2. Quality Management System, Quality
Assurance and Quality Control.
• Within the pharmaceutical manufacturing, the
various functions related to quality management are
critical.
• This chapter deals with two of the three main
functions:
1. Quality assurance (QA).
2. Quality control (QC).
3. Good manufacturing practice (GMP).
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3. The difference between
QMS, QA, GMP & QC
• This topic is confusing because of the need
to understand clearly the difference between
Quality Management System, Quality
Assurance, and Quality Control.
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4. 2.2 Relationship between quality management,
QA, GMP and QC
• The relationship between Q.M, Q.A, G.M.P, and
Q.C can be viewed as a type of a cascade
arrangement as shown in Figure 2.1
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• Quality Management System
• Quality Assurance
• Good Manufacturing Practice.
• Quality Control
6. • Q.M.S, with over all policy of the organization
towards quality, comes above everything else.
• Next comes Q.A, which is the unit that ensures
the policy is achieved.
• GMP is a part of Q.A; it deals with the risks that
cannot be tested & build quality into the product.
• Q.C, is a part of GMP; the part that is focused on
testing of the environment & facilities, as well as
the testing of materials, components & product
in accordance with the standard.
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7. Documentation Cascade
• At the top of the cascade are the International
and National policies, Codes of practice and
Standards, which govern everything that is done
in the pharmaceutical industries.
• At the second level are the statements of the
company goals, mission statement and values to
which the company wishes to adhere.
• At the third level is the company quality policy
that comes from the mission statement.
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8. • At the fourth level is the company quality
system that is developed following the policy
statement.
• At the fifth level are the major departments,
strategies involving R&D, manufacturing and
QA; these set out how they will achieve their
contribution to the quality system that has been
developed.
• At the sixth level are the procedures and
standard that have been developed in each
department to implement the strategies.
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9. •At the base of the cascade are the
individual job instructions and
performance of the work to meet the
standards and procedures that have
been developed.
•It includes the critical records that are
made of each part of the manufacturing
process.
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10. 2.3 Definition of Quality Management
• According the WHO, “The aspect of
management functions that determines and
implements the Quality Policy.
• The manufacturer is obliged to assume
responsibility for the quality of the
pharmaceutical products to ensure that they are
fit for their intended use, comply with the
requirements of the marketing authorization and
do not place the patient at risk because of
inadequate Safety, Quality or Efficacy.
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11. • The pharmaceutical product quality parameters
are laid down in individual product
specifications.
• These specifications ensure that the product
fulfils the basic requirements of Identity,
Purity, Strength and bioavailability.
• Identity: The product must comply with the
information given on the product label.
• Purity: This defined as the extent to which a raw
material or a drug in dosage form is free from
undesirable chemical, biological, or physical
entities as defined by the specifications.
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12. • Bioavailability:
• Upon administration, the product must provide
the active ingredient for the intended
therapeutic/biological availability.
• Bioavailability is the rate and extent of
absorption of a drug from a dosage form as
determined by its concentration/time cure
in the systematic circulation, or by its
excretion in the urine.
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13. Definition of Quality Assurance
• In EU guidelines QA is defined as a wide range
concept which covers all matters which
individually, or collectively influence the quality of
the product.
• QA provides confidence for the
customer weather that is Pharmacist, Doctor or
Patient in quality of drug being supplied.
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15. The road to a Pharmaceutical
Quality System
Dr. Majed R. Feddah
Here you will find answers to the following questions:
How has the concept of “quality“ in the pharmaceutical
industry changed over the past decades?
16. I. Introduction
•Pharmaceutical quality has been continuously improved
over the past decades.
•Until the eighties, the philosophy was that Quality
Control (QC)Testing alone could determine the quality
of the product. This concept had serious limitations.
•In-contrast to other industries, where it is feasible to
test 100 % of products.
•Pharmaceutical testing must rely on representative
samples.
17. 20/06/2023
•Testing of 100 % of products
would leave nothing for the
patient! However, problems
can go undetected when only
samples are tested.
•Example, sterile products on
the market have shown
microbiological contamination
even though the samples were
free of microorganisms.
18. • Realizing that testing alone could not determine
whether a product was meeting its predefined
specifications gave rise to the concept of the Quality
Assurance partnership.
• To judge the quality of a pharmaceutical product, it is
necessary to obtain and analyze additional information
as to how it has been manufactured?
• This awareness led to the development of measures
such as batch record review, investigation reporting &
approval of manufacturing documents by the quality
department.
19. • The QA concepts implemented by companies had one
major drawback:
They were reactive rather than proactive.
• All activities focused on assessing the status quo ( تقييم
الراهن الوضع
) & fixing problems as they arise.
• Compliance with GMP regulations was the main focus, &
HealthAuthority inspections supported this narrow view.
20. •Due to:
• Complexity of the operational in the
pharmaceutical industry.
•The growing size of pharmaceutical companies,
•It became increasingly difficult to ensure
compliance with all aspects of GMP regulations.
