically listed, the need for these documents is implied in the lists of requirements under QA, GMP and QC. The first two documents remind us that the need to record everything that a company does before the materials reach the production floor and continues after the finished product is sent to the warehouse. Stock control documentation is required for raw materials, packaging materials and finished products. The records include batch numbers, status, quantities and expiry date. They may be manual or electronic, but must take into account the status of the batch in question. They ensure an appropriate system of material rotation, such as FIFO (first in, first out) or EEFO (earliest to expire, first out). The records will be validated by the physical stock check carried out periodically in the warehouse. For distribution, there should be one record per batch of material. It should contain the batch number, quantity and destination of each delivery. This means that, in the case of a product recall, the information on distribution can be obtained rapidly from a single source. Using copy invoices as distribution records is not advisable unless the batch number is recorded. If a computer-controlled stock management system is used, this can provide a very acceptable method of recording distribution.

For various forms of (purified) water
Water QualityManual For various forms of (purified) water Full details of design of system, operation and maintenance Details of testing requirements (chemical, microbiological). Partly the supplier’s data, partly in-house data The requirement for a water quality manual reflects the importance of purified water, in its various forms, to the pharmaceutical industry. The manual should contain full details of the design of the system, its operation and maintenance. It should also contain details of testing requirements. Microbiological and chemical quality has to be developed. The manual is a combination of information from suppliers' manuals and internal procedures.

Basic Principles of GMP
Active Pharmaceutical Ingredients One of the objects of a pharmaceutical manufacturer, is to manufacture pharmaceutical products for human, or veterinary use. This is achieved through compounding and combining of products or different raw materials. These include active pharmaceutical ingredients, and excipients. In this module, we are going to review the GMP requirements and guidelines for the manufacture and control of raw Active Pharmaceutical Ingredients (API). It must be made clear, that a “common sense” approach is needed when inspecting a manufacturer of APIs. The inspector also needs to have the required experience when inspecting such a manufacturer. Do not expect to find the same finishes as for pharmaceutical product manufacture, when inspecting the API manufacturer. The premises, equipment and general appearance may be quite different to what you expect for a manufacturer of final dosage forms. The module covers WHO GMP text for the manufacture of API (mainly through synthesis and not other means of manufacture). The programme is as follows: Presentation 60 minutes Group session 60 minutes Test 10 minutes plus 20 minutes discussion

Active Pharmaceutical Ingredients
Areas to be Covered General considerations Personnel Premises Equipment Sanitation Documentation Retention of records and samples Production As you would expect, we shall be looking at the GMP topics or sections as listed here. Within production we will be considering processes, starting materials, intermediates, active ingredients, packaging, quality control, stability, audits, storage, complaints and defects and rejected materials. Please remember that, in general, the principles of GMP for products apply just as much to bulk active pharmaceutical ingredients. What we are concerned with here are the detailed differences where the application of GMP principles has to be different for bulk active pharmaceutical ingredients because the type of process or plant is different. Let us now look at each area in more detail.

General Considerations Overall control Consistent uniform batches Compliance with GMP production quality control General guidelines Co-operation in production Human and veterinary preparations There are some fundamental differences between the finished product manufacture we have been discussing up to now on the programme, and bulk active ingredient manufacture. These differences concern plant configuration, type of process and the background of the people involved. Some of them mean that strict application of GMP as we have been discussing them is often not practical. The end result that we are seeking is that the quality of the materials coming from bulk active ingredient manufacture is appropriate to the finished product into which they will go. The key to achieving this result is to ensure that the overall process is under control. If the manufacture of APIs is haphazard, unplanned activities occur which will result in: - product which is not uniform - product not meeting the specifications - possible creation of dangerous working conditions. Many of the processes used in the manufacture of bulk actives are chemically hazardous. This is an additional reason for ensuring that processes are under control. Companies that have not been subject to this type of regulation frequently complain that it is all too expensive and unnecessary. Yet what they often have are processes that are uneconomical because they experience large amounts of rejects. When a process is under control, then reliability of process will be greatly enhanced and so production will be more economical. All of the following sections are targeted at ensuring that we have consistent manufacture, leading to the production of consistent quality product using well designed and regulated processes. Manufacturers must take responsibility for their actions. GMP should be applied from the point in the process where the quality of the starting materials, or process, can affect the quality of the active pharmaceutical ingredient. The decision as to where this point starts lies with the national drug regulatory authority. The good practices we shall be discussing are intended as guidance. In this area of manufacturing it is possible to reach the same end point of quality active ingredients using different routes. It may be necessary to adapt the guidance given to allow an individual company to reach the goal of GMP using a different route. If companies are cooperating together to manufacture and pack a bulk active, then the form of this cooperation should be described in written procedures. The process can be seen in similar terms to contract manufacturing. This is true even if no money is actually changing hands. It is the process of collaboration that is the same. All activities of packing, repackaging and labelling must be subject to relevant GMP guidelines on label and batch control. A very common activity in this sector is the repackaging of products. This occurs because demand by the pharmaceutical sector is very small. Brokers then take supplies in bulk and carry out repackaging. This must be conducted with due care paid to the need for identification, packing, labelling, cleaning and storage. We should be aware that this guidance applies to pharmaceutical ingredients for both human and veterinary medicines.

