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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 2

What is being made?
Most of us when attempting a task need some sort of documentation
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And if the documentation is wrong or you worked „by heart”…
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Why are documents so important? 1
• Communication
How can I know what to do?
• Cost
• Audit trail
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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
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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!
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• 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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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
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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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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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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
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• 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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• Photographs can be documents and part of a herbal identification; provided they are properly authorised and controlled
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• Flow charts provide substantial information at a glance
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• What must be labelled?
Finished products – country-specific regulatory requirements and withinfactory 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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• 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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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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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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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)
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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
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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
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(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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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
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• 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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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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• 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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• 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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• 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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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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Areas to be Covered
• General considerations
• Personnel
• Premises
• Equipment
• Sanitation
• Documentation
• Retention of records and samples
• Production
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General Considerations
• Overall control
• Consistent uniform batches
• Compliance with GMP
– production
– quality control
• General guidelines
• Co-operation in production
• Human and veterinary preparations
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There are some important differences between the finished product (=medicinal product) manufacture and API manufacture!
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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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• 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
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• Special purposes
– antibiotics, hormones, cytostatic substances
Less campaign working, rather dedicated premises, i.e.:
– separate specifically designed enclosed areas
– separate air handling systems
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• Hygiene
– clothes, washing, toilets
– eating, drinking, smoking migth be dangerous for the workers, not vice versa
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• 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 46

• Process monitoring and control
– calibrated, checked
– records
• Defective equipment
– removed or labelled
– repaired, documented
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• 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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• 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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Record and reference sample retention
• Activities are traceable
– production and quality control
• Retention of records and samples
– retention period
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• 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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under
GMP
Manufacture of starting materials
Measuring-in the starting materials
Manufacture of internediates
I s ol ation
, purification
Physical processing, packaging
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under
GMP
Collection of the animal tissue
Cutting, mixing, other possible processing
Measuring-in the starting materials
I s ol ation, purification
Physical processing, packaging
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under
GMP
Collection of the herbal material
( cultivation, harvesting
)
Cutting, primary extractions
Measuring-in the starting materials
I solation, purification
Physical processing, packaging
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Collection of the herbal material (cultivation, harvesting) under
GMP
Cutting, primary extraction(s)
Further, critical extraction
Physical processing, packaging
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Under GMP
Collection of the herbal materials (cultivation, harvesting)
Cutting
Physical processes, packaging
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Under GMP
Cell cultures: development of the initial and working seeds
Maintenance of the working seed
Fermentation
Isolation, purification
Physical processing, packaging
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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
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• Processing procedures
– According to the master formula
– critical steps defined and validated
– supervision
– labelling
• vessels, containers, equipment
– daily activities - information
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• 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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• Active pharmaceutical ingredients
– meet specifications
– limits for residue and reactants
– sterile APIs
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• 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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• 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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• Written programme
– stability indicating methods difficulties: what are the degradation products?
• Samples
– containers
– storage conditions
• Expiry
(degradable APIs) or retest date
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• Regular independent inspection
– expert or team of experts
– production and quality control
• Records
• Suitable conditions based on stability studies
• Distribution records for each batch
– written SOP
– facilitate recalls
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• 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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• 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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• 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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