21. Quality Management
• The industry began to adopt the term Quality Management
(QM) & to adapt number of GMP topics such as:
• Change control.
• Recall management.
•Equipment maintenance.
•Validation.
•Handling of discrepancies, etc.
22. In conclusion
• The status quo was no longer tenable الراهن الوضع يعد لم
لالستمرار ًقابال:
• Pharmaceutical manufacturers could do much better.
Furthermore, traditional metrics were said to be hiding
poor performance, & compliance “infrastructure” with
quality-related costs currently running in excess of 20 %,
was uneconomical.
• The agency’s findings showed that too often, processes
were not understood in detail, & that this was still the
case once scaled up for commercial production.
23. 20/06/2023
• The FDA introduced its Quality Management Systems
(QMS) with the So-called “GMP initiative for the 21 st
century“.
• The QMS concept has helped other industries to
increase their process robustness & thus bring down the
price of quality.
24. • This approach allows the
pharmaceutical industry to take the
move from Reactive to Proactive
behavior, to recognize discrepancies
& not only fix them, but introduce
measures that prevent reoccurrence.
• As consequence, the pharmaceutical
industry will move into a loop of
continual improvement & finally
increase the robustness of its
processes, in production as well as in
business. Drug
25. Benefit of QMS
• A Quality Management System enables
a company to implement:
• Effective, Efficient,Transparent & Simple processes &
Structures to achieve continual compliance.
• In addition, this will benefit the company’s business in
terms of Improved quality, Optimized costs, Inspection
readiness and Customer satisfaction.
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26. Summary
• Over the past decades pharmaceutical
organizations became more and more complex and
thus needed to adapt the concept of “quality” from
”Quality Control” to modern approaches like
Pharmaceutical Quality Systems
• as laid down in ICHQ10.
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27. 1.C Introduction to the PQS
Here you will find answers to the following questions:
1. What are the fundamentals of a PQS?
2. What is the role of senior management within the
concept of a PQS.
3. What is the central document of a PQS?
4. What are basic documentation requirements?
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28. 1.C.1 General requirements
• The overall aim of implementing a Pharmaceutical
Quality System (PQS) is to:
• Continually improve the effectiveness & efficiency
of the organization’s performance & thus achieve
compliance with GMP regulations around the
world.
• A PQS must be led in a systematic & visible manner
and involve people at all levels.
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29. • A company performs many
internal activities such as
Manufacturing, Research,
Development,Clinical trials,
registration, marketing,
purchasing,Warehousing and
Distribution, etc.
• Activities need to be addressed
in a PQS which describes all the
processes that have to be
managed.
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31. 20/06/2023
I
• Product Development
II
• TechnologyTransfer
III
• Commercial Manufacturing
IV
• Product Discontinuation.
All
these
activities
should
be
included
in
a
life
cycle
approach
32. • Implementing a PQS has a significant impact on the
“classical” organization of a company.
It necessitates:
1. Process-oriented thinking.
2. Definitions of the responsibilities within a process.
3. Identification of interfaces, within & between different
processes
4. The nomination of process owners for the processes
identified.
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33. • The establishment of Key
Performance Indicators (KPIs)
for measuring the
effectiveness of a process &
thus the value it brings to the
company.
• The routine assessment of
process performance &
identification of potential
improvements.
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34. Senior Management
•A PQS requires the systematic
involvement of senior management
in the functioning & success of a PQS.
•In practice, senior management directs the
organization towards its quality objectives by:
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35. Roll of Senior Management in PQS
1. Determining responsibilities within the organization (Global,
Regional, Local).
2. Providing sufficient resources (infrastructure – e.g. offices,
manufacturing, IT – time & personnel).
3. Defining information & communication flow at all levels of
the organization.
4. Integrating the concept of Quality Risk management at all
levels of the organization.
5. Implementing a concept of Knowledge Management أدارة
المعرفة.
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36. 6. Promoting all initiatives that lead to improved process
robustness (production processes as well as business
processes).
7. Encouraging the implementation of concepts that will
enable continual improvement at all levels.
8. Using the (regular) Management Review to direct the
PQS and thus the organization.
9. It must be stressed that outsourced operations and
related activities also need to be covered by the PQS.
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37. 1.C.2 Documentation
•1.C.2.1 General
• A documentation system remains a fundamental
component of a PQS.
• The objective of documentation is to identify & describe
what needs to be in place.
• It is an essential tool to keep all processes in a state of
control and it must satisfy GMP requirements.
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38. • Senior management defines the
documentation that is required to
run a PQS & support effective &
efficient operation of the processes.
It includes:
1. Senior management’s commitment to quality.
2. A quality manual.
3. Documented procedures.
4. Documents & records needed for an efficient PQS.
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39. • GMP documentation, especially regarding
Master Production Instructions & laboratory
documentation, provides detailed information.
• GMP requirements need to be reflected in the
PQS for reasons of compliance.
