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Basic Principles of GMP
Documentation
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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
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What is being made?
Most of us when attempting a task need some sort of documentation
Documentation
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And if the documentation is wrong or you worked „by heart”…
Documentation
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Why are documents so important? 1
• Communication How can I know what to do?
• Cost
• Audit trail
Documentation
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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
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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
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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.)
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Documentation
General Principles – I• Documents should be
– designed– prepared– reviewed – distributed with care
• Design of documentation
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General Principles – II
• Inspectors should look at the
“Style” of the document
– Instructions in the imperative
– Short sentences
– Not long sentences
Documentation
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Documentation
General Principles – III
• Approval of documentation– Approved, signed and dated by
appropriate authorized persons– No document should be changed
without authorization
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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
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DocumentationGeneral 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
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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
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Documentation of premises
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Documentation
• Photographs can be documents and part of a herbal identification; provided they are properly authorised and controlled
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Documentation
• Flow charts provide substantial information at a glance
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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
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Documentation: how to prepare culture media for
sterility testing
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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
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Example: manufacturing Batch Record
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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
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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
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Master Formulae 3Packaging 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)
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Master Formulae 4Packing 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 criteriaAll Master Formulae are references in
records. They are available in both Production and QC
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Documentation: Master Formula for tabletting
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Batch Processing Records 1For 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
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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
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Batch Packaging RecordsAlso 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
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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
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Example: SOP
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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)
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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
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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
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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?
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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
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Basic Principles of GMP
Active Pharmaceutical Ingredients
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Active Pharmaceutical Ingredients
Areas to be Covered• General considerations• Personnel• Premises• Equipment• Sanitation• Documentation• Retention of records and samples• Production
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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
Differences
There are some important differences between the finished
product (=medicinal product) manufacture and API
manufacture!
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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
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Personnel
•Skill needed different from drug product manufacture
•Authorized person rather chemical engineer than pharmacist
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API: Premises
• General– suitable construction and environmentmuch 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
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API: Premises 2
• Special purposes– antibiotics, hormones, cytostatic
substancesLess campaign working, rather
dedicated premises, i.e.:– separate specifically designed
enclosed areas– separate air handling systems
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API: Premises 3
• Hygiene– clothes, washing, toilets– eating, drinking, smokingmigth be dangerous for the workers,
not vice versa
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API: Equipment• Design, construction, location and maintenance
– intended use, cleaning, contaminationmuch 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
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API: Equipment
• Process monitoring and control– calibrated, checked – records
• Defective equipment– removed or labelled– repaired, documented
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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
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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
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API
Record and reference sample retention
• Activities are traceable– production and quality control
• Retention of records and samples– retention period
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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
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Chemical synthesis
Manufacture of starting materials
Measuring-in the starting materials
Manufacture of internediates
Isolation, purification
Physical processing, packaging
under GMP
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From animal origin
Collection of the animal tissue
Cutting, mixing, other possible processing
Measuring-in the starting materials
Isolation, purification
Physical processing, packaging
under GMP
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From herbal origin
Collection of the herbal material (cultivation, harvesting)
Cutting, primary extractions
Measuring-in the starting materials
Isolation, purification
Physical processing, packaging
under GMP
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Herbal extract APICollection of the herbal material (cultivation, harvesting)
Cutting, primary extraction(s)
Further, critical extraction
Physical processing, packaging
under GMP
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Cut/Powdered herbal drug is the API
Collection of the herbal materials (cultivation, harvesting)
Cutting
Physical processes, packaging
Under GMP
5757
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
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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
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API: Production
• Processing procedures– According to the master formula– critical steps defined and validated– supervision– labelling
•vessels, containers, equipment
– daily activities - information
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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
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API: Production 2
• Active pharmaceutical ingredients– meet specifications– limits for residue and reactants– sterile APIs
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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
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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
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API: Stability studies
• Written programme– stability indicating methodsdifficulties: what are the degradation
products?
• Samples– containers– storage conditions
• Expiry (degradable APIs) or retest date
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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
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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
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Exam topics
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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
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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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