1. THE ROLE OF QUALITY ASSURANCE IN
PHARMACEUTICALS
History, Current Trends And Future
Challenges
National and Kapodistrian University of Athens – Department of Pharmacy
Athens, 20th of May 2016
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4. History Of
PHARMACEUTICAL GMP
Pharmaceutical regulations and
GMP requirements were created
and put in place as responses to
tragic circumstances and to prevent
future tragedies.
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5. History Of
PHARMACEUTICAL GMP
• 1901 - children who received antitoxin for diphtheria
treatment died of tetanus because the horse serum that had
been used to prepare the antitoxin was contaminated with
tetanus.
• syrup to calm “colicky” babies and “tonics” for adults often
contained alcohol, opium, or morphine, which addicted many
people who used them.
Response: 1906 Pure Food and Drug Act – First Act required
selected dangerous ingredients to be labeled on all drugs.
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6. History Of
PHARMACEUTICAL GMP
• 1930s - The wrong raw material and an elixir of sulfanilamide,
anti-infective drug used in 1935. One company used diethylene
glycol, a poisonous solvent and chemical analog of antifreeze, in
an oral “elixir of sulfanilamide.” Before the problem was
discovered, 107 people died, many of them children.
Response: Congress passed the Federal Food, Drug and Cosmetic
(FD&C) Act of 1938. For the first time, companies were required to
prove that their products were safe before marketing them. Still this
major act covering till today FDA oversight to cosmetics and
therapeutic devices.
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7. History Of
PHARMACEUTICAL GMP
• In 1941, nearly 300 people were harmed (some of them died)
by one company’s sulfathiazole tablets, a sulfa drug tainted
with the sedative phenobarbital.
Response:That incident caused FDA to drastically revise
manufacturing and quality control requirements, leading to what
would later be called GMPs.
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9. History Of
PHARMACEUTICAL GMP
• 1960s - Thalidomide was marketed in Europe as a sleeping pill
and to treat morning sickness.When regulatory agencies gave
permission to sell the drug for that indication, they had no
knowledge of its serious side effects. It turned out to be
teratogenic: It caused serious deformities in developing
fetuses.
Response: Manufacturers must prove efficacy of products before
marketing them and ensure stricter control over drug testing.
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10. THALIDOMIDE
TRAGEDY
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Children whose mothers
took thalidomide in the first
trimester were born with
severely deformed arms and
legs. An estimated 10,000
cases of infant deformities in
Europe were linked to
thalidomide use.
11. History Of
PHARMACEUTICAL GMP
• 1970s - The 1972 Devonport, UK, incident resulted in at least
five deaths when drug products designed to be sterile became
contaminated and recipients developed infections. An
unwritten change to autoclave operation, communicated orally
between operators, resulted in dextrose IV solutions that were
not uniformly sterile.
Response: GMPs for drugs (21 CFR Parts 210 and 211) and
medical devices (21 CFR 820) were made final in 1978.They
were intended to help ensure the safety and efficacy of all
products.
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12. History Of
PHARMACEUTICAL GMP
• 1980s - Poisoned acetaminophen capsules. In 1982, 12-year-old
Mary Kellerman died after taking an extra-strength Tylenol
acetaminophen capsule, Six other people died after taking the
same drug. Johnson & Johnson announced a nationwide recall of 31
million bottles of Tylenol.The investigation revealed that a
criminal tamperer had opened up and laced some capsules with
cyanide.The company destroyed all 31 million bottles of the
largest-selling over-the counter (OTC) medicine in the country.
Response: FDA issued tamper-resistant packaging regulations for all
OTC human drug products and incorporated them into the GMPs.
Congress passed the Federal Anti-Tampering Act in 1983, making it
a crime to tamper with packaged consumer products.
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14. History Of
PHARMACEUTICAL GMP
• In the 1980s, FDA began publishing a series of guidance
documents that have had a major effect on our interpretation of
current GMPs.