• The documentation created to run a PQS and to
comply with GMP requirements should fulfill
criteria with respect to:
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41. • Documentation may be available in any
form or media, such as paper, micro-
fiche, electronic (CD/DVD) etc., suitable
to needs.
• In a GMP environment, quality-related
activities are to be recorded at the time
that they are performed.
• (see Chapter 1.D.4 Evaluation activities).
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42. • Deviations from established procedures need to be
documented & explained and /or investigated:
• Complaint & recall procedure has to be in place.
• Contract manufacturing (including laboratories) needs to
be carefully managed, e.g. through evaluation,
assessment & documentation (including a quality
agreement).
• All (GMP) activities and responsibilities have to be
defined in writing. (see Chapter 17 Contractors and Suppliers).
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43. 1.C.2.2 Quality manual
• The central document of a PQS is the Quality Manual.The
quality manual should be made as comprehensive as possible.
The main elements to be incorporated include:
• The scope of the PQS.
• A description of the main processes, their
interactions & the description of major
responsibilities.
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44. 1.C.2.3 Control of documents
• All documents & records required by the PQS are
subject to appropriate control.
A documented procedure needs to be established
to define the following controls:
1. Drafting.
2. Review.
3. Approval.
4. Updating of documents.
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45. 1.C.2.4 Control of records
• Records provide evidence of conformity to requirements.
• They should be legible, readily identifiable &retrievable.
• A documented procedure should define the control
needed for Identification, Storage, Protection, Retrieval
Retention time & Disposition of records.
• The control of records includes Hard copies as well as
Electronically-stored data.
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46. Records
1. Raw materials.
2. Intermediates.
3. Labeling.
4. Packaging materials.
5. Batch production.
6. Laboratory data (including Certificates of Analysis & stability
data),
7. Calibration,
8. Distribution,
9. Complaints and returns. 20/06/2023
47. Summary
• The implementation of a PQS includes the
introduction of a process-oriented thinking.
• The way how the PQS is organized is laid down in
the “Quality Manual”.
• All documents and records required by the PQS
are subject to appropriate control.
• Senior Management is systematically involved in
the PQS & directs the PQS by applying various
tools, such as the “management review”.
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49. 1.D Main elements of a PQS
Here you will find answers to the following
questions:
1. What are the four major processes of a PQS?
2. How can the GMP requirements be linked to
these four processes?
3. What new elements that go beyond the GMP
requirements are needed to run a PQS?
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50. 1.D Elements of a PQS
•D.1 Management responsibility.
•D.2 Resource management.
•D.3 Manufacturing operations.
•D.4 Evaluation activities.
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53. D.3 Manufacturing operations.
• D3.1-Planning.
• D3.2-Desing and Development.
• D3.3-Purchasing.
• D3.4-Production and Service Provision.
• D3.5-Control of Monitoring and Measuring Device.
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55. • D4.7-Risk Management.
• D4.8-Corective and PreventiveAction (CAPA).
• D4.9-Continual Improvement of the organization.
• D4.10-Control of non-Conforming Product.
• D4.11-Measurement of Customer Satisfaction.
• D4.12-Measurment of Employees Satisfaction.
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56. 1.D.1 Management responsibility
•1.D.1.1 Management commitment.
• Commitment and active involvement of senior
management are essential.
• They should provide evidence of its commitment of
(PQS) by:
1. Stress on the importance of meeting patient needs,
regulatory (GMP) & legal requirements, environmental,
health & safety aspects,
2. Ensuring that the organization has knowledge of the
regulatory requirements.
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57. 3. Establishing quality policy.
4. Ensuring that quality objectives are established.
5. Defining responsibilities.
6. Adopting continual improvement,
7. Defining methods to measure the organization’s
performance.
8. Conducting regular management reviews.
9. Ensuring the availability of sufficient resources
(manpower, time and infrastructure).
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58. 1.D.1.2 Quality policy
• Management should stress the importance of
compliance with regulatory/GMP requirements & the
continual improvement in performance of the PQS.
• Quality policy should become part of daily business.
• The quality policy needs to be understood at all levels
within the organization.
• Quality is the responsibility of all persons involved in a
process.
• The quality policy should be reviewed for continuing
suitability.
• 20/06/2023
59. 1.D.1.3 Quality planning
• Management is responsible for the quality
planning of the organization.
Quality Planning is driven by:
1. Strategies & organizational objectives.
2. By patient needs.
3. By regulatory requirements.
4. By risk management.
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60. The “SMART” criteria
• S = Specific.
• M = Measurable.
• A = Achievable.
• R = Relevant.
• T = Time-framed
Should be applied to establish quality objectives.
The output of quality planning should be submitted for
management review
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61. 1.D.1.4 Representative
• Senior management should make sure that
responsibilities & competencies are defined for
all employees.
• People throughout the organization should be
given the responsibilities & authority necessary
to enable them to contribute to the
achievement of quality objectives.