Differences There are some important differences between the finished product (=medicinal product) manufacture and API manufacture!

Personnel Qualified and competent production and quality control sufficient number education, knowledge, experience Organizational chart with responsibilities Written job description or instructions Trained Health diseases open lesions The first of the specific areas that we look at, is that of requirements for personnel. If the people involved in the manufacture of active pharmaceutical ingredients are well trained and motivated then most other problems can be dealt with. Just as with finished product GMP, the company should: Be employing people who have the correct qualifications and experience for the job that they do. Have a clear organizational chart (structure). Be working with written job descriptions (people should not have so much to do that quality can suffer). Be training people for the work that they are to do. Be sure that people who can come into contact with exposed product do not have any form of communicable disease or open wounds or lesions. If we look at all the things that we have said about the people involved in bulk active ingredient manufacture then we have actually not made any distinction in this area at all. Everything that is required of people involved in finished product manufacture is also required of those in bulk active ingredient manufacture.

Personnel Skill needed different from drug product manufacture
Authorized person rather chemical engineer than pharmacist

API: Premises General suitable construction and environment
much more corrosive than drug preparation manufacture adequately adapted and sufficient size mix-ups or contamination (sometimes open tanks!) more possibilites (almost every substance white powder) logical work flow The environment where the plant is constructed should be appropriate to the work that is to be done. If processing has to be done in open tanks then consideration needs to be given as to whenever this will influence final material quality. If tanks are open and dust can enter them then a filtration step before crystallization may be suitable to fit the quality requirements. For further contamination, e.g. insects, other measures are needed. It is important to consider these matters on a case-by-case basis. It is important that the design of the facility should not contribute to potential mix-ups or contamination. There should be a logical workflow to ensure that a material passes through all the steps that are required for it to be correctly processed. Some products will require special handling facilities and precautions due to the nature of the material. This is especially the case for sterile materials and also penicillins. Hormone products and cytostatic materials are other examples where special precautions are required. For some materials even greater care may be required in the active ingredient facility than in the final product facility. The reason for this is that the API plant is handling material at 100% assay – its highest potency. Often the final product plant is handling these very potent materials at very low dose levels. The problems may be different. The precautions may also be different.

API: Premises 2 Special purposes
antibiotics, hormones, cytostatic substances Less campaign working, rather dedicated premises, i.e.: separate specifically designed enclosed areas separate air handling systems The environment where the plant is constructed should be appropriate to the work that is to be done. If processing has to be done in open tanks then consideration needs to be given as to whenever this will influence final material quality. If tanks are open and dust can enter them then a filtration step before crystallization may be suitable to fit the quality requirements. For further contamination, e.g. insects, other measures are needed. It is important to consider these matters on a case-by-case basis. It is important that the design of the facility should not contribute to potential mix-ups or contamination. There should be a logical workflow to ensure that a material passes through all the steps that are required for it to be correctly processed. Some products will require special handling facilities and precautions due to the nature of the material. This is especially the case for sterile materials and also penicillins. Hormone products and cytostatic materials are other examples where special precautions are required. For some materials even greater care may be required in the active ingredient facility than in the final product facility. The reason for this is that the API plant is handling material at 100% assay – its highest potency. Often the final product plant is handling these very potent materials at very low dose levels. The problems may be different. The precautions may also be different.

API: Premises 3 Hygiene clothes, washing, toilets
eating, drinking, smoking migth be dangerous for the workers, not vice versa To ensure hygienic working conditions, separate facilities should be provided just as in final product manufacture, for changing of clothes, washing and toilets as well as for food preparation, eating, drinking and smoking.

