Topic 1: Principles of cGMP

APH3011
Current Good Manufacturing
Practice & Process Improvement
(cGMPP)

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Part 1-1 Introduction to Principles of cGMP
What makes good medicine?
See Hint in slide 18:
(quality aspect in medicinal product)
1. Identity
2. Product (Safety) – Overall aspects meets
specifications
3. Purity – Ensuring purity of product by
maintaining a clean facility, eliminate cross
contamination and control microbial growth.
4. Efficacy & Strength – Capacity of drugs
produces effect of intended results, right
dosage strength, and consistency in potency

Please note that the answer will be shared during online lecture,
please refer to the respective Lecture recording.

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 What went wrong?
Tutorial Preparation
• Barcelona 28 AUG 2019
• Spanish Agency of Medicines and Medical Devices (AEMPS) reported
• Farma-Química Sur accidentally sold a strong vasodilator, most commonly used to
treat alopecia (hair loss), as omeprazole, which is a drug used to treat heartburn and
acid reflux.
• The pharmaceutical error in southern Spain became the cause of a hypertrichosis
outbreak that has affected 17 babies so far.

• https://elpais.com/elpais/2019/08/28/inenglish/1566982064_703884.html
https://www.youtube.com/watch?v=Ss19zd4Zwho

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 Drugs Production
GxP (good practices)
Drug is made into a
Scientists invent drugs for
product – tablet,
a specific purpose.
inhaler, or syringe,
Tests are done in labs to
and administered in a
see if the drugs will work.
clinical trial. The
results are used for
further development.
Development
Manufacturing
Research

Products
approved for
manufacturing and a
GMP license is
granted

APH 3011 cGMPP

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 Learning Objectives
Topic 1: Describe the general principles of cGMP
1. Describe the objective of cGMP and understand how it associate with
Quality Risk Management.
2. Explain the impact of product quality on patient safety.
3. Identify the main regulatory bodies for regulating the manufacturing of
pharmaceuticals and healthcare products.
4. List the general principles of good practices (GXP) in regulatory
requirements such as ISO, good laboratory practice and good
documentation practice.
5. Identify the process workflow in a typical cGMP manufacturing
environment.
Topic 7.1 Apply process improvements in quality system.
• Describe the importance of quality system in - self-inspection/ quality audit
process
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 In a Manufacturing cGMP organisation
Managing
Director (Site
Director)

Qualified Person

Head of Quality Head of Supply Logistics &

Materials Production Marketing Sales Warehouse
(QA) chain Distribution

Quality Control Supplier

Engineering
Manager(QC) Management
(Contract
Manufacturing)
Regulatory Facilities
Manager Management
Purchasing

Pharmacovigilance Planning

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 General Knowledge
1. In Singapore what are the types of good manufacturing practices standards
and guidelines for pharmaceutical (therapeutic products)?
https://www.hsa.gov.sg/therapeutic-products/overview

https://www.hsa.gov.sg/therapeutic-products/guid
ance-documents

https://www.hsa.gov.sg/therapeutic-products/
register/gmp-conformity-assessment

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1. GMP/ cGMP What is GMP?
 Current Good manufacturing practice.
2. GxP
 General term for good practice guidelines and regulations. These
guidelines are used in several industries including pharmaceutical,
clinical, food and cosmetics.
 Titles of good practice guidelines usually begins with “Good” and
end in Practice with the specific practice descriptor in between.
 GxP represents the abbreviations of these titles, where x (a
common symbol for a variable) represent the specific descriptor.
3. Example GMP Orientation video (Pharma Company)
 https://www.youtube.com/watch?v=LTveeuXeRKk
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 List of GxP in industry.
Industry x
Food, medical, cosmetic Manufacturing
Distribution Distribution
Hospital, trials, studies Clinical
Documentation, records data (G) Documentation (P)
Laboratory Good Laboratory Practice
Clinical Laboratory Clinical Laboratory
Pharmacovigilance Drugs safety PharmacoVigilance
Regulatory Affairs Regulatory

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 Why is cGMP important?
Examples of past tragedy cases
1.Sulfathiazole Tablets 1940
2.Devonport incident clothier report 1972
3.Baxter - Heparin 2008

• Incident prompted health regulatory to require detailed

production controls throughout the pharmaceuticals
industry.
• Birth of good manufacturing practices GMP became the
control standards for all basis for production
pharmaceuticals.
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Case 1: Sulfathiazole disaster 1940
•Winthrop Chemical Company (New York)
•places sulfathiazole tablets contaminated with
phenobarbital in the US market
•Resulting 300 hundreds of deaths and injuries.
•FDA's investigation - production revealed
numerous control deficiencies in the plant and
serious irregularities in the firm's attempt to
recall the tainted tablets.