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62. • Management should appoint a representative who,
is responsible & authorized:
• To make sure that the processes needed for the
PQS are:
1. Established
2. Implemented
3. Maintained.
• Quality Assurance Manager should report to the
General Manager.
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63. 1.D.1.5 Resource management
Senior management should determine & provide
adequate & appropriate resources to implement &
maintain the PQS:
• Human resources.
• Financial resources.
• Materials.
• Infrastructure (facilities and equipment).
• Time.
• For more detailed discussion of resource management see Chapter 1.D.2 Resource management
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64. 1.D.1.6 Internal communication
• Senior management should ensure that appropriate
communication are established between all levels of
the organization.
• Quality issues should be considered as a standard
topic on the agenda of all appropriate meetings.
• Procedures should exist for notifying responsible
management of quality-critical situations in a timely
manner.
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65. 1.D.1.7 Management review
• Senior management should review the PQS at
predefined intervals to ensure its continuing
Suitability, Adequacy & Effectiveness.
• The review should cover environmental, health
and safety aspects.
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66. • Records of management reviews are to be
maintained.
• Available data is to be provided as input to senior
management review to support their decision-
making process.
These data includes:
• Follow-up actions from previous management
reviews.
• Audit observations/results (internal & external
audits & inspections by authorities).
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67. • Supplier qualification.
• Product conformity (product quality review).
• Complaint, deviation and manufacturing changes.
• Feedback from outsourced operations.
• Process performance, e.g. key performance
indicators (KPI),
• Status of corrective & preventive actions (CAPA).
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68. • Changes that could affect the PQS.
• Recommendations for improvement.
• The output from the management review should
include any decisions & actions taken relating to:
Continual improvement of the effectiveness of the
PQS & its processes.
• Continual improvement of product (relating to
customer requirements).
• Setting priorities of activities & resources needed.
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69. 1.D.1.8 Outsourced operations
1. Ensured that measures are in place to assure the
quality of product and processes:
2. Assessment, prior to outsourcing, of the
suitability & competency of the contract
acceptor.
3. Definition of responsibilities & communication
processes for quality-related activities.
4. Monitoring & review of performance of the
contract acceptor.
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70. 1.D.2 Resource management
1.D.2.1 Provision of resources
• Resources should be identified & available by
management to:
1. Implement & maintain the PQS & continually improve its
effectiveness.
2. Maintain equipment and facilities.
3. Train and educate employees.
4. Plan for future needs.
5. For information management and technology.
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71. 1.D.2.2 Human resources
• Management has to provide an adequate number of
personnel who are qualified with the appropriate
education, training, and/or experience to perform work &
to meet requirements.
• Determining the necessary competence & education for
personnel performing work.
• Issuing job descriptions & qualifications for all functions
throughout the organization.
• Training provided regularly by qualified individuals
covering, at minimum, the particular operations that the
employee performs.
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72. Evaluation of the effectiveness of training:
• Testing the actual content of procedures performed
Observing the employee performing task(s)
• Checking the accuracy of the work & results.
• Ensuring that personnel are aware of the relevance &
importance of their activities & how they contribute
to the achievement of quality objectives.
• Maintaining appropriate records of education,
training, skills and experience.
• More information on this topic is given in Chapter 2.B.1 Qualification requirements and Chapter 2.C Trainin
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73. 1.D.2.3 Infrastructure
Infrastructure includes:
• Buildings (including utilities &
workspaces).
• Equipment & computerized
systems..
• Management has to ensure that
the organization determines,
provides & maintains the
infrastructure needed to conduct
operations according to standards.
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74. Regarding buildings:
Be located, designed, and constructed to facilitate
cleaning, maintenance, and operations as
appropriate to the type & stage of manufacture.
Allow adequate space for the orderly placement
of equipment & materials to prevent mix-ups &
contamination.
Have adequate cleaning, washing & toilet facilities.
Have laboratory facilities separate from
production areas.
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75. Be adequately lit in all areas to facilitate cleaning,
maintenance, and proper operations,.
Have storage areas offering suitable conditions for all
types of materials (e.g., temperature & humidity).
Include adequate laboratory facilities for quality unit.
Be properly maintained & repaired.
Provide separate areas for eating, drinking & smoking.
Contain the necessary utilities (such as HVAC, water,
gases etc.) to perform the relevant production
operations
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76. Equipment should be:
Of appropriate design, adequate size & be suitably
located for its intended use in order to facilitate
cleaning, sanitization, & maintenance.
Constructed so that surfaces in contact with raw
materials, intermediates, APIs or drug (medicinal)
product do not alter quality beyond the official or
other established specifications.
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77. Computerized systems should be:
Of appropriate design and adequate capacity.
Equipped with the necessary software programs.
Maintained (e.g. with program updates or exchange
of hardware components).
Safe against loss of data.
The infrastructure has to meet all legislative
requirements as laid down by regulatory
authorities.
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78. 1.D.2.4 Information
Data should regarded as a fundamental resource to
be converted into essential knowledge & used for
making decisions.