API: Equipment Design, construction, location and maintenance Cleaning
intended use, cleaning, contamination much more variation than in case of manufacture of dosage forms validated operation Questiones: what processes will be carried out in the equipment? What parameters to control? What material for construction? How will the equipment be maintained? Cleaning sterilised, used, maintained: SOPs, records and checks Turning now to equipment, we shall see that, just as with finished product manufacture, it is important that the equipment is suitable for the purpose for which it is intended. This means that it must be constructed of materials that are appropriate for the reactions that will take place in it. It must be able to be cleaned effectively. The risk of contamination and cross-contamination must be minimized. It should be able to facilitate validated operations – to do this it must be equipped with a means of measuring its performance during processing. In order to achieve all of these things, careful planning should be given to the design of the equipment. The questions we need to ask are: What processes will be carried out in the equipment? What parameters will be measured to control the activities going on within it? What sort of materials of construction will be required for the operations to be undertaken? How will the equipment be maintained? How will the equipment be validated? Equipment will need to be cleaned. This is true even in single-product operations. The cleaning procedures need to be carefully thought through and written down in (SOPs) standard operating procedures. Once the equipment goes into operation, there should be a means of modifying the cleaning procedures as a result of experience. Written records should be kept of the cleaning processes employed, and of the materials that have been processed through the equipment. Of particular importance in a multi-purpose plant is to check on the effectiveness of the cleaning procedure. In a very complex plant with lots of pipework, it may be essential for the quality assurance department to take swabs or samples of wash water or wash solvent to check for residues of the previous product.

API: Equipment Process monitoring and control Defective equipment
calibrated, checked records Defective equipment removed or labelled repaired, documented Just as with safety testing of equipment, the equipment should be checked for its ability to operate the processes it was installed for. This means a validation and calibration programme will be required. Process monitoring equipment should be installed so that the progress of the process can be followed. This may monitor temperature, pressure, pH or some other parameter. It should be regularly checked for operational effectiveness and for calibration. Written records of these checks should be kept, preferably in a plant or equipment logbook. Any equipment that becomes defective should either be removed from manufacturing or, where this is not practical, clearly labelled as such. This is extremely important for both GMP and safety reasons. If the equipment is defective and it cannot be removed it should be isolated from the plant. This isolation can be achieved by locking valves or disconnecting pipework or other services. This is so that it cannot be operated inadvertently. Imagine the disaster if a piece of equipment were to operate unexpectedly while a maintenance worker was repairing it. Some deaths have occurred because of this.

API: Sanitation Written programmes Implementation and training
validated for premises and equipment quality standard for water hygiene , health and clothing practices Final crystallisation: in controlled environment waste disposal Implementation and training Practices not permitted: eating, smoking unhygienic practices The manufacturer of APIs needs to have a written sanitation programme (trainer to expand where this is applicable). This programme needs to include validated (effective) cleaning procedures. It also requires a quality standard for water, hygienic practices for handling product, and disposal procedures for waste materials and residues. Staff need to be aware of the programmes and be regularly trained in them. Also under this section we should consider the issuing of protective clothing. Thought must be given to the type of protective clothing required for the various processes. Often because of the nature of the process, this clothing may be much more rigorous in the level of protection provided than for finished product manufacture. Care has to be taken that this clothing does not work against product quality. It should be maintained in a clean condition so that cross-contamination does not become an issue. There should be no eating, smoking or drinking or other unhygienic practices in the production area. This includes the practice of operators in these sorts of factories of keeping for example plants close to the production area. Final recrystallization, separation, drying, packaging and labelling should all be undertaken in a controlled environment meeting the standards for later finished product manufacture.

