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Good Manufacturing Practices – Part II 3 Specific GMP topics: Premises, Documentation and Validation. WHO EMRO 1 st Workshop on the WHO Prequalification Programme: Priority Essential Medicines, Cairo, Egypt, 6 and 7 June, 2007. Anton Norder, MSc Technical Officer . 20 Avenue Appia

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slide2

Good Manufacturing Practices – Part II

3 Specific GMP topics:

Premises, Documentation and Validation

WHO EMRO 1st Workshop on the WHO Prequalification Programme: Priority Essential Medicines,

Cairo, Egypt, 6 and 7 June, 2007

Anton Norder, MSc

Technical Officer

20 Avenue Appia

CH-1211 Geneva 27

Switzerland

E-mail: nordera@who.int

2

guidelines and references
Guidelines and references
  • Booklet:Quality Assurance of pharmaceuticals. A compendium of guidelines and related materials. Volume 2, second updated edition. Good manufacturing practices and inspection. World Health Organization, Geneva, 2007.
    • Good Manufacturing Practices for pharmaceutical products: main principles. WHO Technical Report Series, No. 908, 2003, Annex 4.
    • Good Manufacturing Practices: starting materials. WHO Technical Report Series, No. 823, 1992.
  • ICH Q7A: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, International Conference on Harmonizationhttp://www.ich.org/cache/compo/276-254-1.html
who guidelines and references cont d
WHO Guidelines and references (cont'd)
  • WHO Good Manufacturing Practices: water for pharmaceutical use. WHO Technical Report Series, No. 929, 2005, Annex 3 http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf
  • Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms. WHO Technical Report Series, No. 937, 2006, Annex 2 http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf
  • Supplementary guidelines on good manufacturing practices : validation. WHO Technical Report Series, No. 937, 2006, Annex 4 http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf
who guidelines and references cont d5
WHO Guidelines and references (cont'd)
  • WHO guidelines for sampling of pharmaceutical products and related materials. WHO Technical Report Series, No. 929, 2005, Annex 4 http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf
  • Good Practices for National Pharmaceutical Control Laboratories. WHO Technical Report Series, No. 902, 2002, Annex 3. http://whqlibdoc.who.int/trs/WHO_TRS_902.pdf#page=37
  • As well as specific GMPs on:
    • Sterile pharmaceutical products (2002)
    • Biologicals (1993)
    • Investigational pharmaceutical products for clinical trials in humans (1996)
    • Herbal medicinal products (1996/97)
    • Radiopharmaceutical products (2003)
however there s more gmp s
However there's more GMP's:
  • PIC/S GMP (Pharmaceutical Inspection Co-operation Scheme): www.picscheme.org ; adopted by many countries, e.g. European Union, or partially (Canada, Australia)
  • National GMP's in many countries (e.g. USA (www.fda.gov), China, India, Brazil, Argentina, etc.)
  • International Conference on Harmonization (ICH): www.ich.org
  • Also refer to ISO, e.g in cases of filter types in HVACs, clean room design, risk management, etc.
overview of specific gmp topics to be covered in this presentation
Overview of specific GMP topics to be covered in this presentation:
  • Part 1:Premises in relation to buildings, design, equipment, etc.
  • Part 2:Documentation
  • Part 3:Qualification and validation
part 1 premises
Part 1: Premises

Arrival of goods Visitors entrance Workers entrance Shipment of goods

Material Flow

People Flow

Zone: Clean

Zone: Packaging

Zone: Controlled

premises specific areas
Premises: specific areas

Note that specific requirements are given for specific areas:

  • Ancillary areas (gowning rooms, toilets, refreshment rooms, maintenance areas, animal housing etc)
  • Storage areas
  • Weighing areas
  • Production areas
  • Quality control areas

12.11 – 12.36

premises ancillary areas
Premises: ancillary areas
  • Rest and refreshment rooms separate from manufacturing and quality control areas
  • Changing, washing and toilet areas accessible and appropriate numbers
  • Maintenance workshops separated from production - if not possible – tools in reserved areas
  • Animal houses well isolated – separate air handling and entrance

12.11 – 12.14

premises receipt and storage of goods
Premises: Receipt and storage of goods
  • Separate receiving and dispatch bays
    • Materials and products protected from weather
  • Area to clean incoming materials provided
premises receipt and storage of goods14
Premises: Receipt and storage of goods