To manage information it is necessary to:
1) Identify information needs.
2) Identify access to information.
3) Identify sources of information (internal and
external).
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79. 4) convert information into knowledge.
5) Use data, information and knowledge to fulfill
strategies and meet quality objectives.
6) Ensure appropriate security and confidentiality
of information.
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80. 1.D.3 Manufacturing operations
• Manufacturing operations
include all activities involved in
the realization of the product,
from setting specifications to
the transportation of the
product to the user.
• The majority of GMP
requirements relate to this
major process of a PQS.
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81. 1.D.3.1 Planning
• Manufacturing operations should be planned in line
with the PQS requirements of other processes.
• Planning of process equipment, including laboratory
equipment, is a vital part of preparations for
product realization.
• Equipment should be of adequate design and be
appropriately qualified before use in manufacturing
(see chapter 6 Qualification).
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82. • Schedules and procedures should be established
for the Preventive maintenance of equipment.
• (see chapter 4.H Maintenance).
• Established Cleaning procedures to prevent
contamination or carry-over.
• (see chapter 8 Cleaning Validation).
• Where computerized systems are used in a GMP-
relevant process, hardware & software should be
appropriately Qualified & Validated.
• (see chapter 9 ComputerValidation).
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83. • Changes to any equipment (including computer
systems & laboratory equipment) should be done
under a defined change control system to maintain
its qualified status.
• (see Chapter 1.D.4.3 Change management and chapter 19.C Change control).
• All activities described above are subject to risk
management.
• (see chapter 10 Risk Management).
• Materials used in manufacturing operations should
be defined by appropriate specifications
and acceptance criteria.
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84. • All activities should be defined from the receipt of
materials to sampling & testing as well as storage &
release for use or rejection.
• The equipment should be qualified & the production
process validated.
• Activities not covered by the manufacturer’s PQS,
such as contract manufacturing (incl. laboratories),
activities of brokers or distribution, should be
subject to a written contract defining, in detail, the
Quality responsibilities of each party.
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86. 1.D.3.2 Design and development
• The design and development process comprises
planning:
• Determination.
• Review and verification of inputs & outputs & the
control of changes.
To achieve a robust manufacturing process, it is
mandatory to perform all the above mentioned steps.
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87. 1.D.3.3 Purchasing
• Purchased items which could impact final product
quality should be procured to defined requirements &
according to written procedures from an approved
supplier.
• Procedures should be written to describe the
receipt, initial visual check of labels & containers,
identification, quarantine, storage, handling,
sampling, testing & approval or rejection of
materials.
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89. • Suppliers should be selected on the basis of their
ability to supply the items. Supply chain and/or
manufacturer qualification for critical materials,
utilities and services is mandatory.
• Particular attention should be paid to:
• Changes to the supply chain and/or the
manufacturing processes which could impact the
organization’s final product, e.g. changes in method
might impact product purity or performance.
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90. • Purchasing documentation, which may include
data relating to the supplier’s and/or
manufacturer’s PQS, e.g. Good Manufacturing
Practices (GMP), Hazard Analysis Critical Control
Point (HACCP).
• Purchasing data would also be expected to
include Certificates of Analysis/Conformity.
• Verifying that the product is as ordered, so as to
prevent cross-contamination or product
disruption.
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91. Receipt of a material requires the following actions
1. Initial visual check of labels & containers to verify
that the material is correct & that there is no
evidence of damage, tampering or contamination.
2. Assignment of a unique code or batch number.
3. Identification of the material status.
4. Bulk deliveries in non-dedicated tankers require
assurance of the absence of cross-contamination.
5. Materials are kept under quarantine & should not be
mixed with existing stocks until approved.
(see also Chapter 11.M.2 Stock management system and Chapter 11.M.9 Process Flow):
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92. 6. Sampling & testing.
7. Sampling is to be performed at defined locations &
by procedures designed to prevent contamination.
8. Containers from which samples have been
withdrawn should be marked.
9. Samples should be representative of the batch of
material from which they are taken.
10.Each batch should be tested for conformance with
specifications unless the supplier’s Certificate of
Analysis has been verified as accurate.
(see also Chapter 11.M.2 Stock management system and Chapter 11.M.5.4 Sampling):
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93. 11.As a minimum requirement, an identity test on
each batch is mandatory.
12.Processing aids, hazardous or highly toxic raw
materials, and other special materials do not
need to be tested if a Certificate of Analysis
shows that these materials conform to
established specifications or are shown to be
suitable for the intended use.
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94. Approval or rejection of material
• Material that conforms to specifications may be
approved by the quality unit.
• Rejected material should be identified & controlled
under a quarantine system designed to prevent their
unauthorized use in manufacturing.
• Materials should be handled & stored in a manner to
prevent degradation, contamination, & cross-
contamination.
