1 Good Manufacturing Practices in the manufacture of medicines The World Health Organization (WHO) GMP rules are the subject of the course.

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Good Manufacturing Practices

in the manufacture of medicines

The World Health Organization (WHO) GMP rules are the subject of the course

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I am afraid, the industrial drug manufacture is a bit more complicated than this…

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starting already outside, in the yard

4active substance manufacture

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dosage-form manufacture

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computer-aided manufacture

7control lab

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GMP certificate

issued by the

national GMP compliance monitoring authority

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GMP

• Basic Principles• Specific rules

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GMP: „soft” and „hard” law

„The manufacturer should possess adequate…

• number of personnel...• with adequate qualification...• manufacturing area…”

Impossible to specify the values in a law!

The inspector will decide on the spot whether the requirement is met!

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Introduction

to the Training Course

Basic Principles of GMP

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Programme Overview – IBasic Principles of GMP

1. Quality Management 2. Sanitation and hygiene3. Validation

4. Complaints and recalls

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Programme overview IIBasic Principles of GMP

5. Contract production and analysis 6. Self Inspection

7. Personnel

8. Premises

9. Equipment

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Programme overview - IIIBasic Principles of GMP

10. Materials

11. Documentation 12. Sterile production13. Active pharmaceutical

ingredients

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Programme overview - IV

GMP Inspection Process14. Introduction

15. The role of the inspector

16. Preparation for the inspection17.Types of GMP inspection18. The inspection

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Basic principles of GMPin more detail

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1. Quality Management

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European Union Directive

„The manufacturer shall establish and implement an effective pharmaceutical QA system, involving the active participation of the management and personnel of the different services involved”

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The Quality Management

• The first, introductory chapter of the WHO GMP

• Having defined some concepts and terms, it summerises what is also detailed in other chapters (do not be surprised if its parts are also reproduced

elsewhere)

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Quality Management

Objectives• To understand/identify key issues in

quality assurance/quality control• To understand/identify specific

requirements on organization, procedures, processes and resources

• To develop actions to resolve your current problems

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Quality Management• Determines and implements the “quality

policy”• The basic elements are:

– an appropriate infrastructure or “quality system” encompassing the Procedures, Processes, and Resources

– the systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for “Quality”

The totality of these actions is termed “Quality Assurance”

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Quality Management• Terminology may differ (e.g. from ISO)

– “Quality System” is said to be rarely used in drug manufacturing

• The concepts of QA, GMP and Quality Control are interrelated aspects of Quality Management. – They are described on the following slides in

order to emphasize their relationship and their fundamental importance to the production and control of pharmaceutical products

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Quality Management

Principles of Quality Assurance• Wide-ranging concept

– covers all matters that individually or collectively influence the quality of a product = responsibility of everyone

• Totality of the arrangements– to ensure that the drug is of the right quality for

the intended use

• Quality Assurance incorporates GMP– and also product design and development which

is outside the scope of this module

Requirements for QA Systems

Think over what should be done properly during drug manufacture!

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Quality Management

Requirements for QA Systems – I1. Ensure products are developed correctly2. Identify managerial responsibilities3. Provide SOPs for production and control

Standard Operating Procedures

4. Organize supply and use of correct starting materials

5. Define controls for all stages of manufacture and packaging

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Quality Management

Requirements for QA Systems – II6. Ensure finished product correctly

processed and checked before release7. Ensure products are released after

review by authorized person8. Provide storage and distribution 9. Organize self-inspection

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Quality Management GMP

• Ensure that products are consistently produced and controlled

• Diminishes risks that cannot be controlled by testing of product– Cross-contamination– Mix-ups

the most life-threatening mistakes!