Cleaning of incoming containers

  • Cleaning with a cloth, or duster
  • Cleaning by using a vacuum cleaner
  • Use of air curtains and air tunnels
premises receipt and storage of goods15
Premises: Receipt and storage of goods
  • Storage areas of sufficient capacity
  • Orderly storage of categories of materials and products
  • Separate and segregated areas: starting materials, packaging materials, intermediates, bulk, finished products, quarantined, released, rejected, returned and recalled products and materials

12.15, 12.16

premises receipt and storage of goods18
Premises: Receipt and storage of goods
  • Appropriate temperature and relative humidity conditions within defined limits
    • Provided, controlled, monitored and recorded
  • Good storage conditions: clean, dry and appropriate lights

12.16, 12.17

premises receipt and storage of goods19
Premises: Receipt and storage of goods
  • Quarantine area: clearly marked and access restricted
  • Separate sampling area is the norm: no risk for contamination or cross-contamination
  • Segregated areas for rejected, recalled and returned materials and products
  • Safe and secure areas for highly active, radioactive materials, narcotics and other materials (risk of abuse, fire, explosion)

12.18 – 12.20, 12.22

premises receipt and storage of goods21
Premises: Receipt and storage of goods

Printed packaging materials

  • Critical to ensure correct labelling of products
  • Special attention to sampling of printed packaging materials
  • Special attention to safe and secure storage
  • Ensure compliance with specifications, prevent mix-ups

12.21

premises weighing
Premises: weighing
  • Weighing operations – in separated areas
  • Appropriate design (see also GMP on HVAC)
  • Provision for dust control
  • Smooth, impervious, durable, easy-to-clean finishes
  • Cleaning procedures and records
  • Documentation, e.g. SOPs, logs and records

12.23

requirements on premises
Requirements on premises:
  • Design
    • Walls, floors, ceilings, ledges, drains, air supply, dust extraction
  • Prevention of build-up of dirt and dust to avoid unnecessary risks of contamination
    • Cleaning programme, appropriate cleaning, cleaning records
  • Effective cleaning and disinfection
    • Choice of materials and chemicals, validation
  • Drains – prevent backflow
  • Protection from insects, birds, vermin and weather
    • from receipt of raw materials to dispatch of released product

12.2, 12.3, 12.7, 12.9, 12.29

design of premises
Walls, floors, ceilings – smooth and easy to clean

No ledges or areas where dust can accumulate

Prevention of build-up of dirt and dust to avoid unnecessary risks of contamination

Design of premises:
premises production areas
Premises: production areas

Minimize risk of cross-contamination:

  • Dedicated and self-contained facilities for some products such as highly sensitizing materials (e.g. penicillins) or biological preparations (e.g. live microorganisms)
  • Separate facilities for other products such as some antibiotics, hormones, cytotoxic substances
  • Non-pharmaceuticals normally not in the same facility, e.g. pesticides, herbicides

12.24

premises production areas27
Premises: production areas
  • Layout in accordance with sequence of production
  • Appropriate cleanliness level
  • Adequate work and in-process storage space
  • Orderly and logical positioning of equipment
    • minimizes risk of contamination, mix-ups and missing production steps
  • Specially designed areas for packaging
  • Layout to avoid mix-ups and cross-contamination

12.32, 12.26, 12.31

premises production areas28
Premises: production areas
  • Starting and packaging materials, intermediates and bulk exposed to environment:
    • Interior surfaces (walls, floors, ceilings) – smooth, free from cracks and open joints
    • No shedding of particles
    • Easy and effective cleaning permitted
  • Disinfection if needed

12.27

premises production areas29
Premises: production areas
  • Design of pipework, light fittings, and ventilation points – no recesses that are difficult to clean
  • Access for maintenance from outside production areas
  • Drains of adequate size, and equipped to prevent back-flow
  • Open channels avoided

12.28, 12.29

premises production areas30
Effective ventilation with air control facilities

Including filtration of air to a sufficient level to prevent contamination and cross-contamination – also external environment

Control of temperature and relative humidity where necessary

Regular monitoring of conditions during production and non-production periods

Premises: production areas

12.30

avoiding cross contamination
Avoiding cross contamination
  • Special precautions should be taken to prevent generation and dissemination of dust
  • Proper air control – supply and extraction, suitable quality
  • Due to uncontrolled release of:
    • dust, gas, particles, vapours, sprays, organisms, residue, insects
  • Dedicated and self-contained areas for:
    • Live vaccines
    • Live bacterial preparations
    • Certain other biological materials
    • Penicillin products

