Peran dan Tanggung jawab

Apoteker
di Industri Farmasi

10/26/2020 1
 People Method Safety Building,
Quality Facility,
01 02
System and
Efficacy
Utility
Structure PRODUCT Infrastructure

03

Environment Health
Safety
Environment

• People
• Skill
• Competency
• Capability
 People
01 02
Global Global
Certification Structure PRODUCT Infrastructure • GMP Certification
• GMP • TPM
• Pharmacopeia • LEAN
• ISO 9001
• LEAN
• Six Sigma 03
Environment

• ISO 14001 Global

• ISO 45001
Certification
• ISO 50001
 Quality
GMP
Assurance
-Quality system→ responsibility
-Risk management -Facilitas : bangunan, alat,
-Development/Design control Industri personalia, material
-Training
-Production-Process control
-Control of Intrm., IPC, etc
Farmasi -Validasi
-Protap
-Quality audit-self inspection
-Dokumentasi → non
-Purchasing control
conforming product/deviation
-Labelling and Packaging control
→ identification-traceability
-Handling, storing and system
distrubuting of materials Quality -Recall
-Document control → product -Product complaint
release, deviation etc Control -Distribusi
-Metoda pengujian dan Validasi MP - Proses - Formulasi
➔ Kimia dan Mikro
- Pengelolaan Sumber daya
-Sampling, Retained sample - QMS
-Fasilitas → personal, alat dsb. Produksi - RISK MANAGEMENT
-Refference Standard
-FG Spec., labeling
-Dokumentasi 10/26/2020 4
-Testing dan Product assesment, stability study
Peran Apoteker
Di Industri Farmasi
I. Managing PEOPLE
II. Managing OPERATIONS
III. Managing PRODUCTS
IV. Managing CHANGES
V. Managing CUSTOMERS and SUPPLIES
VI. Managing RESULTS
10/26/2020 5
Peranan VI. Managing Result

Apoteker
Think Strategically

Build up Robust
Process

Financial Strategic Result

di Industri
Management Focus

Project Risk Management

Management

IV. Managing Change V. Managing Customers &

Suppliers

Cultural Change
Product
Managing Knowledge and
Complexity Distribution
Support
Knowledge Benchmarking Internal Service Product Complaint
Management Result Competitor Level Management

Transformational Site Organizational Leading Change External Customer Purchasing Inventory

Technology Effectiveness Services

I. Managing People II. Managing Operation III. Managing Products

Right First Time

(RFT)
Cost of Goods
Employee Capacity and Yield Sold (COGS)
Relations Management Management
Material Flow Plant Utilization Product and Product Capacity
Communication
Process Transfer Preparation

Utility Service Level Plant Cycle Time Quality Cycle Time

Leading & Reward &
OEE Management Agreement (PCT) (QCT)
Managing People Recognition
Quality Management HSE Operations Cost Batch Size Inventory Product Quality &
Talent Pool SWOT Training and People Succession
Systems & GMP Management Management Coverage Regulatory
Analysis Development Planning
Compliance Compliance

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6 6
Industry 4.0
- The numbering system used in software development, and

Industry

Revolution 1.0 2.0 3.0 4.0

Mechanisation and The arrival of Internet Computer The Infancy of
Resources Steam power Electricity electronics Industry
Digitalization

Mechanization Mass Cyber

Evolution production Automation physical world

7
What Industry 4.0

Convergence of PEOPLE, Focus2)

3 (three) principle elements
PHYSICAL SYTEMS, and DATA
- Intelligence
to increase
- Connectivity
QUALITY, PRODUCTIVITY and
- Flexible automation
PROFIT1)
It was predicted

eliminate dull, human-centric, the best that

dangerous humanity can bring
and dirty work creativity, problem solving,
to become
and the entrepreneurial spirit
1) Alasdair Gilchrist
2) Dr. Enno de Boer

10/26/2020 8
Industry 4.0, What about us ?
Pharma 4.0
is about responsiveness itself !
Big bang changes are not an option in
our regulated world
What does the evolution to
Pharma 4.0 look like?