API: Documentation Master formulae (named also „Master process record”) written instructions master formula contents authorisation outdated documents amendments Batch documentation batch manufacturing record contents contract production data recording Although we speak here about a “master formula”, this document may be known by other names. Typically it might be “master batch sheet”, “master process record” or similar. We are talking about a documentation that describes the way in which a product will be made. The documentation should describe the formula and the manufacture and control of a typical batch. The documentation should be written to cover each step of production storage and quality control. The documentation should be regularly reviewed and updated if necessary. Good practice is to review the documentation once per year and assess whether changes are required. The documentation must be authorized. The documentation should describe step by step, all the processes and quality control procedures to be used. Qualified and trained personnel from the production and quality assurance should be responsible for the preparation and circulation of the master documentation. Obsolete documentation should be withdrawn from use but retained in a central file for future reference only. As amendments are made, these should be formally authorized by an assigned and responsible, competent person. Amendments should be considered for early adoption in a new master document. Amendments should only be implemented after authorization by the relevant responsible person. As each batch is prepared for manufacture, a batch documentation should be made available. This should be completed for each batch as processed. It should contain all the relevant parts of the master documentation. Normally a photocopy is made of the current master documentation; copy needs to be authorized for use. This ensures that all the relevant information is provided in the batch documentation. The information is included in the batch documentation is covered in detail in the text of the WHO GMP guidelines. If contract manufacture is required at some or all stages, then this must be recorded in the batch documentation. As with finished product records, any data recorded by electronic means must comply with all the requirements mentioned in the section on documentation. Again it can be seen from the above that there are no significant differences from the documentation for finished product manufacturing.

Record and reference sample retention
API Record and reference sample retention Activities are traceable production and quality control Retention of records and samples retention period Records are needed in order to allow the history of a batch to be traced. This means recording the starting material and packaging material lot numbers, and all processing activities. All activities should be traceable – including production and quality control activities. Records and samples of the API should be kept at least up to the expiry date of the finished product plus one year as a minimum. If there is no expiry date then the records should be kept for a specific time. This will normally be agreed with the national drug regulatory authority. The batch records and samples should be readily available during the storage period.

APIs Where starts the GMP? (As a rule, many synthesis steps, no need to introduce GMP to all of them) = identify the first step, key to the product quality! Some basic rules: -the closer ot the endproduct the higher the GMP level -normal fermentation: introducing materials and seed lot to the fermentor, biotechnology: also maintenance of the seed lot -teas (comminuted herbal parts): only their packaging

Chemical synthesis Manufacture of starting materials
under GMP Manufacture of starting materials Measuring-in the starting materials Manufacture of internediates Isolation, purification Physical processing, packaging

From animal origin Collection of the animal tissue
under GMP Collection of the animal tissue Cutting, mixing, other possible processing Measuring-in the starting materials Isolation, purification Physical processing, packaging

From herbal origin under GMP Collection of the herbal material (cultivation, harvesting) Cutting, primary extractions Measuring-in the starting materials Isolation, purification Physical processing, packaging

Herbal extract API Further, critical extraction
under GMP Collection of the herbal material (cultivation, harvesting) Cutting, primary extraction(s) Further, critical extraction Physical processing, packaging

Cut/Powdered herbal drug is the API
Under GMP Collection of the herbal materials (cultivation, harvesting) Cutting Physical processes, packaging

Biotechnological manufacture (fermentation)
Under GMP Cell cultures: development of the initial and working seeds Maintenance of the working seed Fermentation Isolation, purification Physical processing, packaging 57

Classi fermentation Under GMP Development/identification of the cell culture (seed) Maintenance of the working seed Introduction of the working seed inti the fermentor Isolation, purification Physical processing, packaging 58

API: Production Processing procedures According to the master formula
critical steps defined and validated supervision labelling vessels, containers, equipment daily activities - information During production, it is clear that manufacture should take place in accordance with the master process documents. All the critical steps should be identified and records made throughout the process. The requirements for record-keeping and labelling of the status of plant and equipment are no different to those for finished product manufacture, and should include details of supervision and labelling.

API: Production 2 Starting materials Intermediates
receiving, quarantine, sampling testing release, reject, storage, labelling dispensing SOP exceptions for hazardous materials (some e.g. PCl 5 not tested, manufacturer’s certificate accepted) Intermediates labelling storage All handling of starting materials should be in accordance with written standard procedures. Starting materials should be received, quarantined, sampled, identified, examined for compliance with established specifications, released or rejected, stored, labelled and dispensed in accordance with the written instructions. The only significant difference from finished product manufacture arises when the material concerned is so hazardous as to prevent normal handling. Some starting materials may not be tested for compliance because of the hazards involved: examples are dimethyl sulfate and phosphorous pentachloride. This is acceptable when a batch certificate of analysis is available from the vendor and when there is a reason based on safety or other valid consideration. Intermediate products are frequently made during active ingredient manufacturing. When this is the case, they should be tested in accordance with their specification, labelled and stored in the correct way. They are, after all, about to become starting materials for the next stage of the process. In this respect they should be treated no differently than other starting materials. When processing is finished, each batch should be checked against the specification for all the tests. Typically this will include assay, moisture content and residues testing.

