GOOD MANUFACTURING PRACTICE (GMP) IN THE MAKING

OF (PHARMACEUTICALS) MEDICINES
What are Medicines?
Medicines come in various forms.
Liquids, creams, powders, ointments, tablets, capsules, eye drops, lotions,
injections and many more.
MEDICINES are administered in order to:-
• Treat a disease or illness
• Prevent a disease or illness
• Alleviate the symptoms of a disease or condition
• Modify bodily functions
• Diagnose a disease or condition
• To keep you healthy
 ORIGINS OF MEDICINES

• Medicines have been produced and used for generations. Origins of

production were from plants and animal materials.
• Their effectiveness were sometimes tied to magic and witchcraft or
faith.
• Synthetic chemical substances to treat diseases were started in the last
century in about 1910 by individual chemists or druggists working in
their own small laboratories.
• Later local dispensing chemists developed making prescriptions one at
a time for mixtures and powders, and hand made tablets.
 THE MODERN AGE PHARMACEUTICAL INDUSTRY

• The modern age pharmaceutical industry started slowly and took off in
the 1940s with factories which grew and grew to meet demand for
modern medicinal products.
• When making modern medicinal products, we must work with
constant care and attention to quality.
• We cannot afford to get it wrong.
• We must follow all the basic rules of Good Manufacturing Practice
(GMP).
 WHAT IS GOOD MANUFACTURING PRACTICE
(GMP)

• GMP involves Quality control, Quality Assurance, Regulatory Affairs.

• Ensure that pharmaceutical products are consistently manufactured
to a quality appropriate to their intended use.
• GMP is the day to day part of the pharmaceutical industry that
concerns all areas of manufacture, packaging, storage, transportation,
checking and testing of medicinal products.
• Also includes all staff who work in cleaning, maintenance, and
keeping records.
 WHAT IS QUALITY IN THE PHARMACEUTICAL INDUSTRY

Quality is when a product meets or complies with a specification. In the

pharmaceutical industry we say – “Quality is fitness for purpose”.
A product is fit for purpose only when:-
• It is the right product
• It is the right strength
• It is free from contamination
• It is not deteriorated
• It is in the right container and properly labelled and sealed.
 REASONS FOR GMP

• Confidence in the manufacture and supply to patients

• Medicines to have desired effects and cause no harm or danger
• Patients cannot detect defects or faults until it is too late
• Patients trust in the quality of the medicines
• To safeguard against the weaknesses of product testing
• Avoid wrong labelling and mix-ups.
GMP is all about the care and attention necessary to ensure that we get
things right all the time.
 BASIC RULES OF GMP

• Be sure you have the correct written instructions

• Always follow instructions exactly with no ‘cutting corners`
• Ensure that the correct materials are being used, calibrated and clean
• Prevent contamination and mix – up
• Always guard against labelling errors
• Always work accurately and precisely
• Keep things and yourself clean and tidy
• Always look out for errors and mistakes
• Make clear and accurate records of work done
 CLEANLINESS AND AVOIDING CONTAMINATION

• One important aspect of GMP is preventing contamination of

products. Things that can contaminate products include:-
• Dust, grit, and particles.
• Chemical substances from other ingredients
• Germs and other types of micro - organisms
 RULES ABOUT CLEANLINESS AND PREVENTION OF
CONTAMINATION

• Always maintain high standards of personal cleanliness – body, hair,

and clothing. Always wash hands after visiting the toilet.
• Always wear protective clothing properly
• Never handle products or chemicals directly by hand – use gloves
• Do not handle medicinal products if you have infections, colds,
coughs, stomach upsets, cuts.
• Eating, drinking, chewing, smoking, are not permitted
• Always check that your work place is clean and tidy
• If you have cleaning procedures, follow the instructions exactly
 (Continued) RULES ABOUT CLEANLINESS AND PREVENTION
OF CONTAMINATION

• Always check that equipment and containers have been properly

cleaned before use
• Always work with care to avoid creating dust and spillages
• Always be on the alert for possible sources of contamination
 GMP OF PERSONAL HYGIENE

• GMP requires that everyone is trained in personal hygiene

• Each person is responsible for his own hygiene and cleanliness
• Skin flakes cause contamination; micro – organisms live on them and can
cause infection
• Hair must be washed and kept clean
• Beard and moustache must be managed well
• Nose and mouth. Don’t shout or sneeze or cough
• Beware of make-up, and Jewellery must not be worn
• Hands must be kept clean. No smoking, drinking, and chewing
• Staff must be medically fit and smart appearance
 PACKAGING GMP

• The general rules and principles of GMP apply to packaging.