• (see also Chapter 11.M.2 Stock management system and Chapter 11.M.5.5 Quarantine):
• (see also Chapter 11.M Warehouse and logistics):
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95. • Placement of stored material should allow
easy cleaning and inspection.
• Stored material should be used on a “first-in,
first-out” principle.
• Materials should be re-evaluated after
prolonged storage to determine their
suitability for use.
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96. 1.D.3.4 Production & service provision
• Production & service provision should be systematically
planned & controlled to pre-determined conditions derived
from comprehensive process understanding (e.g.
specifications, process parameters, contents & scope of
service, operating procedures).
• Operating under these conditions reduces the potential for
non-conformities, delivers material that is fit for use &
provides the basis for continual process improvement.
• In order to reduce costs of failure & to control the
production process, all steps should be monitored.
adequately NO
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97. • Document control, pre-approved manufacturing procedures,
batch record review & handling of deviations.
• Equipment qualification, process validation, analytical
method validation & cleaning validation.
• Change control.
• Production activities (chemical as well as biotech) such as in-
process controls, blending, recovery of materials, hygiene,
calibration, cleaning, sanitation, maintenance, contamination
control as well as packaging & labeling of APIs &
intermediates.
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GMP requirements for production & service provision
are related to the following topics:
98. • Utilities (e.g. air, piping), water treatment &
containment.
• Design & construction of facilities & process
equipment.
• Sampling (including retention samples), testing &
release of materials & products.
• Storage & distribution of materials & products,
• Stability of drug (medicinal) products, APIs &
intermediates, where appropriate,
• Returns.
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99. • The responsibilities for all production
activities should be defined in writing.
• Significant changes in the manufacturing
process should be evaluated, approved and
authorities notified, as appropriate, before
implementation.
• All quality-related complaints should be
investigated according to a written procedure
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100. 1.D.3.5 Control of monitoring and
measuring devices
• It is necessary to confirm that devices used to
monitor product characteristics are suitable for
their intended purpose.
• Devices should be checked, calibrated & regularly
maintained.
• This includes computerized systems, laboratory
instruments, reference materials, standard
analytical solutions and buffer solutions used for
process controls.
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101. 1.D.4 Evaluation activities
• 1.D.4.1 Deviation investigation
The PQS should ensure that deviations from
established procedures are identified & recorded.
Incidents that could affect the quality of the
product or the reliability of records or test results
should be investigated.
The Quality Unit is responsible for making sure
that these deviations are investigated & resolved.
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102. 1.D.4.2 Product Quality Review (Annual
Product Review)
• The Product Quality Review itself is a GMP
requirement & should be conducted annually, or if
justified, on another routine basis, to evaluate
process consistency through reviews of:
• In-process control & test results for trending.
• All batches that failed to meet established
specification(s)
• All critical deviations or non-conformities & related
investigations
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103. • Any changes made to the processes or
analytical methods.
• Results of the stability monitoring program.
• All quality-related returns, complaints &
recalls
• Adequacy of corrective actions.
• The current impurity profile versus the
established impurity profile.
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104. • The Product Quality Review may be used
to evaluate process performance with
respect to validation.
• Quality Review and Annual Product Review.
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105. 1.D.4.3 Change management
• A continual improvement is a dynamic entity, in
Pharmaceutical Quality System.
• Quality-related changes should be planned,
carefully controlled, & fully documented.
• All relevant stakeholders, including regulatory
authorities should be involved and/or notified
of the proposed change, according to its nature
and significance.
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106. Change control procedures
• Evaluation & approval of proposed changes to
specifications, test procedures, production
processes, production equipment, etc., should be
controlled by written procedures.
• Evaluation of a proposed change should include
consideration of the following:
1. Significance of the proposed change.
2. Effect on quality of API or final drug product.
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107. 3. Impact on drug (medicinal) product subsequently
manufactured from the API (e.g. through changes
to impurity profile, crystal form, particle size,
residual solvents, stability etc.)
4. Need for operator training
5. Need to involve regulatory authorities
6. Need to revalidate processes.
Proposed changes should be reviewed & approved by
the relevant departments and the Quality Unit.
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108. Implementation of changes:
• All documents affected by the change should be
identified & revised accordingly.
• Changes to documents should be reviewed & approved
by the same functions that performed the original
review & approval.
• Where appropriate, the nature of the change(s) should
be identified in the revised document or attachments.
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109. 1.D.4.4 Audits
• Internal quality audits, covering quality system elements
& GMP requirements, provide a regular & systematic way
of obtaining objective evidence about how
the Pharmaceutical Quality
System is functioning.
• They are an effective means of
highlighting activities requiring
attention & are, therefore,
a means of driving continual improvement.
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110. •This approach should be achieved through the
use of documented procedures for planning,
implementation & follow-up of internal quality
audits.
•This to verify compliance with documented
PQS activities, quality manual claims, & GMP &
other regulatory requirements.
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111. • Internal quality audits should be scheduled as
part of an ongoing PQS internal audit program,
covering the scope of the quality system
documented in the quality manual.