• Issuance of Guideline on General Principles of ProcessValidation
in 1987 outlined current thinking or expectations of process
validation for drugs and devices.
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15. History Of
PHARMACEUTICAL GMP
• In 1989, an outbreak of toxic reactions to over-the-counter l-
tryptophan, a dietary supplement, resulted in 38 deaths and
probably thousands of less severe reactions.The event was the
result of a manufacturing process change that increased the
level of a harmful byproduct. Doses that had previously been
safe now caused toxicity.
Response: clarification of requirements for characterizing drug
impurities and new requirements for evaluation of minor
impurities.
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16. BASIC MILESTONES IN HISTORY OF
PHARMACEUTICAL REGULATIONS
AND GMP
• 1906 Pure Food and Drug Act
• 1938 Federal Food, Drug and Cosmetic (FD & C) Act
• 1941 Tragedy with Sulfathiazole tablets tainted with Phenobarbital
Result: FDA revises manufacturing and quality controls drastically,
the beginning of what will later be called GMPs.
• 1962 The “Thalidomide Tragedy” leads the US Congress to add
GMP to the Food, Drugs and Cosmetic Act. FDA publishes first
Regulation on Good Manufacturing Practices” – A drug which is
not made following GMP is adulterated (Contaminated).
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17. BASIC MILESTONES IN HISTORY OF
PHARMACEUTICAL REGULATIONS
AND GMP
• 1969 The World Health Organization publishes the first
universal guideline “Basic Rules for the Manufacture of
Pharmaceuticals and the Assurance of their Quality”.
• 1974 Allergic reaction due to extremely small traces of
penicillin in other drug products lead to demands for
separation of penicillin and non-penicillin production.
• 1975 The EU Directive 75/319 lays down the basic procedures
(approximations) for the registration, trade and compensation
for damages for “Medicinal Products” with the EU.
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18. BASIC MILESTONES IN HISTORY OF
PHARMACEUTICAL REGULATIONS
AND GMP
• 1978 CGMPs Final Rules for Drugs (21 CFR Parts 210–211).
• 1982 Temper-Resistant Packaging Regulations Issued for OTC
Products.
• 1987 Guideline on General Principles of Process Validation.
• 1989 EU publishes its Directive on the “Approximation of
provisions for GMP in the European Community”, i.e. a legal
basis is established for pharmaceutical GMP within the
European Community.
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19. BASIC MILESTONES IN HISTORY OF
PHARMACEUTICAL REGULATIONS
AND GMP
• 1996 PIC accepts the European industry’s GMP Guide.
• 1998 “GMPs for Starting Materials” is added to the ICH work programme
to be decided by an Expert Working Group.
• 2001 ICH Q7A API Guidance ICH’s “Good Manufacturing Practice
Guidance for Active Pharmaceutical Ingredients (APIs)”.
• 2001 – Issuance of Directive 2001/83/EC of the European Parliament and
of the Council on the Community code relating to medicinal products for
human use.
• 2011 – Issuance of Directive 2011/62/EU of the European Parliament and
of the Council for prevention of the entry into the legal supply chain of
falsified medicinal products.
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21. WHAT IS QUALITY ?
• Quality is not an act, is a habit (Aristotle)
• Quality means: Do it right when no one is looking (Henry Ford)
• Fitness for Use (Juran)
• Conformity with Specifications (Crosby)
• Capability of product to satisfy customer’s needs (Ishikawa)
• Quality is inversely proportional to variability (Montgomery)
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22. WHAT IS QUALITY OF DRUG ?
• The degree to which a set of inherent properties of a product,
system or process fulfills requirements specifically for quality
of drug substance and drug product (ICH Q9).
• The suitability of either a drug substance or drug product for
its intended use.This term includes such attributes as identity,
strength and purity (ICH Q6A).
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23. WHAT IS GMP
(GOOD MANUFACTURING
PRACTICE) ?