APH3011 – cGMPP
1 APH 3002/ 3010: Current Good Manufacturing Practice
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 Case 2: Devonport incident
clothier Mar 1972
 Evans Medical was a subsidiary of
Glaxo - one of largest
manufacturer of generic
pharmaceuticals in UK.
 Release non-sterile dextrose infusion
bottles into market causing 5 death.
 Investigation:

 cause of disaster is to be found mainly due to human error - failings at plant due to simple
carelessness to poor management.
 No imminent technological advance in the field of production of intravenous fluids which will
eliminate the need for skilful men devoted to their work.

APH3011 – cGMPP
1 APH 3002/ 3010: Current Good Manufacturing Practice
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 Case 3 Baxter - Heparin (2008)
 Vials of blood thinner heparin recalled following reports of hundreds
of patients experiencing severe allergic reactions.
 Heparin manufactured in Changzhou SPL Company (China)
 Contaminant was identified as an "over-sulphated" derivative of
chondroitin sulfate, mimics the in-vitro properties of heparin.
 FDA conducted an inspection of the facility and found many
problems:
 No assurance that processing steps used to manufacture heparin sodium, USP are capable of
effectively removing impurities.
 Fail to have adequate systems for evaluating the suppliers of heparin crude materials
 Insufficient system for evaluating supplied crude materials of heparin to ensure acceptable for use.
 The test methods performed for heparin sodium USP have not been verified to ensure suitability
under actual conditions of use.
 Equipment used to manufacture heparin sodium USP is unsuitable for its intended use.

APH3011 – cGMPP
 What’s cGMP?
USFDA definition :
• Provides for systems that assure
– proper design,
– monitoring, and control of manufacturing processes and
– facilities.
• Adherence to the CGMP regulations assures the quality of drug
products by requiring manufacturers of medications to control
manufacturing operations adequately.

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 What’s cGMP?
EMA definition :
• Describes the minimum standard that a medicines manufacturer
must meet in their production processes. The European Medicines
Agency (EMA) coordinates inspections to verify compliance with
these standards and plays a key role in harmonising GMP activities
at European Union (EU) level.
• Any manufacturer of medicines intended for the EU market, no
matter where in the world it is located, must comply with GMP.
• GMP requires that medicines:
– are of consistent high quality;
– are appropriate for their intended use;
– meet the requirements of the marketing authorisation or clinical trial authorisation

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 Objectively
cGMP sets: Minimum requirements that a
pharmaceutical/ biopharma, medical device,
complementary health products manufacturer must
meet to assure that the products produced are of
• high quality cGMP
requirements
• do not pose any risk to the patient safety
• appropriate for their intended use;
• meet the requirements of the marketing cGCP
requirements
authorisation or clinical trial authorisation .
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cGMP compliance Focus:
What’s are the expected QUALITY in medicinal products?
1. Identity – Is the drug what you say it is? Drug identity is confirmed
when the efficacy and the intended use is consistent with published
description in insert/label
• Label control (printing process)
• Identification test (codes prevent counterfeits)
• Line clearance, reconciliation and yields test (ensure all control
materials are accounted)
2. Product (Safety) – Overall aspects meets specifications and products
are made according to validated SOPs, practice of change control,
inspection and verification of raw materials, production in facilities I – identity
avoid contamination. S - safety
3. Purity – Ensuring purity of product by maintaining a clean facility with
clean equipment, eliminating cross contamination and controlling P - potency & purity
microbial growth.
4. Efficacy & Strength – Capacity of drugs produces effect of intended
E - efficacy
results, right dosage strength, and consistency in potency – ensuring
verification of formulation, validation of processes, and maintenance
of QC test programs.
Reference: "Framework for Continuous Improvement,” Journal of GXP Compliance,Vol.13 No. 1 (Winter 2009),
pp. 79-89
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Poor quality medicine is a global problem affecting
public health. Products may be substandard because of poor
manufacturing or may be deliberately counterfeited or falsified to be
sold for profit.

What are the impacts?

• danger to patients
• may result in treatment failure
• or the development of drug resistance

https://www.pharmaceutical-journal.com/news-and-analysis/event/poor-quality-medicines-
pose-a-danger-to-patients/20066604.article?firstPass=false

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 cGMP guidelines
established by NRAs
• EU GMP
https://ec.europa.eu/health/documents/eudralex/vol-4_e
n

cGMP regulation mandate by NRAs

• USFDA 21 CFR Part 211 & 210
• https://www.fda.gov/drugs/pharmaceutical-qualit
y-resources/current-good-manufacturing-practice-
cgmp-regulations
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 Who regulates cGMP and ensures good
medicines are supplied?
• Regulatory bodies – regulates the manufacturing of
pharmaceuticals and healthcare products.
• National Regulatory Agencies (NRA) are responsible
for ensuring that products released for public distribution
(normally pharmaceuticals and biological products, e.g.
vaccines) are evaluated properly and meet international
standards of quality and safety.