API: Production 2 Active pharmaceutical ingredients
meet specifications limits for residue and reactants sterile APIs Each batch of Active Pharmaceutical Ingredient must meet specifications for quality, purity and identity (as well as other parameters). Specifications for tests and limits for residue and reactants should be available. The general principles for the manufacture of sterile products are also applicable for the manufacture of sterile APIs. When a sterile bulk active ingredient is being manufactured, all of the relevant requirements for sterile pharmaceutical products should be complied with.

API: Production 3 Packaging packaging material selection
procedures to prevent error labelling, including: Product name Quality Batch number Expiry or retest date Warnings, if required Storage conditions Names of manufacturers and suppliers Once manufacture is complete, the material has to be packed for shipment to the next stage of processing into the finished product. As with finished product manufacture, the selection of packaging materials must be done to ensure that there is no effect on the product. Thought must also be given to method of transport and to the conditions that will be found during transport. Written specifications are needed. Standard approved procedures are needed to ensure that there is no mix up during packing and labelling. Containers should be marked with basic information as listed in the WHO GMP text. This information includes: Product name Quality specification Batch number Expiry or retest date Warnings, if required Storage conditions Names of manufacturers and suppliers

API: Quality Control Independent unit
Duties: Approve, reject or release specifications and methods sampling, sanitation and hygiene reprocessing stability complaints Laboratory access and requirements Contract laboratories The organization, responsibilities and authority of the quality control department are in principle no different from those for quality control in finished product manufacture. The head of QC should be independent from production and report to the senior management of the company. The QC department should approve all specifications for all materials, packaging materials and bulk active ingredients. It should also approve all sampling procedures, sanitation and hygiene procedures, methods of reprocessing and any other instructions relating to product quality. It is responsible for product release decisions for all materials. It should ensure that stability is monitored. It should be responsible for the investigation of complaints about the quality of the bulk actives. The QC department should have access to a laboratory that is staffed and equipped to perform all the tests required. Tests need to be performed in accordance with written methods using equipment that is calibrated regularly. If outside laboratories are used, then this must be stated in analytical records. The contract analysis module outlines the conditions that should be met.

API: Stability studies
Written programme stability indicating methods difficulties: what are the degradation products? Samples containers storage conditions Expiry (degradable APIs) or retest date Material stability studies should be undertaken. A written programme is required setting out the stability-indicating test methods. Stability samples should be stored in suitable containers at temperature and humidity to simulate market conditions. Many active ingredients do not have specific expiry dates. If testing does not indicate a reasonable shelf-life, e.g. two years or more under anticipated storage conditions, then the products can be labelled with an arbitrary expiry date and should be retested on or before that date.

APIs: Self-Inspection and Quality Audits
Regular independent inspection expert or team of experts production and quality control Records Storage Suitable conditions based on stability studies Distribution records for each batch written SOP facilitate recalls Self-inspection and quality audits To be sure that GMP are being adhered to and that needed improvements are identified and implemented, a system of regular, independent self-inspection and auditing is recommended. The results of these inspections should be recorded and followed-up. The system of inspection discussed elsewhere in this programme is recommended. Storage During product development, the appropriate storage conditions should have been established based on stability studies. These should be used to store the active pharmaceutical ingredient. Records of storage conditions should be kept. As the material is distributed, records should be kept of the distribution, including batch numbers, so that if a recall is necessary there is a way of tracing all the material sent out.

APIs: Complaints and Defects
Written instructions Prompt action and investigation record facts Product review system Reject materials Written procedures starting materials, intermediates, packaging materials identified storage pending fate The requirements for handling complaints and defects in bulk active ingredients are the same as those applied to finished products. The same benefits that come from a systematic review of complaints about finished products also are available to the active ingredient manufacturer. Active ingredient manufacturers must have a written procedure for handling rejects and recalls. These apply to all APIs made in the factory. It is important that all materials which have been rejected or recalled are very clearly labelled as such and stored in separate store secure from mix-up with APIs released for distribution.

Exam topics

Documentation in GMP Its purpose
Its types (mention minimum 5, emphasise the differents between the 2 most important manufacturingand packaging document) Design, preparation, approval and distribution of documents

Manufacture of active pharmaceutical ingredients
Differences from the product manufacture: Personnel training and the Qualified Person Differences in premises and equipment handling Where does the GMP start? (different productions!)

Basic Principles of GMP

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