• The part of quality assurance which ensures that products are
consistently produced and controlled in accordance with the
quality standards appropriate to their intended use and are in
compliance with their marketing authorization specifications
(Directive 2003/94/EC).
• GMP involves also Production and Quality Control of
Pharmaceutical products.
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24. WHAT IS QUALITY CONTROL
(QC) ?
Quality control is that part of Good Manufacturing Practice
(GMP) which is concerned with sampling, specifications and
testing and with the organization, documentation and release
procedures which ensure that the necessary and relevant tests
are actually carried out and that materials are not released for
use, nor products released for sale or supply, until their quality
has been judged to be satisfactory (EU GMP Part I).
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25. WHAT IS QUALITY ASSURANCE
(QA) IN PHARMACEUTICALS ?
Quality assurance (or Quality Management) is a wide-range
concept covering all matters that individually or collectively
influence the quality of a product. It is the totality of the
arrangements made with the object of ensuring that
pharmaceutical products are of the quality required for their
intended use (WHO). Quality Management therefore
incorporates Good Manufacturing Practice.
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26. WHAT IS PHARMACEUTICAL
QUALITY (MANAGEMENT) SYSTEM
PQS ?
Management system to direct
and control a pharmaceutical
company with regard to quality.
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28. PQS SHOULD ENSURE
• Manufacture of medicinal products with appropriate quality
attributes.
• Product and process knowledge is managed throughout all
lifecycle stages; Pharmaceutical Development Technology
Transfer Commercial manufacturing Product
Discontinuation
• Good Manufacturing Practice is always taken into
consideration through design, development and manufacture
of products with clearly specified manufacture and control
operations.
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29. PQS SHOULD ENSURE
• Managerial responsibilities are clearly specified.
• Supply and use of the correct starting and packaging
materials, from the approved suppliers and supply chain.
• Processes are in place to assure the management of
outsourced activities.
• A state of control is established and maintained by developing
and using effective monitoring and control systems for process
performance and product quality.
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30. PQS SHOULD ENSURE
• Deviations during manufacture or control should be
investigated, Root Cause should be found and appropriate
CAPAs should be undertaken in order to avoid potential
deviations occurring in the future. Effectiveness of CAPAs
implementation should be evaluated through Quality Risk
Management principles (QRM).
• All necessary controls on intermediate products, and any other
in-process controls and validations are carried out.
• Continual improvement of PQS is facilitated through the
implementation of quality improvements through gained
knowledge from process and product (QbD, SPC, PQR).
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31. PQS SHOULD ENSURE
• Evaluation of planned changes and their approval prior to
implementation, taking into account regulatory notification and
approval where required through Change Control
management.
• Evaluation of changes to confirm the quality objectives were
achieved and that there was no unintended deleterious impact
on product quality.
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32. PQS SHOULD ENSURE
• Medicinal products are not sold or supplied before batch
release certification by Qualified Person (QP).
• Medicinal products are stored, distributed and subsequently
handled so that quality is maintained throughout their shelf life
(GDP).
• Regular self-inspection and/or quality audit for appraisal the
effectiveness and applicability of the Pharmaceutical Quality
System.
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33. BASIC ELEMENTS OF PQS
• Senior management has the ultimate responsibility to ensure
an effective Pharmaceutical Quality System is in place,
adequately resourced and that roles, responsibilities, and
authorities are defined, communicated and implemented
throughout the organisation.
• Management review, with the involvement of senior
management, of the operation of the Pharmaceutical Quality
System to identify opportunities for continual improvement of
products, processes and the system itself.
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34. BASIC ELEMENTS OF PQS
The Pharmaceutical Quality System
should be defined and documented.
A Quality Manual or equivalent
documentation should be
established and should contain a
description of the quality
management system including
management responsibilities.
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36. CHAPTER 1 - PHARMACEUTICAL
QUALITY SYSTEM
• The design of the system should incorporate appropriate risk
management principles including the use of appropriate tools.
