GMP

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GOOD MANUFACTURING PRACTICE [GMP]
Manufacture of Investigational
Medicinal Products (IMPs)
Tajuddin Akasah
B.Pharm.Hons.(USM)., M.Phil., Ph.D. (UK)
Head of Centre for GMP
National Pharmaceutical Control Bureau
WHO Collaborating Centre
For Regulatory Control of
Pharmaceuticals
Member of Pharmaceutical
Inspection Cooperation Scheme
MS ISO 9001:2000 Certified
National Pharmaceutical Control Bureau
Ministry of Health Malaysia
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SCOPE TO COVERSCOPE TO COVER
Quality
Background
GMP and QA
Elements of GMP
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QUALITY?
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How and Why? some assumptions
I like the brand!
I trust the brand!
I like the box!
My mother uses it!
My friend uses it!
My doctor says so!
The pharmacist sells it!
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THALIDOMIDE AND HEAVY
METAL POISONING
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Regulator’s concern ….
Quality, Safety and EfficacyQuality, Safety and Efficacy
[pharmaceuticals]
Quality and SafetyQuality and Safety
[health supplements and traditionals]

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How do we ensure ?
Quality (meet specs, intended
use) and
Safety (Heavy metals and
microbial limits, no prohibited
ingredients, ADR monitored)
Efficacy (proven clinically)
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DO YOU KNOW THAT THE MEDICINE
USED IS NOT ‘TESTED’?
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?
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Quality
QC test is destructive
Unable to do on every tablet
Require sampling
Compliance to GMP is crucial
Quality being ‘built-in’ from the start to
finish
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WHAT IS GMP?
Good Manufacturing Practice
GMP is that part of QA which ensures that
products are consistently produced and
controlled to the quality standards appropriate
to their intended use and as required by the
marketing authorisation or product
specifications
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WHAT IS QA?
Quality Assurance
It is the sum total of the organised
arrangements made with the objective of
ensuring that medicinal product are
of quality required for their intended
use. QA therefore incorporates GMP plus
Quality Control (QC).

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GMP IMPLEMENTATION IN MALAYSIA
GMP for pharmaceuticals in
Malaysia since 1984
WHO and ASEAN
Guidelines
MALAYSIAN Guidelines
PIC/S since 1st Jan 2002,
Malaysia became the 26th
member state
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Background
A short history of GMP
First introduced by the
Canadian Authorities – mid
1960s
Since then GMP acceptance
– as a ‘way of life’ in the
pharmaceutical industry
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Background
It might be assumed that
40 years of experience of GMP
84 countries
Would have eliminated many dangers to
the patients due to quality failure in
manufacturing but….
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MistakesMistakes
109 infants have died in Nigeria
due to failure to follow GMP
Supplier mislabelled ethylene
glycol (anti freeze) as propylene
glycol and the manufacturer
failed to perform adequate
QC – identification and potency
test
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OTHER EXAMPLES
Slimming pills in Singapore 2002
Slimming pills in Malaysia 2004
Tablet with hairs in Brunei 2004
Adulterated Trad Med in Yemen 2004
Nepal 2004
Wrong labelling in Malaysia 2005
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GMP COMPLIANCE IS CRUCIAL
WHAT ARE THE ELEMENTS OF GMP?

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Ch. 1. Quality Management System
Ch. 2. Personnel
Ch. 3. Premises and Equipment
Ch. 4. Documentation
Ch. 5. Production
Ch. 6. Quality Control
Ch. 7. Contract Manufacture and Analysis
Ch. 8. Complaint and Product Recall
Ch. 9. Self Inspection
Annexes 1-18 (specific)
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QUALITY MANAGEMENT SYSTEM
Developed, established, implemented
Policies and objectives
Organisational structure, functions
Responsibilities, procedures
QC and specifications
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PERSONNEL
~ separate people responsible
for production and quality
control (independent of
each other)
~ appropriately trained in
quality system, GMP and
regulatory requirements
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PREMISES* & EQUIPMENT*
Suitably located, designed,
constructed and maintained
The need to
avoid any risks of
contamination from
environment
cross-contamination
product mix-up
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Premises & Equipment…
Campaign working is
acceptable but…
Separate or dedicated
facilities for
Penicillin, steroids,
hormones etc.
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Hormone Production

