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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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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• 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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• 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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• 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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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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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

Differences

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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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




under GMP

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From herbal origin

Collection of the herbal material (cultivation, harvesting)

Cutting, primary extractions




under GMP

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Herbal extract APICollection of the herbal material (cultivation, harvesting)

Cutting, primary extraction(s)

Further, critical extraction


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



Under GMP

5858

Classi fermentation

Development/identification of the cell culture (seed)

Maintenance of the working seed

Introduction of the working seed inti the fermentor



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!)