Risks and dangers to be avoided :-
• Contamination of product
• Mix up with another product
• Wrong labelling
• Place drugs in the wrong carton
 PACKAGING – Clearance Check

• One GMP rule which is particularly important to packaging is called

the Clearance Check or Cleaning Validation.
• This ensures to prevent contamination or mix up arising from ‘left
overs` from a previous batch.
Contamination from previously packaged batch can occur through:-
• Improper cleaning of vessels
• Tablets, capsules left behind in hoppers or counting machines
• Unclean pipe lines
• Product can hide anywhere and then pop up into the next batch
 BATCH PACKAGING DOCUMENTATION

• Hazards and mix ups can occur due to labels and other printed
packaging materials left on the line. To guard against these, before
any packaging operation starts, checks should be made to:-
• Ensure that the work area, line, and equipment are clean and clear of
any product, product residues, and materials labels.
• The Clearance Checks should be recorded. The completed check list
forms part of the Batch Packaging Documentation.
 THE PAPER WORK - DOCUMENTATION

• GMP is about having written instructions, following those instructions,

and making records. There are very good practical and patient safety
reasons for these.
• To be clear about what we are going to do
• To confirm that we have done it
• To keep records of what we have done
• To enable us to investigate complaints, defects, problems, deviations.
• To help us decide on, and take, any necessary corrective action
 DOCUMENTATION

There are different types of documentation:-

• Specification
• Manufacturing Instructions and Packaging Instructions
• Standard Operating Procedures
• Out of Specification
 SPECIFICATION

These are documents that state the standards which different materials
and products should meet, and describe the tests which should be
carried out to show compliance with those standards.
These include:-
• Chemical raw materials
• Active Pharmaceutical Ingredients (API)
• Excipients
• Packaging materials
• Products manufactured
 MANUFACTURING AND PACKAGING INSTRUCTIONS

These are documents pertaining to:-

• The materials needed
• Quantities to use
• Equipment to use
• The operations and checks to carry out
The Batch Manufacturing and Packaging instructions must be used and
followed and signed to confirm work done
No work should be carried out from memory!
 STANDARD OPERATING PROCEDURES (SOP)

Are important group of documents. They give instructions and

information on how to carry out a wide range of operations.
These include tests for raw materials, intermediates, finished products,
instruments calibrations, out of specification, cleaning validation and
more.
These instructions must be followed to the latter. Deviations from the
instructions are not acceptable and must be reported
 OUT OF SPECIFICATION

• Any tests carried out that fails to meet the specification is called OOS.
• These must be investigated to find out the cause by a senior staff.
• Detailed check is carried out. The findings must be reported:
• Is it the right material/drug tested?
• The chemicals, solutions are they off?
• Are the right volumes and weights used?
• Instruments, balances, are they calibrated?
• What analyst suspected is the error source.
 STERILE MANUFACTURING

• Sterile products are products that have to be sterile.

• But what exactly do we mean by ‘sterile’.
• It does not mean ‘super clean’.
• It means that no ‘germs’ (micro-organisms) are present.
• Products which are for injection have to be sterile.
• The body can defend itself against a moderate number of germs when
swallowed.
• We just do not have the same defences against germs that are injected into us.
• This applies to products we put into the eyes, wounds, or to wash out body
cavities. These products must be free from particles as well.
 STERILE GMP Principles

The standard Rules and Principles of GMP applies to manufacturing of

sterile products. But there are:
Additional GMP requirements
• People making Sterile Products need special training in the
precautions and techniques necessary.
• If you work near exposed products or materials you must be dressed
in special protective clothing. They must be carefully put on, following
the written instructions which must be provided.
• The biggest source of product contamination is people. Very high
standards of personal hygiene and cleanliness are necessary.
 STERILE GMP principles (Cont’d)