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DOCUMENTATION
Complete history of each
batch from starting
material to finished
products,traceability
BMR, SOPs, Formulas
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WHEN
ATTEMPTING A
TASK WE NEED
SOME SORT OF
DOCUMENTATION
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If the documentation is wrong!
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PRODUCTION – Starting materials
Consistency of
production is
influenced by quality
of starting materials
Specifications
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Manufacturing Operations
Standard Operating Procedures (SOPs)
Cleaning Procedures and Validations
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Principles applicable to Comparator Product
If significant changes were made
to the quality of the
comparator product (dosage
form, packaging materials,
Storage, etc.)
Stability, comparative
dissolution, bioavailability
data should be made available
to prove the original quality
characteristics

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Expiry Date
The expiry date on the original package
may NOT be applicable when repacked
The sponsor is responsible to determine a
suitable use-by date (product nature,
characteristics of container, storage
conditions)
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Randomisation Code
Procedures should describe the
generation, distribution, handling &
retention of randomisation code
used for packaging investigational
products
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Blinding Operations
A system should be implemented to allow
for a proper identification of the blinded
product
System + randomisation code - must allow
proper identification & traceability
Sample of blinded IMPs should be retained
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Milo + Nescafe
Ikan kering + Telor Goreng
1/1000th
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ValidationValidation
The documented act of
proving that any
procedure, process,
equipment, material,
activity, or system
actually leads to the
expected results.
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Qualify a system and/or equipment
ValidateValidate a process
Qualify an autoclave, whereas you
validate a sterilisation processvalidate a sterilisation process
Qualification or ValidationValidation ?

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Production
actual & theoretical yield
abnormal discrepancy
should be investigated
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Packaging & Labelling
Line clearance
Label reconciliation
Independent
checking by QC staff
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Thai labels
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QUALITY CONTROL
Concerned with
sampling, specifications,
testing, documentation,
release procedures.
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Quality Control…
Accuracy of therapeutic dose (content
uniformity)
Release of active substance (solubility,
dissolution)
Estimation of stability (accelerated &
stress conditions, shelf life, storage
conditions)
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CONTRACT MANUFACTURE &
CONTRACT ANALYSIS
Must be correctly defined
agreed and controlled in
order to avoid
misunderstandings
Must clearly defines the
duties of the giver and
receiver

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COMPLAINTS AND
PRODUCT RECALL
Complaints must be
reviewed according to
SOPs
For all contigencies there
should be aproduct recall
procedures
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SELF INSPECTION
Conducted in order to monitor the
implementation and compliance
with GMP principles
To propose necessary corrective
measures
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GMP FLOW CONCEPTGMP FLOW CONCEPT
Black Grey White
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Contaminations
Microbiological
Pyrogen
Particulate
Sources
Personnel
Environment/surface
Equipment
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And finally…
GMP

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GMP – GOOD MANUFACTURING
PRACTICE and not
Good Massage Practice
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IS IT TOUGH?
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Some useful websites
http://www.bpfk.gov.my
http://www.picscheme.org
http://www.tga.health.gov.au
http://www.who.org
http://www.fda.gov
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QUESTIONS & ANSWERS
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HOW DO WE MONITOR MANUFACTURERS?
WE AUDIT
[ROUTINE, VERIFICATION,
INVESTIGATIVE & ETC.]!
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Grading of GMP Compliance and
Frequency of Audits
12 MTHS6 MTHS6 MTHSPOOR
18 MTHS12 MTHS12 MTHSS’FACTORY
24 MTHS24 MTHS18 MTHS
STATUS
GOOD
LOWMEDIUMHIGHRISK

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AUDIT FINDINGS
EXAMPLESWHY?WHAT?
BAJU KOYAK,
TEMPERATURE
RECORD NOT SIGNED
COMMENTS FOR
IMPROVEMENT
MINOR
PROCEDURE NOT
COMPLETE, NO
TRAINING, BAJU
KOYAK
QUALITY DEFECTS
NOT EFFECTING
HUMAN LIFE
MAJOR
WATER SYSTEM,
HVACS, X- CONT’N,
BAJU KOYAK
EFFECT HUMAN
LIFE
CRITICAL