• Pharmaceutical Quality System should facilitate innovation and
continual improvement and strengthen the link between
pharmaceutical development and manufacturing activities.
• It should be fully documented and its effectiveness monitored.
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37. CHAPTER 2 - PERSONNEL
• Personnel should have the necessary qualifications and practical
experience.
• Personnel in responsible positions should have specific duties
recorded in written job descriptions and adequate authority to
carry out their responsibilities.
• Personnel whose duties take them into production and storage
areas or into control laboratories, and for other personnel whose
activities could affect the quality of the product, such as cleaning,
maintenance, validation, etc., should be trained regularly.
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38. CHAPTER 3 - PREMISES AND
EQUIPMENT
• Premises and equipment must be located, designed,
constructed, adapted and maintained to suit the operations to
be carried out.Their layout and design must aim to minimise
the risk of errors and permit effective cleaning and
maintenance in order to avoid cross-contamination, build-up of
dust or dirt and, in general, any adverse effect on the quality of
products.
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39. CHAPTER 4 - DOCUMENTATION
• The various types of documents, instructions and records used
should be fully defined in the manufacturer's Pharmaceutical
Quality System.
• Good documentation constitutes an essential part of the quality
assurance system and is key to operating in compliance with GMP
requirements.
• Suitable controls should be implemented to ensure the accuracy,
integrity, availability and legibility of documents. Instruction
documents should be free from errors and available in writing.
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40. CHAPTER 4 - DOCUMENTATION
Continue
Basic types of GMP documents required in PQS:
• Site Master File (SMF)
• Quality Manual
• Quality Policies
• Standard operating procedures (SOPs)
• Specifications
• Manufacturing Formulae, Processing, Packaging and Testing
Instructions
• Protocols
• Technical – Quality agreements
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41. CHAPTER 5 - PRODUCTION
• Production operations must follow clearly defined procedures;
they must comply with the principles of Good Manufacturing
Practice in order to obtain products of the requisite quality and
be in accordance with the relevant manufacturing and
marketing authorisations.
• Prevention of cross-contamination in production.
• Validation: all manufacturing, packaging, testing and other
processes which may have an impact to quality of the drug
product should be validated and fully documented.
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42. CHAPTER 5 – PRODUCTION
Continue
Starting materials including APIs, excipients, primary
and secondary packaging materials should be
procured by approved and qualified vendors and
their quality should be assessed against pre-defined
quality specifications before their use in
manufacturing and packaging processes.
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43. CHAPTER 6 – QUALITY CONTROL
• Quality Control is concerned with sampling,
specifications and testing as well as the organisation,
documentation and release procedures which ensure that
the necessary and relevant tests are carried out, and that
materials are not released for use, nor products released
for sale or supply, until their quality has been judged
satisfactory.
• The independence of Quality Control from Production is
considered fundamental to the satisfactory operation of
Quality Control. 43
44. CHAPTER 6 – QUALITY CONTROL
Continue
Other duties of Quality Control:
• Establishment, validation and implementation of all quality
control procedures.
• Oversee the control of the reference and/or retention samples
of materials and products.
• Ensure the correct labelling of containers of materials and
products.
• Ensure the monitoring of the stability of the product.
• Participate in the investigation of complaints related to the
quality of the product. 44
45. CHAPTER 7 – OUTSOURCED
ACTIVITIES (Subcontracting)
• Any activity covered by the GMP Guide that is outsourced
should be appropriately defined, agreed and controlled in
order to avoid misunderstandings which could result in a
product or operation of unsatisfactory quality.
• There must be a written Contract between the Contract Giver
and the Contract Acceptor which clearly establishes the duties
of each party.
• The Quality Management System of the Contract Giver must
clearly state the way that the Qualified Person certifying each
batch of product for release exercises his full responsibility.
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46. CHAPTER 8 – COMPLAINTS,
QUALITY DEFECTS AND PRODUCT
RECALLS
• A system and appropriate procedures should be in place to
record, assess, investigate and review complaints including
potential quality defects, and if necessary, to effectively and
promptly recall medicinal products from the distribution
network.
