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1 Basic Principles of GMP Documentation. 2 General Principles – I Documentation is an essential part of QA and relates to all aspects of GMP Purpose of.

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Presentation on theme: "1 Basic Principles of GMP Documentation. 2 General Principles – I Documentation is an essential part of QA and relates to all aspects of GMP Purpose of."— Presentation transcript:

1 1 Basic Principles of GMP Documentation

2 2 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

3 3 What is being made? Most of us when attempting a task need some sort of documentation Documentation

4 4 And if the documentation is wrong or you worked „by heart”… Documentation

5 5 Why are documents so important? 1 Communication How can I know what to do? Cost Audit trail Documentation

6 6 Why are documents so important? 2 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 Documentation

7 7 Why are documents so important? 3 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! Documentation

8 8 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.)

9 9 Documentation General Principles – I Documents should be –designed –prepared –reviewed –distributed with care Design of documentation

10 10 General Principles – II Inspectors should look at the “Style” of the document –Instructions in the imperative –Short sentences –Not long sentences Documentation

11 11 Documentation General Principles – III Approval of documentation –Approved, signed and dated by appropriate authorized persons –No document should be changed without authorization

12 12 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

13 13 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

14 14 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

15 15 Documentation of premises

16 16 Documentation Photographs can be documents and part of a herbal identification; provided they are properly authorised and controlled

17 17 Documentation Flow charts provide substantial information at a glance

18 18 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

19 19 Documentation: how to prepare culture media for sterility testing

20 20 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

21 21 Example: manufacturing Batch Record

22 22 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

23 23 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

24 24 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)

25 25 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

26 26 Documentation: Master Formula for tabletting

27 27 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

28 28 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

29 29 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

30 30 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

31 31 Example: SOP

32 32 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)

33 33 Standard Operating Procedures 2 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

34 34 Standard Operating Procedures 3 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

35 35 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?

36 36 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

37 37 Basic Principles of GMP Active Pharmaceutical Ingredients

38 38 Active Pharmaceutical Ingredients Areas to be Covered General considerations Personnel Premises Equipment Sanitation Documentation Retention of records and samples Production

39 39 Active Pharmaceutical Ingredients General Considerations Overall control Consistent uniform batches Compliance with GMP –production –quality control General guidelines Co-operation in production Human and veterinary preparations

40 Differences There are some important differences between the finished product (=medicinal product) manufacture and API manufacture! 40

41 41 Active Pharmaceutical Ingredients 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

42 42 Personnel Skill needed different from drug product manufacture Authorized person rather chemical engineer than pharmacist

43 43 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

44 44 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

45 45 API: Premises 3 Hygiene –clothes, washing, toilets –eating, drinking, smoking migth be dangerous for the workers, not vice versa

46 46 API: Equipment Design, construction, location and maintenance –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

47 47 API: Equipment Process monitoring and control –calibrated, checked –records Defective equipment –removed or labelled –repaired, documented

48 48 API: Sanitation Written programmes –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

49 49 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

50 50 API Record and reference sample retention Activities are traceable –production and quality control Retention of records and samples –retention period

51 51 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

52 52 Chemical synthesis Manufacture of starting materials Measuring-in the starting materials Manufacture of internediates I s ol ation, purification Physical processing, packaging under GMP

53 53 From animal origin Collection of the animal tissue Cutting, mixing, other possible processing Measuring-in the starting materials I s ol ation, purification Physical processing, packaging under GMP

54 54 From herbal origin Collection of the herbal material ( cultivation, harvesting ) Cutting, primary extractions Measuring-in the starting materials I solation, purification Physical processing, packaging under GMP

55 55 Herbal extract API Collection of the herbal material (cultivation, harvesting) Cutting, primary extraction(s) Further, critical extraction Physical processing, packaging under GMP

56 56 Cut/Powdered herbal drug is the API Collection of the herbal materials (cultivation, harvesting) Cutting Physical processes, packaging Under GMP

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

58 58 Classi fermentation 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 Under GMP

59 59 API: Production Processing procedures –According to the master formula –critical steps defined and validated –supervision –labelling vessels, containers, equipment –daily activities - information

60 60 API: Production 2 Starting materials –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 –testing –labelling –storage

61 61 API: Production 2 Active pharmaceutical ingredients –meet specifications –limits for residue and reactants –sterile APIs

62 62 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

63 63 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

64 64 API: Stability studies Written programme –stability indicating methods difficulties: what are the degradation products? Samples –containers –storage conditions Expiry (degradable APIs) or retest date

65 65 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

66 66 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

67 67 Exam topics

68 68 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

69 69 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!)


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