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 Examples of NRAs
Country / Geography Name of Regulatory Agency
United States of America US Food and Drug Administration (USFDA)
European Union European Medicines Agency (EMA)
Japan Pharmaceuticals and Medical Devices Agency (PMDA)
Australia Therapeutic Goods Administration (TGA)
United Kingdom Medicines and Healthcare Products Regulatory Agency
(MHRA)
Taiwan Food and Drug Administration,Taiwan (TFDA)
Singapore Health Sciences Authority (HSA)
Malaysia Drug Control Agency (DCA),
China National Medical Products Administration (NMPA)
India Drug Controller General of India (DCGI)
Thailand Thai Food and Drug Administration (TFDA)

In a global marketplace with cross-border import / export of manufactured

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16 products, whose GMP do you follow?
APH 3002/ 3010: Current Good Manufacturing Practice
 cGMP Standards / Guidance / Regulation
• Many countries have formulated their own
requirements for GMP based on WHO’s GMP.
• Others have harmonized their requirements, e.g.
the Association of South-East Asian Nations
(ASEAN), the European Union and through the
Pharmaceutical Inspection Convention PIC/S.

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• Guidelines cGMP
– Established and published guidance with the objective of
harmonization and improving trade
– E.g. World Health Organization (WHO), The International Conference
on Harmonization (ICH), PIC(S) Pharmaceutical Inspection
Convention Pharmaceutical Inspection Co-operation Scheme
• Standards
– Established and published standards, usually independent, non-
governmental international organization with a membership. E.g. ISO
International Organization for Standardization
• Regulation / Legislation
– Adopted guidelines or standards by NRAs e.g. MHRA, H.S.A, EMA to
mandate as regulations.
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 Major cGMP codes
Codes
PIC(s) - Guides to GMP
EU- Guides to GMP
USAFDA CFRs – 210 & 211 & 820
ISO 13485 – Medical devices, MDSAP, SS620
ISO 22716 - production, control, storage and shipment of cosmetic
products.
EXCiPACT GMP & GDP Certification
API – ICH Q7A
WHO – GMP Guidelines

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 Other related QMS standards to cGMP
ISO 9001:2015 specifies requirements for a quality management
system when an organization:
a) needs to demonstrate its ability to consistently provide products
and services that meet customer and applicable statutory and
regulatory requirements, and
b) aims to enhance customer satisfaction through the effective
application of the system, including processes for improvement of
the system and the assurance of conformity to customer and
applicable statutory and regulatory requirements.
c) All the requirements of ISO 9001:2015 are generic and are
intended to be applicable to any organization, regardless of its
type or size, or the products and services it provides.

APH3011 – cGMPP
https://www.iso.org/standard/62085.html 25
 WHO
16 Oct 2019 to continue
18 Oct 2019 2pm to 3pm

 Aimed primarily at diminishing the risks inherent in any

pharmaceutical production, which may broadly be categorized in two
groups:
 cross contamination/mix-ups and
 false labelling
 WHO has established detailed guidelines for good manufacturing
practice, which requires that manufacturers must not place patients at
risk as a result of inadequate safety, quality, or efficacy
 Risk assessment now plays an important role in WHO quality assurance
guidelines.

APH3011 – cGMPP
26 https://www.who.int/medicines/areas/quality_safety/
quality_assurance/production/en/
 The International Conference on
Harmonisation
ICH established in1990 with 3 founding member (Europe, Japan and the US ) in realization of
importance of independent evaluation of medicinal products before they are allowed on the market was
reached at different times in different regions. This realization was driven by tragedies, such as that with
thalidomide in Europe in the 1960s.
European Union
World Health Organisation
EFPIA -
MHLW JPMA
European Federation of Pharmaceutical
FDA PhRMA
Canada Industries and Associations
Swissmedic
and Health
Canada
Japan Ministry of
Switzerland Health, Labour and
Welfare

International Federation of Pharmaceutical Japan Pharmaceutical

Manufacturers & Associations (based in Manufacturers Association
Geneva)

Pharmaceutical Research and

The US Food and Drug Administration
Manufacturers of America

The International Conference on Harmonisation (ICH) ICH Q10 is the quality system guideline (i.e.
of Technical Requirements for Registration of Pharmaceuticals for Human
Use
cGMP) for Pharmaceutical Organization.