*) ISPE‘s Pharma 4.0 SIG : Lorenz Binggeli, Hans Heesakers, Christian Wolbeling and Thomas Zimmer, PhD
 Holistic Production Control System

INDUSTRY 4.0
To PHARMA 4.0
*) ISPE’s Pharma 4.0 Special Interest Group (SIG)

October, 7th 2019

 NOT YET CONSIDERED
CURRENT SINGLE-
01
SUBMISSION-BASED
CONTROL STRATEGY Enable production-specific changes related to
GMP, facilities, utilities, or equipment to
mitigate process variability
01
02
Plays a key role in ensuring that It is difficult to foresee the variation of
Critical Quality Attribute (CQA) MCA, Impurity, etc. over the complete
are met. product life cycle during the development
phase
02 03

Quality Target Product Profile Refining the control strategy, comes out of
development and to enhance it
(QTPP) is realized
into one that can be executed in
manufacturing.
04
Data Integrity are not yet fully implemented

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 ROOT of THE EVOLUTION*)

US FDA vision on ICH of Technical Requirement

pharmaceutical risk-based for Registration of
cGMP for the 21st century Pharmaceuticals for
Human use

A maximally efficient, agile, Pointed out the need for a

flexible pharmaceutical life cycle
manufacturing sector that approach in
reliable produces high-quality drug ICH Q8 - Q10 – ICH Q12
without – ICH Q13 – Q14
extensive regulatory oversight

*) Dr Janet Woodcock, 2005

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 Driving toward Pharma 4.0

▪ Remain Competitive
▪ Increasing Complexity
▪ Regulators Increasing Push For 02 Pharma 4.0 Technology
Continuous Product Monitoring

In the past Future

Continuous Increasing
Regulator accepts real time monitoring pressure on R&D dept.
Annual Product 01 predicted and rectified to develop not only
Quality Review before it turns into new products faster,
deviation, avoiding but also more
the associated down personalized
time and loss of therapies
product

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 Industry 4.0
PHARMA 4.0 =
Capabilities
New Enabler and Elements in PHARMA 4.0 OPERATING MODEL
Digital Maturity

RESOURCES INFORMATION SYSTEM

Digitalization Holistic Value network
Workforce 4.0 available Integration and Traceability
And Qualified
PHARMA 4.0
ORGANIZATION AND CULTURE
PROCESSES Communication Decision
Holistic control strategy life Makin
cycle management

Data Integrity by Design

What does a PHARMA 4.0 look like
1. Made up
of machines, equipment and computer all of
the machines and equipment even the
individual components
→ Fitted with multiple sensors, constantly
monitor every aspect of the process
→ Self a ware components, report their
own condition such as useful life they
have left, prediction when they’re likely
to fail – saving in down time
10/26/2020
2. Big data evolution
→ draw data from sources that have
traditionally been disconnected and looks
for relationship and trends e.g. combining
data from inline inspection, testing,
monitoring with data from equipment
maintenance, engineering system, CPV,
ERP etc
→ All data needs to be processed –
advanced analytical tools – Big Data and
Artificial Intelligence will play in data
analytics
16
What does a PHARMA 4.0 look like

Pharma 4.0 is more

APC introduced in
nineties (1990th)
reactive and only tell what
gone wrong, not what about
to go wrong
Data – business insights
unavailability → buried in
unstructured, dispersed,
incomplete data
than just process
control
Old New
3. Control Increasing, monitoring
through the production
Strategy cycle – not just the
production line
Offers predictive analysis
over the production
lifecycle

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 FOF - Pharma 4.0

Industry Data Integrity

capabilities by Design
Digitalization Pharmaceutical
Big Data Quality System

Workforce for The Future

 Industry capabilities Factory Of the Future

PROCESS
▪ Shorter product change over times
▪ Continuous Processes STAGES
▪ Compliance
▪ Agility and
MODEL ▪ flexibility
▪ Modular factory
▪ Automation Workforce (the People)
▪ Robotic ▪ Technologies
OPERATIONAL ▪ Statistic-data interpretation
EXCELLENCE ▪ Knowledge understanding of facilities and
production processes
▪ Business processes
▪ Technical processes Good Engineering Practice
▪ IT supported documentation ▪ Project management capabilities
▪ Big Data - Digitalization ▪ Cost

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 Digital Maturity Level
Digitalization Industry 4.0

How can autonomous response be achieved?

What will happen?

Why is it happening?

What is happening?