• Up to the stage when products are sealed inside containers, they

must be manufactured in special ‘clean’ or Sterile areas.
• Clean rooms are of special design, easy to clean and disinfect, with
special supply of filtered air. Filters remove particles and germs from
the air coming into the room.
• Clean rooms must be entered through special Changing Rooms.
• People entering ‘clean rooms’ must not wear make up, jewellery or
wrist watch. Not suffering from any disease or condition to cause
spreading of germs.
Sterile GMP principles (cont’d)
• Nothing that can cause contamination should be taken into ‘clean
rooms’. No eating, drinking or chewing.
• Clean rooms require very disciplined standards of behaviour. No
singing, talking, whistling, cough , sneeze.
 RULES ABOUT ENTERING AND WORKING IN CLEAN ROOMS

• Keep body, hair, face, hands, and finger nails clean.

• Report any illness, cuts, skin problems.
• Follow the written changing and wash up procedure exactly.
• Check that protective clothing is worn properly.
• Do not wear cosmetics, jewellery or wrist watches.
• Leave all personal items in the changing room.
• Do not take papers, documents or paper materials into clean rooms
unless they have been particularly approved.
• No eating, chewing, or drinking.
Rules about entering and working in clean
rooms (cont’d)
• Always move gently and steadily.
• Do not move vigorously.
• Keep talking to absolute minimum.
• Avoid coughing or sneezing
• Do not touch other operators.
• Avoid scratching, touching nose / mouth, rubbing hands.
• Disinfect gloves if worn.
• Always check for worn or damaged gloves or garments and change them as
necessary.
• Keep garments fully fastened. Do not pick up any dropped items from the
floor unless it’s a hazard.
 WHAT PRESSURES ARE THERE IN OUR
WORKPLACE CAUSING US TO IGNORE GMP
WHAT PRESSURES DO YOU ANTICIPATE IN OUR WORKPLACE THAT
PREVENTS OR MAKES IT DIFFICULT FOR US TO FOLLOW GMP
 PRESSURES IN OUR WORKPLACE

What pressures are there on us to ‘cut corners’ in our work and to ignore
GMP systems and procedures?
• Time pressures to get the job finished come what may
• Too much work
• Unrealistic job times
• Equipment turnaround times
• Lack of Equipment / breakdown
• Personal problems / Own mind not on the job
• Pressure from colleagues
• Bonuses which reflect only speed not accuracy
• Not trusting colleagues
WHAT PRESSURES ARE THERE IN OUR WORKPLACE TO IGNORE GMP
(Cont’d)

• Fear of recriminations
• Own bad habits
• Lack of attention to detail
• Poor attitude to following procedures & instructions
 PRINCIPLES OF GOOD MANUFACTURING PRACTICE

• Don’t anticipate results

• Never assume, always double check
• Follow procedures and fill in forms correctly
• Admit a mistake at once to keep the damage to a minimum
• Prevent the errors in the first place
 REGULATORY AFFAIRS – GMP & THE LAW

• Regulatory Affairs, Quality Assurance (QA) & Quality Control (QC) play a
major role in the pharmaceutical industry. Quality Assurance ensures that
products meet the required standard and specification and GMP compliance.
• QA checks all the paper work, reports, and tests from manufacturing of the
products, and QC tests. Qualified Person (QP) does the final checks and
signs for the release of the drugs.
• Regulatory Affairs ensures Legal compliance of licensing and marketing
of the products. Market approval is assessed by:- safety, Quality, and
Efficacy. The Government Committee (UK) on Safety of Medicines
oversees the licensing.
• The Government Medicines Control Agency (MHRA) exerts legal control
and competence (by regular Auditing) of manufacturers. Other countries
have similar controls.
 REGULATORY INSPECTIONS AND EXTERNAL AUDITING OF THE
PHARMACEUTICAL INDUSTRY

• QA conducts internal audit to help improvement. Regulatory inspectors

priority is assessment of compliance.
For the external audit, prepare your defence in advance for:-
• Unexpected deviations
• Changes
• Errors
• Process change
• Rejects
• Complaints
Cost is not acceptable as legitimate reason for deviation or system
implementation.
 REGULATORY INSPECTIONS AND EXTERNAL AUDITING

• Proper preparation prevents poor performance. Be inspection ready!