• Root cause analysis (RCA) work should be applied during the
investigation of quality defects.
• The effectiveness of recall procedure should be periodically
evaluated to confirm that they remain robust and fit for use
through mock-recalls performance.
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47. CHAPTER 9 – SELF INSPECTION
• Self inspections should be conducted in order to monitor the
implementation and compliance of PQS with GMP principles
and to propose necessary corrective measures.
• Self inspections at production, quality control, storage areas,
premises, maintenance, distribution chain, etc. should be
examined at intervals following a pre-arranged programme in
order to verify their conformity with the principles of Quality
Assurance.
• Self inspections should be conducted in an independent and
detailed way by designated competent person(s) from the
company. 47
48. PHARMACEUTICAL QUALITY
SYSTEM – SIX SYSTEMS FDA
APPROACH
• Quality System
• Production system
• Facilities and equipment
system
• Materials system
• Laboratory controls system
• Packaging and Labelling
system
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49. DEVIATION INVESTIGATION AND
ROOT CAUSE ANALYSIC (RCA)
• Root cause analysis work should be applied during the
investigation of quality defects.
• In cases where the true root cause(s) of the quality defect
cannot be determined, consideration should be given to
identifying the most likely root cause(s) and to addressing
those.
• Appropriate CAPAs should be identified and taken in
response to a quality defect.The effectiveness of such actions
should be monitored and assessed.
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55. QUALITY RISK MANAGEMENT
• Quality risk management is a systematic process for the
assessment, control, communication and review of risks to the
quality of the drug (medicinal) product across the product
lifecycle.
• Harm – damage to health, including the damage that can occur
from loss of product quality or availability.
• Hazard - the potential source of harm.
• Risk – the combination of the probability of occurrence of harm
and the severity of that harm.
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56. QUALITY RISK MANAGEMENT
OVERALL RISK = S x O x D
S = Severity of the consequences of the harm
O = Probability of occurrence of the harm
D = Detectability, ability to detect the hazard
(source of harm)
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58. PRODUCT QUALITY REVIEW
• Review of starting materials including packaging materials
used in the product.
• Review of critical in-process controls and finished product
results (SPC, trend analysis).
• Review of all significant deviations or non-conformances, their
related investigations, and the effectiveness of resultant
corrective and preventive actions taken.
• Review of all changes carried out to the processes or analytical
methods.
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59. PRODUCT QUALITY REVIEW
Continue
• Review of Marketing Authorisation variations submitted,
granted or refused, including those for third country (export
only) dossiers.
• Review of the results of the stability monitoring programme
and any adverse trends.
• Review of all quality-related returns, complaints and recalls
and the investigations performed at the time.
• Review of adequacy of any other previous product process or
equipment corrective actions.
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60. PRODUCT QUALITY REVIEW
Continue
• For new marketing authorisations and variations to marketing
authorisations, a review of post-marketing commitments.
• The qualification status of relevant equipment and utilities, e.g.
HVAC, water, compressed gases, etc.
• Review of any contractual arrangements as defined in Chapter
7 (Technical – Quality agreements) to ensure that they are up to
date.
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63. CONTINUOUS IMPROVEMENT OF
PHARMACEUTICAL QUALITY
SYSTEM – PDCA CYCLE (E. Deming)
Plan: Corrective and
Preventive actions (CAPAs)
Do: implementation of CAPAs
Check: evaluation of
effectiveness of CAPAs
Act: Decision for new CAPAs
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65. FUTURE OF PHARMACEUTICAL
QUALITY SYSTEM
• Till today pharmaceutical product quality is assured by
pharmacopoeal “end point” testing – after the fact quality
control in finished product (Assay, related substances,
dissolution test in tablets, etc.).
• This end-point quality testing was realized to be insufficient to
assure the quality of the individual medication unit (the tablet,
the capsule, the vial) dispensed to the patient.