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Quality Management

Basic Requirements for GMP – I1. Clearly defined and systematically

reviewed processes2. Critical steps validated3. Appropriate resources: personnel,

buildings, equipment, materials4. Clearly written procedures 5. Trained operators

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„Clearly defined and systematically reviewed manufacturing processes”

• = all relevant quality specifications, SOPs and batch documentation must be prepared in harmony with each other

• It also means that the Departments involved know each other’s task to eliminate discrepancies

• Also: QC/QA staff is acting as coordinator and is involved in all decisions

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„Critical steps validated”• There is a variability in the quality of

incoming materials and in the performance of the equipment, we need to check whether the process works with all varibaility that can arise

• The process of checking and documenting variability = validation

• if validation, we have sufficient knowledge of materials, equipment and process = what variables arelikely to arise.

• Then we carry out controlled experiments to ensure that whatever variables cab occur, the product still meets the specification

• Validation is also needed when there is any change in materials, process or equipment

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„Appropriate resources: personnel, buildings, equipment and materials”

• These all should be available to produce a quality product.

• Thus, the company should evaluate all of the elements it needs to produce a drug to see that it has sufficient resources

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„Manufacture is based on clearly written procedures”

• Procedures:– batch manufacturing instructions– testing instructions– SOPs needed for all departmants

• Preparing these documents is very important task (see Documentation)

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„Trained operators”

• Documentation, instructions, etc. are not enough if the operators can not work with them properly

• Training includes also follow-up training

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Quality Management

Basic Requirements for GMP – II6. Complete records, failure

investigations7. Proper storage and distribution 8. Recall system9. Complaint handling

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„Complete records, failure investigations”

• (We have just seen there are manufacturing, packaging, QC, etc. instructions how to perform the work)

• Also records are needed to show what and how was actually done each time, by whom, etc.

• If there is a reason later to come back to check what happened with a given batch, the only possibility is to check the records

• E.g. when failures are found later

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„Proper storage and distribution”

• When a new drug is developed, stability studies determine the storage conditions and its shelf-life

• However, the storage conditions should be met!

• Also during distribution!

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„Recall system”

• If quality problems detected when the product is already on the market, there should be a system to recall them (from wholesalers or from pharmacy level)

• System, for there can be different ways anddegress of severity, depending upon the reasons for the recall

Simple circular information by letter<by fax<TV and press warning if life threatening, etc.

Involvement of national regulatory authorities – according to local law

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Complaint handling

• If the complaint of a purchaser or consumer is possibly related to manufacturing defects, it is worth of investigation

• This way its re-occurrence can be prevented

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Quality Management Cascade

Quality relationships

Quality Management (overall policy)

Quality Assurance (concept ensuring that the policy is achieved)

GMP (how to do it)

Quality Controlincluding

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Quality Management Quality Control (QC) Department

• Each holder of a manufacturing authorization should have a QC Department

• Independence from production and other departments is considered to be fundamental

• Under the authority of an appropriately qualified and experienced person with one or several control laboratories at his or her disposal.

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Quality Management

Basic Requirements for Quality Control

Resources• Adequate facilities• Trained personnel• Approved procedures

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Quality ManagementBasic Requirements for Quality

ControlTasks

• Sampling• Inspecting• Testing• Monitoring (materials, environmental conditions)

• Releasing/rejecting

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Basic Requirement for Quality Control - I

Objects• Starting materials• Packaging materials• Intermediates• Bulk products• Finished products• Environmental conditions

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Basic Requirements for QC - II

1. Sampling approved by QC department not necessarily done by them, but ensuring samples are representative

2. Validated test methods accurate, precise, robust, specific, linear…

3. Records of sampling, inspecting, testing, of incoming materials, intermediates, bulk and packaged finished products

4. Review and evaluation of production documentation for release: not only test results

5. Failure investigations for all deviations 6. Ingredients comply with the marketing

authorization

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Basic Requirements for QC - III

7. Ingredients are of the required purity 8. Proper containers compatibility!

9. Correct labelling mislabelling = life-threatening error

10. Release of batches by the authorized person who has the right – predetermined persons with adequate qualification and experience

11. Retained samples of starting materials and products

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Other Duties of the QC Department

1. Establish QC procedures and validation in the first time then its „release”

2. Reference standards and their storage! Mainly test results rely on the comparison with the reference standards…

3. Correct labelling 4. Stability testing 5. Complaint investigations6. Environmental monitoring

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Assessment of Finished Products