• Ensure all areas are clean and tidy. All chemicals and solutions are in date
• All instruments and equipment are clean and in calibration
• Staff in the appropriate work – wear and presentable.
• Ensure all relevant documentation is at hand – SOPs, BMRs, Packaging, etc
• Make sure you understand the question asked – seek clarification if necessary
• Answer questions concisely and completely
• Keep your answers short. Never give the inspector more than he needs
• Deal with minor issues immediately – take action and make sure the inspector knows
• Don’t let the inspector rush you – take your time
• Don’t be nervous – create an atmosphere of confidence
 REGULATORY INSPECTIONS AND EXTERNAL AUDITING

• Ensure key staff are available during the inspection

• What is known about the inspector. His areas of specialisation.
• Check that outstanding actions from last visit has been done
• The leader must have broad understanding of the whole operation.
• The leader or someone stays with the inspectors all the time
• Technical experts provide specific technical answers
• Keep track of the inspectors location and never leave him alone
• Provide only documents requested for
• Beware of auditors ‘silence’ tricks.
 REGULATORY INSPECTIONS AND EXTERNAL AUDITING

• Show mutual respect. Don’t be intimidated. Avoid confrontation (you will

never win)!
• If you cannot answer a question, admit it, and then call the right person to
answer. Never lie!
• Don’t bluff or be over confident to prove yourself
• Companies have provided misrepresented and fraudulent data with
resultant penalties.
• After the audit process, the inspector provides a report showing Minor
and Major faults.
• Remember: Successful external audit builds trust and confidence in the
company ‘s products.
 STABILITY STUDIES & GMP – (PHARMACEUTICALS)

• The purpose of stability testing is to provide evidence on how the quality of

a drug varies with time under the influence of a variety of environmental
factors such as temperature, humidity and light and to establish a shelf life,
and recommend storage conditions.
• These tests the drugs thermal stability, sensitivity to moisture, or potential
for solvent loss. The choice of test conditions is based on climatic
conditions of the regions, mindful of storage, shipment, and subsequent
use.
In the general case, storage conditions for stability testing are:-
Long term (minimum 12mths) ---- 25C / RH 60C
Intermediate (minimum 6mths) ------ 30C / RH 65C
Accelerated (minimum) 6mths ----- 40C / RH 75C
 STABILITY STUDIES & GMP – (PHARMACEUTICALS)

• Studies should include testing for components susceptible to change

during storage likely to influence quality, safety and/or efficacy.
• The testing covers appropriate physical, chemical, biological,
degradation, and microbiological attributes.
• Testing is done at 3 months intervals to cover the test period.
• Results should not show significant change (i.e exceeding acceptance
criteria) for the drug product. Eg 5% water loss is a significant change.
• Shelf life is then assigned to the drugs based on the results.
INTERNATIONAL CONFERENCE ON HARMONISATION (ICH)

ICH is a joint initiative involving both regulators and industry across a

number of countries on the testing procedures which are required to
ensure the safety, quality and efficacy of medicines.
Most new drugs and medicines are developed in Western Europe, Japan,
and USA. At its inception in 1990, the scope of ICH was confined to
registration in these regions and with affiliated institutions.
The main goal is to have a set of recognised common standards across
all the regions. These are embodied in :- British Pharmacopoeia (BP);
USA – (FDA, PhRMA); Europe – European Pharmacopoeia (EP); Japan
(JPMA).
INTERNATIONAL CONFERENCE ON HARMONISATION (ICH)

• Observers were to act as a link with non – ICH countries and regions
• The observers were:-
• World Health Organisation (WHO)
• The European Free Trade Area EFTA
• Canada
IFPMA
International Federation of Pharmaceutical Manufacturers Association
represents research based pharmaceutical industry and other
manufacturers in 56 other countries. It has close association with ICH.
INTERNATIONAL CONFERENCE ON HARMONISATION (ICH)

• The ICH secretariat operates from offices in Geneva.

• Regional workshops are organised on the implementation of the ICH
Guidelines by experts.
• These workshops provide an update and interaction with all users of
the guidelines.
INTERNATIONAL CONFERENCE ON
HARMONISATION (ICH)
STABILITY STUDIES & GMP –
(PHARMACEUTICALS)