16.10 - 11

16.12(a)

avoiding cross contamination cont d
Avoiding cross contamination (cont'd)
  • Campaign production:
    • Separation in time
    • Followed by appropriate cleaning
    • Validated cleaning procedure
  • Ventilation systems and airlocks
    • Appropriately designed ventilation system with air supply and extraction systems
    • Supply or incoming air should be filtered
    • Recirculation of air versus 100% fresh air supply
    • Proper airflow patterns
    • Pressure differentials
    • Appropriately designed airlocks

16.12(b)

16.12 (c and d)

avoiding cross contamination cont d33
Avoiding cross contamination (cont'd)
  • Clothing
    • Protection of operator and product
    • Fit for its intended use
    • Highly potent products or those of particular risk - need for special protective clothing
    • Personnel should not move between areas producing different products
    • Garments need to be cleaned

16.12(e)

avoiding cross contamination cont d34
Avoiding cross contamination (cont'd)
  • Cleaning and decontamination
    • Procedure for removing soil and dirt
    • Remove all cleaning chemical residues or disinfectant residues
    • Remove and/or reduce micro-organisms
    • Validated (known effectiveness of the procedure)
    • Use cleanliness status labels
    • Test for residues
  • Closed processing systems
    • For example: totally enclosed water purification systems
    • Tanks fitted with appropriate filtration - without removable lids
    • Present special cleaning difficulties, sometimes use

clean-in-place (CIP)

16.12(f, h and i)

16.12(g)

sanitation in production operations
Sanitation in production operations
  • Work-flow
    • designed to avoid potential contamination
  • Access
    • to production areas restricted to authorized personnel
    • direct operators, QC staff, warehouse staff, maintenance personnel, cleaners
    • the more critical the area - fewer number of persons there
  • Simultaneous operations
    • not permissible to process different products in different areas with a common ventilation system
    • permissible to carry out secondary packaging activities for different products within a packing hall with adequate physical separation
sanitation in production operations cont d
Sanitation in production operations(cont'd)

Area clearance checks:

  • Process of checking
    • all materials and documentation from the previous batch removed
    • all plant and equipment thoroughly cleaned and appropriate status labelling
    • checklist useful
  • The area clearance check should be carried out by two persons
    • between batches of same product, acceptable for both checks to be carried out by production personnel
    • for product changeover, second check carried out by QC staff
    • all checks carried out in accordance with written SOP and results recorded on the batch documentation.
e g line clearance in packaging
E.g. line clearance in packaging
  • Absence of all materials from previous run, including printing masters
  • Includes checks on materials and components
  • Batch number
  • Expiry date
  • Printed packaging material including cartons, leaflets, foil . . .
sanitation in production operations cont d38
Sanitation in production operations(cont'd)
  • Cleaning and cleaning validation
    • degree of cleaning depends on whether consecutive batches are of same or different product
  • Check cleaning agent is fully removed
  • If possible hot water alone used for cleaning
    • all cleaning and disinfecting solutions carefully prepared and expiry dated
  • For sterile products: Final rinse with purified water, or water for injection
  • Full records kept
sanitation in production operations cont d39
Sanitation in production operations(cont'd)
  • Maintenance and repair
    • activities inevitable in manufacturing area
    • Should present no risk to product
  • Whenever possible, all planned maintenance outside normal operating hours
  • Emergency work in working area followed by thorough clean down and disinfection before manufacturing recommences
  • Area clearance by QC
basic principles on premises in gmp
Basic Principles on premises in GMP
  • The temperature and relative humidity should be controlled, monitored in accordance with an SOP, and the results recorded. The limits should be appropriate according to the materials stored and product processed
premises maintenance
Premises: maintenance
  • Careful maintenance done
  • Repairs and maintenance should not present any hazard to the quality of the products

12.6

premises of quality control labs
Premises of Quality Control Labs
  • QC laboratories should be separate from production areas
  • Separate areas for biological, microbiological and radioisotope methods
  • Suitable design with sufficient space to avoid mix-ups and cross-contamination
  • Suitable space for storage samples, reference standards, solvents, reagents and records

12.33, 12.34

part 2 documentation
Part 2: Documentation

Objectives

1. To review general requirements for documents

2. To review specific requirements for each document

3. To consider current issues applicable to your countries

documentation
Documentation
  • Essential part of the QA system, for all aspects of GMP
  • Purpose of documentation
    • Defines specifications and procedures for all materials and methods of manufacture and control
    • Ensures all personnel know what to do and when to do it
    • Ensure that authorized persons have all information necessary for release of product
    • Ensures documented evidence, traceability, provide records and audit trail for investigation
    • Ensures availability of data for validation, review and statistical analysis
  • Design and use
    • Depends upon manufacturer
    • Some documents combined into one, sometimes separate

15.1

documentation47
Documentation

Why are documents so important?

