gmp-part ii

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Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable QualityPrequalification Programme: Priority Essential Medicines

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Good Manufacturing Practices – Part II

3 Specific GMP topics:Premises, Documentation and

Validation

Anton Norder, MScTechnical Officer

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

Cairo, Egypt, 6 and 7 June, 2007

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20 Avenue AppiaCH-1211 Geneva 27Switzerland E-mail: [email protected]

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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

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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

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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)

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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.

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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

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Q C

Offices Gowning

Canteen

Incoming goods

Corridor

Corridor

Shipping

Corridor

Packaging

Weighing Processing

Filling

Raw Materials

& Packaging Storage

Washing

Machine

Shop

Finished Products Storage

Corridor Utilities and Services Waste Treatment

Part 1: Premises

Arrival of goods Visitors entrance Workers entrance Shipment of goods

Material Flow

People Flow

Zone: Clean

Zone: Packaging

Zone: Controlled

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12.11 – 12.36

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

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12.11 – 12.14

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

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TOILETS

AIRLOCK

CANTEEN

FACTORY CHANGEROOM

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Premises: Receipt and storage of goods

Separate receiving and dispatch bays

Materials and products protected from weather

Area to clean incoming materials provided

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Cleaning of incoming containers

Cleaning with a cloth, or duster

Cleaning by using a vacuum cleaner

Use of air curtains and air tunnels

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12.15, 12.16


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

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12.16, 12.17


Appropriate temperature and relative humidity conditions within defined limits

Provided, controlled, monitored and recorded

Good storage conditions: clean, dry and appropriate lights

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12.18 – 12.20, 12.22


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)

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12.21


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

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12.23

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

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Premises: weighing

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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

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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

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12.24

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

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12.32, 12.26, 12.31


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

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12.27


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

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12.28, 12.29


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

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12.30


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

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16.10 - 11

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

16.12(a)

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16.12(b)

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 (c and d)

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16.12(e)


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

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16.12(f, h and i)


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(g)

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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

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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.

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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 . . .

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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

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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

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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

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12.6

Premises: maintenance

Careful maintenance done Repairs and maintenance should not present any hazard to the

quality of the products

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12.33, 12.34

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

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Premises of Quality Control Labs

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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

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15.1

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

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Documentation

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Why are documents so important?

Communication

Cost

Audit trail

Documentation

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15.2

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

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15.4

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

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15.5

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

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15.6 – 15.8

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

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15.9

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

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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 …

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15.10

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?

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15.14 - 15.17

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

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15.18 -15.19

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

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15.21

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

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15.22 – 15.30

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

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Documentation

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Documentation

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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

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Standard Operating procedures (SOPs)

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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

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System life cycle:Retirement

Recommendation

Maturity

Aging

Development

Project Initiation

Releasefor Use

Co

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ptu

aliz

atio

n

Early OperationalLife

O

P

E

R

A

T

I

O

N

AL

L IF

E

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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

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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

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Types of validation documentation

Validation Master Plan (VMP): policy, responsibilities, management of validation process etc.

Validation protocols

Validation reports

Standard Operating Procedures (SOPs)

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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…

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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

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Annex 6


WHO References

Good manufacturing practices (GMP): guidelines on the validation of manufacturing processes

Validation of analytical procedures used in the examination of pharmaceutical materials

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Example of priorities for process validation

Type of process Requirement

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)

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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

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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.

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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

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Some GMP topics not covered today:

Vendor evaluation Personnel Training Recall QC laboratories Stability

Etc.

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http://www.who.int/prequal