Predictive capabil
Computerisation Connectivity Visibility Transparency ity Adaptability

1 2 3 4 5 6
 Big Data - Digitalization
A Step for Pharma 4.0

o Paperless production o Speed up manual process

o Real Time Review o Increase productivity
o Right First Time o Enforce Data integrity
o Tighter control for control o Less Manual Entry
quality o No Double Entry
o Audit readiness

Holistic Control Strategy

(Product Quality & Cost)
Parametric Release – CPM-
CPV
Global Certification
Cost effectiveness
10/26/2020 21
 Data integrity by design

Upholding ALCOA Data Quality

principles

▪ Process and Data Flow

▪ CSV and GAMP
approach

Data Life Cycle

- Security Right Content
- Safety

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 Workforce Capability - HR
▪ Technologies – Computerize system,
Processing big data and AI
▪ Review HC based on
changes of System and ▪ Basic Statistic and related
Technology in Production programs such as Minitab, SAS,
and QC Math works. Interpret data and
statistic; to create data
visualisation and make decisions
based on it

▪ New Culture, mind

set and Behaviour ▪ Industry knowledge and an
in-depth understanding of
facilities and production
processes

▪ Change management
▪ Shopfloor management

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Future People - Worker

Future factory workers will focus on creative problem solving, data evaluationand pl
anning, rather than routine, unsafe tasks.
(Photo courtesy McKinsey & Co.)
10/26/2020 24
ACCEPTABLE APPROVED CERTIFIED
 Quality Management Process
The QM process in Pharma 4.0 should be based on ICH
Q10 and cGMP (EU-PIC/s) “Pharmaceutical Quality Syst
ems” (PQS) which is enriched with “elements and enable
rs” to benefit from new technologies.
Consider of
▪ four “elements” of the operating model and the
▪ New two “enablers” made possible by digitalization
→ Data Integrity by Design and Digital Maturity

a Holistic Control Strategy for the complete product life cycle

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 Pharmaceutical Quality System GMP Standard
ICH Guideline
▪ Product Development
▪ Transfer Technology Current PQS
▪ Commercial manufacturing
▪ PP&PQMS
▪ Product Discontinuation ▪ CAPA System
▪ Change Management
▪ Management Review
Lifecycle Managem
ent
Holistic Manufacturi
Knowledge Mgt. & QRM ng Control New PQS Element
▪ Product & Process & Platform ▪ Data Integrity
understanding ▪ Process Maps
▪ QbD – Product and Materials ▪ Integrated Planning &
capabilities Training
▪ Collaboration & End to End ▪ Environmental Monitoring
Integration of GxP related & Energy Management
IT Systems ▪ Automation : PAT/CPV/
CPM/RTRT/PR

10/26/2020 27
 Industrial Revolution enhances…………

ICH Q10 - PQS with structural organiz ICH and FDA GUIDELINES
ation and processes
• Creating A New QUALITY By DESIGN Element In The Pr • PROCESS VALIDATION GUIDELINES
oduct Life Cycle, • Recommend flexible production processes, including c
ontinued and
• Empowered
o PAT (Process Analytical Technology) • Continuous Process Verification, which enables close m
o Real Time Release Testing onitoring of CQAs and CPPs to ensure high product qua
lity
 Trends in Continuous Manufacturing
• Vertex’s ORKAMBI™ (lumacaftor/ivacaftor)
– 1st NDA approval for using a continuous manufacturing technology for production of the
Cystic Fibrosis drug (tablets) (July 2015)
• J&J Prezista (darunavir)
– 1st NDA supplement approval for switching from batch manufacturing to continuous manufactu
ring process for an FDA-approved HIV drug (tablet) (April 2016)
• Eli Lilly Verzenio (abemaciclib)
– 2nd NDA approval for using a continuous manufacturing
technology for production (September, 2017)
• Trends
– Drug substance
– Drug product
– Small-molecule and biotechnology products
– Control strategy utilizing models

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Barriers to adopting Pharma 4.0
1. Cost to set up Pharma Manuf. Site following Pharma 4.0 principles.
Anyhow, decreasing cost ~ with increasing productivity and reducing down
time and waste ➔ “the power of 1 %”

