GMP-part II

Prequalification Programme: Access to Antimalarial, Antituberculosis and Prequalification Drugs and HIV/AIDS Diagnostics of Acceptable Quality anti HIV/AIDS
Programme: Priority Essential Medicines 1
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 Prequalification Programme: Access to Antimalarial, Antituberculosis and CH-1211 Geneva 27 Prequalification Drugs and HIV/AIDS Diagnostics of Acceptable Quality anti HIV/AIDS Programme: Priority Essential Medicines Switzerland 2 E-mail: nordera@who.int
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 Harmonization http://www.ich.org/cache/compo/276-254-1.html
Prequalification Programme: Access to Antimalarial, Antituberculosis and Prequalification Drugs and HIV/AIDS Diagnostics of Acceptable Quality anti HIV/AIDS Programme: Priority Essential Medicines 3
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'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:
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:
Part 1: Premises in relation to buildings, design, equipment, etc.

Part 2: Documentation
Part 3: Qualification and validation
Part 1: Premises
Arrival of goods Visitors entrance Workers entrance Shipment of goods
QC Incoming goods Corridor Corridor Raw Materials & Packaging Storage
Offices Gowning
Canteen Shipping
Material Flow People Flow Zone: Clean Zone: Packaging
Corridor
Weighing
Processing
Filling
Packaging
Finished Products Storage
Zone: Controlled
Washing
Machine Shop Corridor Waste Treatment
Utilities and Services
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
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
F C O Y A T R
C A G H N E R O O M
A IR LO K C T ILE S O T
C N E N A T E
Premises: Receipt and storage of goods
Separate receiving and dispatch bays Materials and products protected from weather Area to clean incoming materials provided
Cleaning of incoming containers
Cleaning with a cloth, or duster
Cleaning by using a vacuum cleaner

Use of air curtains and air tunnels
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
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
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
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
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
Premises: weighing
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 12.2, 12.3, 12.7, 12.9, 12.29 Drains prevent backflow Protection from insects, birds, vermin and weather from receipt of raw materials to dispatch of released product
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
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
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
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
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
Effective ventilation with air control facilities Including filtration of air to a sufficient level to prevent contamination and crosscontamination also external environment Control of temperature and relative humidity where necessary Regular monitoring of conditions during production and non-production periods
12.30
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
16.10 - 11
Dedicated and self-contained areas for: Live vaccines Live bacterial preparations Certain other biological materials Penicillin products
16.12(a)
Avoiding cross contamination (cont'd)
Campaign production: Separation in time Followed by appropriate cleaning Validated cleaning procedure
16.12(b)
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 16.12 (c and d) Appropriately designed airlocks
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)
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 16.12(f, h and i) 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(g)
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)

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
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 . . .
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
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
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

Careful maintenance done Repairs and maintenance should not present any hazard to the quality of the products
12.6
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
Premises of Quality Control Labs
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

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 15.1 Depends upon manufacturer Some documents combined into one, sometimes separate
Documentation
Documentation
Why are documents so important?
Communication
Cost
Audit trail
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)
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'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:
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:
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
15.9
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
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
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

Include:
Name (e.g. INN) and internal code
Pharmacopoeia (if applicable)

Qualitative and quantitative requirements and limits Supplier Sampling procedure or reference Storage conditions, precautions Retest date
15.18 -15.19
Other data may include:

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
Bulk manufacturing:

Master formulae Batch Processing Records

15.22 15.30
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
Documentation
Documentation
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
Standard Operating procedures (SOPs)
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:

Retirement Recommendation
Project Initiation O P E Development R A Release for Use Maturity I O Aging
N
A L Prequalification Programme: Access to Antimalarial, Antituberculosis and Prequalification Drugs and HIV/AIDS Diagnostics of Acceptable Quality anti HIV/AIDS Programme: Priority Essential Medicines 64 L I F E
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
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
Validation Master Plan (VMP): policy, responsibilities, management of validation process etc. Validation protocols Validation reports Standard Operating Procedures (SOPs)
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

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

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

Type of process
Requirement Every new process before approval for routine
New
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)
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
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
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:
Vendor evaluation
Personnel Training Recall QC laboratories Stability
Etc.
http://www.who.int/prequal

GMP-part II

Enviado por

Dados do documento

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

GMP-part II

Enviado por

Direitos autorais:

Formatos disponíveis

Prequalification Programme: Access to Antimalarial, Antituberculosis and Prequalification Drugs and HIV/AIDS Diagnostics of Acceptable Quality anti HIV/AIDS

Programme: Priority Essential Medicines 1

Guidelines and references

WHO Guidelines and references (cont'd)

WHO Guidelines and references (cont'd)

However there's more GMP's:

Overview of specific GMP topics to be covered in this presentation:

Part 1: Premises in relation to buildings, design, equipment, etc.

Part 3: Qualification and validation

QC Incoming goods Corridor Corridor Raw Materials & Packaging Storage

Material Flow People Flow Zone: Clean Zone: Packaging

Finished Products Storage

Machine Shop Corridor Waste Treatment

Utilities and Services

Premises: specific areas

Premises: ancillary areas

Premises: ancillary areas

Premises: ancillary areas

Premises: Receipt and storage of goods

Premises: Receipt and storage of goods

Cleaning of incoming containers

Cleaning with a cloth, or duster

Cleaning by using a vacuum cleaner

Premises: Receipt and storage of goods

Premises: Receipt and storage of goods

Premises: Receipt and storage of goods

Premises: Receipt and storage of goods

Premises: Receipt and storage of goods

Quarantine area: clearly marked and access restricted

Premises: Receipt and storage of goods

Premises: Receipt and storage of goods

Premises: production areas

Premises: production areas

Layout in accordance with sequence of production Appropriate cleanliness level

Adequate work and in-process storage space

minimizes risk of contamination, mix-ups and missing production steps

Specially designed areas for packaging

Premises: production areas

Premises: production areas

Premises: production areas

Avoiding cross contamination

Avoiding cross contamination (cont'd)

Avoiding cross contamination (cont'd)

Personnel should not move between areas producing different products

Avoiding cross contamination (cont'd)

Sanitation in production operations

Sanitation in production operations (cont'd)

for product changeover, second check carried out by QC staff

E.g. line clearance in packaging

Sanitation in production operations (cont'd)

Cleaning and cleaning validation

Sanitation in production operations (cont'd)

Basic Principles on premises in GMP

Premises of Quality Control Labs

Premises of Quality Control Labs

Why are documents so important?

Documentation: general principles

Instructions in the imperative Short sentences preferred to long sentences

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

Documentation: general principles (cont'd)