• The frequency with which different parts are
audited should be determined on the basis of
importance to overall PQS performance (i.e.
activities with known weaknesses should be
audited more frequently).
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112. • Internal quality audits should be planned,
performed, recorded & followed up by suitably
trained staff who are independent of the area
being audited.
• Internal quality auditors should be experienced
in quality systems & GMP.
• It is the responsibility of the Quality Unit to
make sure that internal quality audits are
performed.
• Internal quality system audit findings should be
discussed with the respective management.
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113. • Output of the internal quality audit program
should be summarized & periodically submitted
to senior management as an integral part of the
management review process.
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114. 1.D.4.5 Complaints
• All complaints should be recorded, promptly
investigated & reported in accordance with a written,
approved procedure.
• Quality-related complaints have GMP significance, & it
is the responsibility of the Quality Unit to assure that
these complaints are investigated & resolved.
• Records of complaints should be reviewed as part of
the product quality review (annual product review) in
order to identify trends & corrective & preventive
actions.
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115. 1.D.4.6 Data analysis
• The successful implementation of an effective
PQS is the need to identify, agree & use realistic
criteria for routinely monitoring performance
trends (KPI – Key Performance Indicator.
• Some general examples are provided: 20/06/2023
116. 1. Quality failures, e.g. cost of production failures
per month.
2. Percentage of on-time deliveries.
3. Failure costs per development project as a
percentage of project costs.
4. Controlled documents overdue for review.
5. Internal audit observation trends.
6. Complaints (numbers, response times).
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117. 7. Recalls and other market withdrawals
8. Laboratory errors & OOS results.
9. Process deviation frequency.
10.Staff training status.
11.Equipment breakdowns per month.
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118. 1.D.4.7 Risk management
• Risk management is the process of identifying,
assessing, and prioritizing potential risks that may
affect a business, organization, or project, and taking
measures to minimize or mitigate those risks.
• The goal of risk management is to ensure that
potential risks are identified and assessed, and that
effective strategies are put in place to minimize or
mitigate those risks.
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119. • Pharmaceutical Quality System should take into
consideration that operations require careful
planning, execution & monitoring to reduce risk & the
costs of failure.
• Major operations where quality risk management
could be applied are listed below:
1. Control should be exercised over labels used during
the manufacture & filling, including label
reconciliation, minimize the risk of label mix-ups or
the use of incorrect or out-of-date labels.
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120. 2. Weighing of material should be performed in an
appropriate area to minimize the risk of cross-
contamination.
3. Drug (medicinal) products & APIs should be handled in
an environment giving adequate protection.
4. Equipment should be designed, constructed, located, &
used so as to minimize the risk of contamination or
mix-ups arising during manufacture.
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121. 5. Equipment should be cleaned at appropriate intervals
when the risk of contamination from microbiological
growth or non-acceptable material build-up becomes
too great.
6. Pipework & valves should be designed to minimize the
risk of contamination.
7. Pipework should be labeled with the name of the
material therein & the direction of flow, & should be
located so that rusting, surface condensation, or
leakage will not lead to contamination.
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122. 8. Prospective validation should apply to all relevant new or
modified processes.
9. It is usually the result of a risk analysis performed on the
proposed new or modified production process.
10.Computerized systems should be designed, implemented
& operated so as to minimize the risk of failures.
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123. 1.D.4.8 Corrective and
Preventive Actions (CAPA)
• The Pharmaceutical Quality System should aim to
prevent occurrence of non-conformities, but when
they do occur, it should allow for implementation of
corrective measures.
• A planned & structured approach to corrective &
preventive actions increases the likelihood that the
root cause of actual or potential quality problems
will be identified & lasting remedial action taken.
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124. • When failures occur, the true underlying cause(s)
should be established & appropriate corrective
measures applied.
• The cause(s) of actual & potential non-conformities
in product, process or the quality system itself
should be identified & eliminated.
• Action should be appropriate to the severity of the
non-conformities.
• Changes resulting from corrective and/or preventive
action should be documented & controlled.
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125. • Corrective action is intended to both rectify any
existing non-conformities & avoid a recurrence.
It is necessary to identify the underlying cause of the
problem.
• Corrective action may arise e.g. from complaints,
recalls, audit findings, management reviews.
• A carefully planned & timely investigation should be
carried out to determine the reason(s) for the non-
conformities & agree appropriate action.
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Corrective action
126. • Details of the non-conformities, the associated
investigation & agreed actions should be recorded.
• Progress with agreed actions resulting from the
non-conformities investigation should be closely
monitored until all are satisfactorily completed.
• Senior management should be notified about the
costs of failure including the respective
corrective actions.
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127. • Preventive action is intended to avoid the
occurrence of a non-conformity.
• Preventive action may include analysis of trends in
process, product, analytical data and equipment as
well as operator performance.
• Sources of information includes audit reports,
product quality reviews (annual product reviews),
recalls, customer complaints.