2. Adequately skilled staff to run the analytics ➔ universities will struggle

to predict what skills industry will require in coming years

3. Security – Pharma 4.0 connecting thousands of individual devices – sensors,

actuators and networks ➔ should reap the benefit of Pharma 4.0 and mitigate
the risk

4. “Inertia of big committees” in large multinationals

Thank you

July 8th 2019

Real Time Release Testing

Real Time Release Testing (RTRT) is the ability to

evaluate and ensure the quality of in-process and/or final
product based on process data Typically include a valid
combination of measured material attributes and process controls

ICH Q8(R2)

10/26/2020 32
Examples of RTRT Approaches
▪ On-line or in-line measurements and/or controls, for example
Tablet weight after compression
▪ Particle size measurement after granulation or milling
▪ Moisture measurement during drying
▪ Blend uniformity
▪ Fast at-line measurements, for example NIR for tablet assay
▪ Disintegration in lieu of dissolution
▪ Models as surrogate for traditional release tests, for example
Multivariate model as a surrogate for dissolution

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At-line analysis Sampling

▪ At-line analysis requires getting a sample from the

process and analyzing it manually at the process
line
▪ Various sampling systems are available to not
disturb production and provide safety
▪ A key element of at-line analysis is ease of
operation of equipment for unskilled operators

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At-line Analysis: Near Infra-red (NIR) Fluid bed drying - NIR

▪ Requirement to test every bag of API entering site

▪ Each batch arriving contains 600 bags
▪ Each batch creates enough work to keep an analyst busy for 2/3 months with
sampling/testing
▪ API was potent with health risks associated with sampling
▪ NIR method developed to identify API through plastic bag
▪ Test performed by trained warehouse operators
▪ Can analyze a full batch in a day

10/26/2020 35
At-line Analysis: Raman spectroscopy Raman for Identity

• Requirement to test all raw materials arriving at site

• Testing outsourced at a cost of over 200,000 USD per year
• Sampling and organizing samples a huge task keeping 1 FTE busy
• Lead time of 2 weeks for results
• Use of Raman simply replaced all need for outsourced testing
• Lead time reduced from 2 weeks to 30 seconds

10/26/2020 36
On-line Analysis: Microwave
Microwave for water content

▪ Microwave technology is cheap, robust and

widely used in oil and associated industries
▪ A fast sample loop system was used to
present the sample to a standard pipe
diameter with the microwave technology
embedded
▪ Instant readings for water content in slurries
(also potential in oil/water mixes etc)

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On-line Analysis UV for CIP
▪ A process at a top 10 Pharma required significant
CIP time resulting in reduced capacity
▪ Cytotoxic nature of compound and risk of cross-
contamination meant lack of commitment to
reduce this CIP cycle time
▪ UV was used to guarantee safety and effect of
cross contamination
▪ CIP cycles reduced by 40%

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Example of An Unified Approach for PAT -RTRT

39
Example of An Unified Approach for PAT - RTRT

10/26/2020 40
Use of process Analyzers - Manufacturing Process

10/26/2020 41
General analysis times

10/26/2020 42
Detailed Comparison - Release specifications for drug product - RTRT

10/26/2020 43
ISPE 18-19 Sep 2018 , DR Thomas Zimmer INDUSTRY 4.0 – Chance and Challenge for Pharmaceutical Operations,
ISPE Pharmaceutical Engineering ISPE July-August 2018 Volume 4
https://ispe.org/pharmaceutical-engineering/july-august-2018/pharma-40-hype-or-reality#footnote3_hp8nfrf

Future of Pharmaceutical Quality and the Path to Get There, Lawrence Yu, Ph.D.
INTERPHEX 2018, April 18

Pharma 4.0 & Smart patient reported outcomes Connecting biology, physics and digital For the benefit of human
wellbeing, Life Science Consultant

Technology and Innovation are driving change in the pharmaceutical industry Stefan Krauß Business
Segment Pharmaceuticals, Siemens AG , 2017
US Food and Drug Administration. Guidance for Industry. “Process Validation: General Principles and Practices.” J
anuary 2011. http://www.fda.gov/downloads/Drugs/Guidances/ UCM070336.pdf

ICH Q10 , Pharmaceutical Quality System, 2008

Cara Pembuatan Obat yang Baik – CPOB 2018

10/26/2020 44
Thank you

July 8th 2019