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66. FUTURE OF PHARMACEUTICAL
QUALITY SYSTEM
• Quality needed to be assured at each step of the
manufacturing process to be as certain as possible that each
dosage unit met its quality specifications.
• Change from traditional quality-by-testing (QbT) approach to
the new quality-by-design (QbD) approach.
• Implementation of Quality Risk management in all steps of
product lifecycle, from product development to product
discontinuation.
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67. PROCESS ANALYTICAL
TECHNOLOGY (PAT)
Process Analytical Technology (PAT): A risk based framework
with goal to design and develop well understood processes that
will consistently ensure a predefined quality at the end of the
manufacturing process.
• Product quality and performance are ensured through the
design of effective and efficient manufacturing processes.
• Product and process specifications are based on a mechanistic
understanding of how formulation and process factors affect
product performance.
• Continuous real time quality assurance through quality
assessments of materials’ attributes and process controls.
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68. REAL TIME RELEASE TESTING
Real Time Release Testing: The ability to evaluate and ensure
the quality of in-process and/or final product based on process
data, which typically include a valid combination of measured
material attributes and process controls.
Process controls through measurements:
• at-line: Measurement where the sample is removed, isolated
from, and analyzed in close proximity to the process stream.
• on-line: Measurement where the sample is diverted from the
manufacturing process, and may be returned to the process
stream.
• in-line: Measurement where the sample is not removed from
the process stream and can be invasive or noninvasive.
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70. FUTURE OF PHARMACEUTICAL
QUALITY SYSTEM –
THE NEW APPROACH
• Quality by Design (QbD): A systematic approach to
development that begins with predefined objectives and
emphasizes product and process understanding and process
control, based on sound science and quality risk management.
• Design Space: The multidimensional combination and
interaction of input variables (e.g., material attributes) and
process parameters that have been demonstrated to provide
assurance of quality.
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73. CONTINUOUS IMPROVEMENT OF
PHARMACEUTICAL QUALITY
SYSTEM – PDCA CYCLE (E. Deming)
Plan: QbD and QRM in
Pharmaceutical Development, and
set of Control Strategy
Do: Implementation of PAT
Check: Data analysis, SPC, Process
Capability Analysis,Trend analysis,
PQR, evaluation of effectiveness of
Control Strategy
Act: Decision for new Control
Strategy if necessary 73
74. NEW ROLES - CHALLENGES OF QA
IN PHARMACEUTICAL INDUSTRY
• QA in the past was considered as “policeman”,“controller”
and the “enemy” of production.
• QA should not be considered anymore as the absolutely
responsible for quality of drug product.
• QA needs to perform a more pro-active role in improving the
PQS by focusing much more in prevention and continuous
improvement rather than appraisal of quality of drug product.
• QA should help top management and senior management to
fulfill their responsibility to improve the PQS.
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75. NEW ROLES - CHALLENGES OF QA
IN PHARMACEUTICAL INDUSTRY
• Traditional responsibilities and duties of QA can be enforced
and applied by periodic and effective audits. If other
departments are doing their work properly, then QA will be
able to significantly reduce its checking and oversight
activities.
• QA also needs to stop doing the work of other departments.
This will free up QA personnel to perform more proactive and
preventive type of activities, which would be more value-
added to the organization.
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76. NEW ROLES - CHALLENGES OF QA
IN PHARMACEUTICAL INDUSTRY
• QA should adopt the use of quality risk management tools in
all processes, should determine the appropriate metrics and
data analysis tools, should determine the root causes of
problems and suggest appropriate CAPAs to improve
processes and product performance.
• QA, with the help of all departments, can suggest corrective
and preventive actions to senior management since senior
management has the capability to fix root causes.
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77. NEW ROLES - CHALLENGES OF QA
IN PHARMACEUTICAL INDUSTRY
Finally, QA should assist senior management to built a “quality
culture” through the organization since “Quality is everyone’s
responsibility” (E. Deming).
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