Transcript Basic Principles of GMP Documentation

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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Documentation
What is
being made?
Most of us when
attempting a task
need some sort of
documentation
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Documentation
And if the documentation is
wrong or you worked „by heart”…
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Documentation
Why are documents so important? 1
•
Communication How can I know what to do?
•
Cost
•
Audit trail
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Documentation
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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Documentation
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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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
–
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designed
prepared
reviewed
distributed with care
• Design of documentation
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Documentation
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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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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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
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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 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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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 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)
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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
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Documentation: Master
Formula for tabletting
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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
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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 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
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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
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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
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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
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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
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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
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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 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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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
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API: Premises 3
• Hygiene
– clothes, washing, toilets
– eating, drinking, smoking
migth be dangerous for the workers, not vice
versa
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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
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checks
API: Equipment
• Process monitoring and control
– calibrated, checked
– records
• Defective equipment
– removed or labelled
– repaired, documented
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API: Sanitation
• Written programmes
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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”)
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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
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packaging
Chemical synthesis
under GMP
Manufacture of starting materials
Measuring-in the starting materials
Manufacture of internediates
Isolation, purification
Physical processing,
packaging
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From animal origin
under GMP
Collection of the animal
tissue
Cutting, mixing, other possible processing
Measuring-in the starting materials
Isolation, purification
Physical processing,
packaging
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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
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Herbal extract API
under GMP
Collection of the herbal material (cultivation, harvesting)
Cutting, primary extraction(s)
Further, critical extraction
Physical processing,
packaging
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Cut/Powdered herbal drug is the
API
Under GMP
Collection of the herbal materials (cultivation,
harvesting)
Cutting
Physical processes,
packaging
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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
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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
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API: Production
• Processing procedures
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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
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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:
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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
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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 methods
difficulties: 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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