Should embrace all relevant factors (not only the QC test results!). For example:

• production conditions• in-process test results• manufacturing documentation• compliance with finished product

specification• examination of the finished pack

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QC Access

• QC Personnel MUST have access to production areas for sampling and investigation

• As appropriate! E.g. not appropriate: entering in aseptic filling suites, or where highly potent dangerous materials are present…

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QC - Summary QC is part of GMP

– sampling– specifications – testing– release procedures– recalls and complaints– decision-making in all quality matters

– authorization– definition of product

quality– laboratory

operations– release decisions– investigation and

reporting

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Quality management

also means:• identification• assessment• cotrol (keeping under control)• presentation (to all interested

persons)of any risk factor that may affect the

quality of the medicine

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Quality ManagementGroup session II

• Imagine you are inspecting a pharmaceutical company for compliance with GMP

• Consider the situations in the next slides which may impact on a company’s quality management programme

• Describe the action to be taken in each case

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Issues 1• Quality Management manual not established

in writing• Limited human resources • Lack of qualified people• Processes not properly validated• Poor SOPs or standard batch documentation• More consideration to cost than quality• Family members in key positions of authority

Quality Management

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Issues 2• Substandard materials deliberately

purchased• Technical staff not involved in purchasing • Inability to re-export substandard

materials• Owner insists on selling rejects• Corruption• No commitment to training

Quality Management

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Before starting: definitions

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Definitions 1

• In-process control IPC: QC during the production

• Campaign working: separated in time

• Quarantine: separation of the the incoming or newly manufactured product until the release

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Definition 2

• Release: decision on a batch: whether it meets the requirement (or not), based on both QC results and batch production records

• Key persons: head of production, head of QC/QA + the qualified person QP if different from the latter

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Definitions 3

• Standard Operating Procedure SOP: description of a technological procedure

• Intermedier product: product between the starting materials and the final product

• Bulk: starting materials and intermediates as well as final products e.g. in barrels

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Definitions 4

• Yield in synthesis: based on the chemical formulas, molecular weights, the reaction equation and the measured-in quantities

• Yield in dosage-form production: based on the measured-in quantities and the quantitative composition of one tablet

Never 100%!

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2. Sanitation and Hygiene

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Sanitation and Hygiene

Objectives• Review measures to ensure good

sanitation in:– premises– equipment– processes

• To review measures to ensure good personnel hygiene

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Sanitation and Hygiene, scope

All aspects of manufacturing• Personnel who enter the manufacturing area

• Premises the level of attention will depend on the nature of the operation carried out there

• Equipment• Apparatus• Production materials and container if not handled properly can

contribute to dirt

• Products for cleaning and disinfection but cleaningagents also controlled = they do their job but do not contaminate the product. Also cleaning tools e.g. brushes

• All potential sources of cross-contamination

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Design of Premises - I

• 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 (e.g. cleaning a warehouse differs from

cleaning a sterile area), its frequency, cleaning records

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Design of Premises - II

• Effective cleaning and disinfection– choice of materials and chemicals,

validation• Drains no back-flow, in sterile areas: at a minimum, • Protection from insects, vermin and

weather– from receipt of raw materials to

despatch of released product

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Design of Premises:

avoidance of cross-contaminationDefinitions:• Contamination: by a foreign matter• Cross-contamination: by a material

also manufactured there

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Avoidance of Cross-contamination - I

• Segregated areas• Ventilation systems and airlocks• Clothing• Closed processing systems• Cleaning and decontamination

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Avoidance of Cross-contamination - II

• Segregated areas and separate facilities for

– live vaccines and other biological materials

– penicillin products – campaign processing

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Avoidance of Cross-contamination - III

Ventilation systems and airlocks – design of ventilation system– incoming air should be filtered – pressure differentials and air extraction positive

pressure

– airlocks – airflow patterns and equipment design – recirculation versus 100% fresh air supply