APH3011
Mission– is
cGMPP
to make recommendations towards achieving greater harmonisation in the interpretation and application of
technical guidelines and requirements for pharmaceutical product registration, thereby reducing or obviating duplication http://www.ich.org/home.html
of testing carried out during the research and development of new human medicines. 17
 • The Pharmaceutical Inspection Co-operation
Scheme (PIC/S) was established in 1995.
• PIC/S is the abbreviation and logo used to describe
both the Pharmaceutical Inspection Convention
(PIC) and the Pharmaceutical Inspection Co-
operation Scheme (PIC Scheme), which operates
together in parallel.

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 Pharmaceutical Inspection Co-operation
Scheme (PIC/S)
• Objectives – lead the international development,
implementation and maintenance of harmonized cGMP
• Sets cGMP policies and trains inspectors.
• Open to any Authority having a comparable cGMP
inspection system. PIC/S presently comprises 52
Participating Authorities coming from all over the world.
• Membership means mutual recognition of members GMP
Licensing and standards.
• Facilitates trade (cGMP clearance for each country omitted)

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 PIC/S aims:

• To harmonize inspection procedures worldwide by

developing common standards in the field of GMP
and by providing training opportunities to
inspectors.
• It also aims at facilitating co-operation and
networking between competent authorities,
regional and international organisations, thus
increasing mutual confidence.

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 PICs Guidelines Objectives & Members
• To facilitate the removal of barriers to trade in
medicinal products,
Examples of Member States
• To promote uniformity in licensing decisions
• United States of America (USFDA)
and to ensure the maintaining of high standards
of quality assurance in the development,
• United Kingdom (MHRA & VMD)
manufacture and control of medicinal products. • Switzerland (Swissmedic)
• Standards are also intended to serve • European Union (EMA)
manufacturers as a basis for the elaboration of • Thailand (Thai FDA)
specific rules adapted to their individual needs. • Republic of Korea (MFDS)
• Is not intended to place any restraint upon the • Singapore (HSA)
development of new concepts or new • Malaysia (NPRA)
technologies, which have been validated and • Japan (MHLW & PMDA)
provide a level of Quality Assurance at least • Canada (Health Canada ROEB)
equivalent to those set out in this GMP guide. • Chinese Taipei (TDFA)
As of 01 Oct 2019,
• Hong Kong SAR, China (PPBHK)
China and India are not • Australia (TGA)
members of PIC(s) • New Zealand (Medsafe)
• Indonesia (NADFC)
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• Others 31
 PIC(s) GMP Guides
https://www.picscheme.org/en/publications?tri=gmp

• Guide is divided into two parts and a number of annexes which are
common to both parts.
• Part I covers GMP principles for the manufacture of medicinal
products.
• Part II covers GMP for active substances used as starting materials.
The annexes provide details on specific areas of activity.
• For some manufacturing processes, different annexes will apply
simultaneously (e.g. annex on sterile preparations and on
radiopharmaceuticals and/or on biological medicinal products)

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 General Principals of cGMP (PICs Part 1)
(1) QMS Topic 1
Quality
Topic 6 Management
Topic 2
System
(9) Self (2)
Inspection Personnel

Topic 4 & 5
Topic 6
(8) (3)
Complaints
& Product Premises &
Recall Equipment
cGMP
Topic 3
Topic 6
(7)
(4)
Outsourced
Documentation
Activities

(6)
Topic 7 Quality
(5) Topic 4
Production
Control

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 Elements of Chapter 1 – PIC(s)

• Pharmaceutical Quality System

• cGMP
• Quality Control
• Product Quality Review
• Quality Risk Management

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 PHARMACEUTICAL QUALITY SYSTEM
PRINCIPLE CHAPTER 1
(in line to ICHQ10)
• Manufacturing Authorisation must manufacture
medicinal products so as to ensure that they are fit
for their intended use, comply with the
requirements of the Marketing Authorisation or
Clinical Trial Authorisation, as appropriate, and do
not place patients at risk due to inadequate safety,
quality or efficacy.

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Self direction learning – Do it yourself!

Learning Objectives Checklist

 Check you have understood the Learning Objectives of the topics.
 Study tutorial questions.
 Check out PIC(s) Part I, 1 Chapter 1 & 9 as well as PIC(s) Part II
Chapter 2.
 Clarify your queries with your tutor during the timetabled tutorial 

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Let’s discuss after the lecture

Case illustration
Temasek Biopharma produces a vaccine that are distributed and sold
to hospital and clinics in Singapore and JB.

1. Which codes should the auditor use to access the facility for cGMP
compliance?
Answer:

2. Someone report an adverse events in JB, which regulation should company

follows and reports to?
Answer:

Please note that the answer will be shared during online lecture,
APH3011 – cGMPP please refer to the respective Lecture recording.
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