  • Communication
  • Cost
  • Audit trail
documentation general principles
Documentation: general principles
  • Documents should be
    • Designed, prepared, reviewed, distributed with care
    • Approved by appropriate responsible persons
  • Comply with marketing authorization
  • Design of documentation important
  • Look at the “Style” of the document
    • Instructions in the imperative
    • Short sentences preferred to long sentences

15.2

documentation general principles cont d
Documentation: general principles (cont'd)
  • Contents of documents should be clear (easy to understand) and include, e.g.
    • Title, nature, objective or purpose
  • Layout in orderly fashion
  • Easy to be filled in and checked
  • Clear and readable – including copies made
  • No errors if master documents are copied for working documents

15.4

documentation general principles cont d50
Documentation: general principles (cont'd)

Documentation control

  • Regular review of documents
  • Kept up to date (current) - amended
  • Superseded documents removed and not used
    • Distribution and retrieval of documentation
  • Retention time for superseded documents

15.5

data entry in documents
Data entry in documents:
  • Clear, readable and indelible
  • Design to allow for sufficient space for entries
  • Changes to entries:
    • signed, dated and reason given
    • original entry still readable
  • Entries at the time of action
  • All significant actions recorded – traceable

15.6 – 15.8

data entry in e documents
Data entry in e-documents:
  • Electronic data processing systems, photographic systems or other reliable means:
    • Systems require SOPs and records
    • Accuracy of records checked
    • Authorized persons - access and changes
    • Password controlled
    • Entries checked
  • Batch records stored electronically:
    • Protected
    • Back-up transfer, e.g. magnetic tape, microfilm, paper print-outs
  • Records kept 1 year after expiry date of product
  • Data readily available during retention period

Validation of

computer system

15.9

different types of documents
Different types of documents
  • Labels
  • Specifications and testing procedures
  • Master formulae and instructions
  • Batch processing and batch packaging records
  • Standard Operating Procedures (SOPs)
  • Records
    • Stock control and distribution records
  • Log books
  • Other documents …
labels
Labels

What must be labelled?

Containers, equipment, premises

Label information?

Clear, unambiguous, company format

Intermediates and bulk products

Colours can be used, e.g. green (accepted), red (rejected)

Different types of labels, e.g. cleaning status, production stage, status of materials

Other types of labels?

15.10

specifications
Specifications
  • Authorized, approved, signed and dated
    • Starting, packaging materials and finished products: include tests on identity, content, purity, quality
    • Intermediates and bulk
    • Water, solvents and reagents
  • QC, QA or documentation centre
  • Periodic review
  • Compliance with current pharmacopoeia
  • Pharmacopoeia, reference standards and spectra available

15.14 - 15.17

specifications starting and packaging materials
Specifications: Starting and packaging materials

Include:

  • Name (e.g. INN) and internal code
  • Pharmacopoeia (if applicable)
  • Qualitative and quantitative requirements and limits

Other data may include:

  • Supplier
  • Sampling procedure or reference
  • Storage conditions, precautions
  • Retest date

15.18 -15.19

specifications finished products
Specifications: Finished products

Include:

  • Name and code reference
  • Names of actives (e.g. INN)
  • Formula
  • Dosage form, package details
  • Reference to sampling
  • Qualitative and quantitative requirements and limits
  • Storage conditions and precautions
  • Shelf life

15.21

production documentation
Production documentation
  • Bulk manufacturing:
    • Master formulae
    • Batch Processing Records
  • Packaging:
    • Packaging instructions
    • Batch Packaging Records

The Master formulae and the Packaging instructions are the connection document between Marketing Authorization, Specifications and the actual records

15.22 – 15.30

standard operating procedures sops
Standard Operating procedures (SOPs)
  • Describe one particular process in detail
  • Required for a lot of activities mentioned in WHO chapter 15
  • Many other activities outlined elsewhere in GMPs also require SOPs
  • SOPs are non-batch related
  • Authorization
  • Periodic review
  • Version management
  • Clear instruction, no ambiguities