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Avoidance of Cross-contamination - IV

Clothing

– protection of operator and product– 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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personnel in different coloured garments

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Avoidance of Cross-contamination - V

Closed processing systems, i.e.– totally enclosed water purification systems– tanks fitted with appropriate filtration -

without removable lids– present special cleaning difficulties,

sometimes use clean-in-place (CIP)

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Avoidance of Cross-contamination - VI

Cleaning and decontamination– procedure for removing soil and dirt– remove all cleaning chemical

residues or disinfectant residues– must remove or reduce micro-

organisms

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Product Operations – Sanitation 1

• Work-flow– designed to avoid potential contamination– access restricted to authorised persons

exclusively• operators• QC staff• warehouse staff• maintenance personnel• cleanersthe more critical the more restriction!

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Production Operations – Sanitation 2

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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Production Operations – Sanitation 3

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

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Production Operations - Sanitation 4

Area clearance checks a)• The area clearance check should be

carried out by two people – between batches of same product,

acceptable for both checks to be carried out by production personnel it is the first manufacturing/packaging step!

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Production Operations – Sanitation 5

Area clearance checks b)• The area clearance check should be

carried out by two people – 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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Production Operations - Sanitation 6

• 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

• Final rinse with purified water, or water for injection (for sterile products)

• Full records kept

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Production Operations – Sanitation 7

• Water systems • Water - major constituent of most products• SOP for cleaning and sanitisation of the

water purification system should include distribution pipework

• Validation and removal of disinfectant before reuse

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Production Operations – Sanitation 8

• 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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Personnel Hygiene 1• Health examinations

– On recruitment for direct operators , repeated on regular basis

• Training - check – induction training for new operators includes

basic personal hygiene training – written procedures - to wash hands before

entering a manufacturing area– signs in changing rooms to reinforce hand

washing!

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Personnel Hygiene 2

• Illness– staff with illness or open lesions

should not handle starting materials, intermediates or finished products

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Personnel Hygiene 3

• Adverse conditions– operators trained to recognize risks – willingness to report illness to the

area supervisor easy? What happens? People can be motivated to the opposite!

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Personnel Hygiene 4

• Contact between product and operator– avoid direct contact– if direct handling unavoidable,

gloves should be worn – check glove disinfection (for

sterile production) and disposal

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Personnel Hygiene 5

• Clothing and changing facilities a)– check changing rooms

(handwashing, towels or hot air hand dryers) opening taps

– check if used clothing stored in separate closed containers while awaiting cleaning

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Personnel Hygiene 6

• Clothing and changing facilities b) – laundering of clean area clothing

must be to SOP and in appropriate facility

– check for procedure for sterilizing and storing clothing for use in sterile area

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Personnel Hygiene 7

• Smoking, eating and drinking should not be allowed in any manufacturing area, including laboratories and storage rooms

• Chewing of gum should be banned

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Personnel Hygiene 8

• There should be no plants kept inside any factory areas.

• Rest and refreshment areas should be separate from manufacturing areas.

• Toilets should not open directly into production or storage areas.

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Sanitation and Hygiene

Group Session

You are inspecting a new factory. What are the key issues for sanitation and the key issues for personnel hygiene that the company should have in place?

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Sanitation and Hygiene Possible Issues – Sanitation 1

• Mixed production• Penicillins• Product versus batch changeovers• Water systems• How long should a “cleaned” status last

for?

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Sanitation and Hygiene Possible Issues – Sanitation 2

• What should happen if a clearance check is required when no QC personnel are on duty?

• Procedures and records

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Sanitation and Hygiene

Possible Issues – Hygiene

• Personal hygiene• Health checks• Dealing with health problems• Personal responsibility • Training records• Frequency of handwashing

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Exam topic

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Sanitation and hygiene in GMP

• Design of premises (walls, ceilings, floors, drains, cleaning programme, protection from external factors)

• Avoidance of cross-contamination (mention measures)

• Campaign working versus dedicated manufacture areas for certain drugs (examples!).

• Clothing• Health measures• Cleaning