15.31 – 15.48

part 3 qualification and validation
Part 3: Qualification and Validation

Definitions:

Validation

Action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material, activity or system actually leads to the expected results

Qualification

Action of proving that any premises, systems and items of equipment work correctly and actually lead to the expected results

(Validation usually incorporates the concept of qualification)

Glossary

system life cycle

Recommendation

Retirement

Project Initiation

O

Aging

Conceptualization

P

E

Validation

Development

R

Release

A

for Use

Early Operational

T

Maturity

Life

I

O

N

A

E

L

F

I

L

System life cycle:
qualification and validation
Qualification and Validation
  • Design Qualification (DQ): documentary evidence that a premises, equipment or process has been designed in accordance with GMP requirements
  • Installation Qualification (IQ): documentary evidence that a premises, equipment or process has been built and installed in accordance with GMP requirements
  • Operational Qualification (OQ): documentary evidence that a premises, equipment or process operate in accordance with GMP requirements
  • Performance Qualification (PQ): documentary evidence that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes

4.3

qualification and validation66
Qualification and Validation

Principle

  • Qualification and validation should be done in accordance with an ongoing programme
    • Initial qualification and validation
    • Annual review
  • Maintain continued validation status
  • Policy described in relevant documentation, e.g. quality manual, or Validation Master Plan

4.5, 4.6

types of validation documentation
Types of validation documentation
  • Validation Master Plan (VMP): policy, responsibilities, management of validation process etc.
  • Validation protocols
  • Validation reports
  • Standard Operating Procedures (SOPs)
validation master plan vmp
Validation Master Plan (VMP)
  • Approval page and table of contents
  • Introduction and objectives
  • Facility and process description
  • Personnel, planning and scheduling
  • Responsibilities of validation team members
  • Process control aspects
  • Equipment, apparatus, processes and systems qualified, validated – and to be qualified or validated
  • Acceptance criteria
  • Documentation, e.g.validation protocols and reports
  • SOPs
  • Training requirements and other elements…
requirements to validation documentation
Requirements to Validation documentation
  • Clearly defines responsibility of performing validation
  • Conducted in accordance with predefined, approved validation protocols
  • Conducted in accordance with predefined, approved acceptance criteria
  • Recorded results and conclusions presented in written validation reports – prepared and stored
  • Processes and procedures should be established on the basis of these results
  • Premises, utilities, equipment and processes
  • Critical importance and particular attention paid to validation of:
    • Analytical test methods
    • Automated systems
    • Cleaning procedures

4.7 – 4.11

qualification and validation70
Qualification and Validation

WHO References

  • Good manufacturing practices (GMP): guidelines on the validation of manufacturing processes
  • Validation of analytical procedures used in the examination of pharmaceutical materials

Annex 6

example of priorities for process validation
Example of priorities for process validation

Type of processRequirement

  • New Every new process before approval for routine
  • Existing:
    • Sterile products All processes affecting the sterility, and

manufacturing environment including

sterilization stage

    • Non-sterile Low dose tablets and capsules: mixing and

granulation; content uniformity (and other

parameters)

Other tablets and capsules: uniformity of mass

(and other parameters)

qualification and validation72
Qualification and Validation
  • A qualification or validation protocol may contain:
    • Objectives of the validation and qualification study
    • Site of the study
    • Responsible personnel
    • Description of the equipment
    • SOPs
    • Standards
    • Criteria for the relevant products and processes
qualification and validation73
Qualification and Validation
  • A qualification or validation report should reflect the elements of the protocol, and may contain elements such as:
    • Title
    • Objective of the study
    • Reference to the protocol
    • Details of materials, equipment, instruments, personnel
    • Programmes and cycles used
    • Details of procedure and test methods

… etc.

possible problems in qualification and validation
Possible problems in Qualification and Validation
  • Lack of time
  • Lack of personnel
  • Lack of experience and knowledge
  • Changes to the process
  • Prospective versus retrospective validation
  • Lack of documentation infrastructure
  • Lack of implementation of validation
  • Poorly designed documents
some gmp topics not covered today
Some GMP topics not covered today:
  • Vendor evaluation
  • Personnel
  • Training
  • Recall
  • QC laboratories
  • Stability
  • Etc.