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Preventive action
128. • As with corrective action, preventive action
should be authorized, carefully planned,
implemented in a controlled manner and
adequately monitored to ensure the desired
outcome.
• Information relevant to preventive (and
corrective) actions including:
• Costs and cost savings should be regularly
collated and presented for management
review.
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129. 1.D.4.9 Continual improvement of
the organization
• To fully benefit the company, the Pharmaceutical
Quality System should involve all staff whose
activities influence quality, have a clear &
unambiguous focus on continual improvement &
incorporate relevant, realistic performance
measures with emphasis on reducing failure costs,
& satisfying (internal & external) customer needs.
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130. • If the Pharmaceutical Quality System is designed
& implemented to emphasize continual
improvement (being driven by the effective use
of internal quality audits, corrective & preventive
action, & management review), then internal
efficiency will rise, leading to a sustainable
reduction in failure costs.
• Similarly, the effective control of nonconforming
product helps to identify the root cause of
quality problems, & in so doing, provides an
important improvement opportunity.
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131. • A comprehensive internal quality audit system is a
vital health check & provides a means of identifying
issues in need of attention, while a planned &
structured approach to corrective & preventive
action increases the likelihood that the basic cause
of actual or potential quality problems will be
identified & lasting remedial action taken.
• In addition, the Pharmaceutical Quality System
should encourage the employees to make suggestions
for improvements by incorporating a system which
makes it easy for employees to communicate
suggestions & which provides for timely review of
these suggestions. 20/06/2023
132. 1.D.4.10 Control of non-conforming product
• Product which does not conform to specification
(OOS) & established processing requirements is
usually identified by inspection and/or testing,
customer complaint or internal quality audit.
• A non-conforming product should be recorded,
clearly identified as non-conforming & physically
segregated, to prevent unintended use until its
disposition (i.e. reworking, reprocessing, release on
conditional status or disposal) can be agreed.
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133. • Subsequent use of non-conforming material should
be approved by the Quality Unit after full review of
the non-conformities or deviation, including results
that are out of specification, & the investigation.
• The likely effect upon related batches of product
should be assessed.
• Any decision to reprocess returned non-conforming
product should take into consideration the fact that
the product has been outside the control of the
manufacturing company.
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134. • Reworked product should be retested in accordance
with documented procedures incorporating
appropriate controls agreed between production and
the Quality Unit.
• Special consideration should be given to the impurity
profile of a reworked batch, including the use of non-
routine measurements if necessary.
• The release of reworked product has to be agreed
with the relevant authority.
• Reprocessing and reworking should be documented &
included in the batch records.
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135. • A new batch number should be assigned following
reworking.
• The nature of the non-conformities together with
details of the associated investigation & justification
for disposition of the non-conforming product should
be recorded.
• If reprocessing becomes a regular occurrence, the
adequacy of the original manufacturing process should
be re-evaluated.
• A written, approved procedure should clarify the
circumstances in which a recall should be considered.
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136. • This document should also indicate responsibilities &
actions in the event of a recall.
• The distribution system should permit prompt
determination of the location of each batch.
• In the event of a serious & potentially life-threatening
situation, the (local & national) authorities should be
informed & their advice sought.
• More information about handling of non-conforming
product is given in the following chapters:
• Chapter 11.K Empty Chapter ■Chapter 11.L Reworking ■Chapter 14.HOut-of-specification results
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137. 1.D.4.11 Measurement of customer satisfaction
• To fully benefit the company, the PQS should
incorporate, realistic performance measures
with emphasis on satisfying customer needs.
Methods for collecting information on customer
satisfaction should be developed, & the results
used as part of the continual improvement
process of the P Q S.
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138. 1.D.4.12 Measurement of employee satisfaction
• A concisely documented Pharmaceutical Quality System,
having the full visible support of senior management, will
lead to better understanding of employee roles,
responsibilities, authorities, & working interfaces.
• It will avoid confusion, & reduce the risk of omission
and/or duplication.
• Less staff time will be absorbed by “fire-fighting” &
crisis management, allowing more time to be devoted to
improving operating efficiency.
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139. • Continually improving operations should result
in measurable improvements in employee
satisfaction with their work & working
conditions.
• Management should periodically survey
employees to measure their satisfaction as well
as to identify opportunities to improve the
Pharmaceutical Quality System
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140. Summary
• This section shows how the specific GMP
requirements of the pharmaceutical industry can be
merged with the general demands of the PQS.
The four main processes of a PQS are
• “Management responsibility”,
• “Resource Management”,
• “Manufacturing Operations”
• and “Evaluation Activities”.
• All GMP requirements can be assigned to one of
these processes
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141. Quality Assurance
UP07 DR. CHRISTIAN
GAUSEPOHL, PAOLOMI MUKHERJI
LECTURER: DR. MAJED FEDDAH
11.B Personnel hygiene
142. Here you will find answers to the
following questions:
• What are the requirements for working clothing?
• What code of conduct (السلوكية )القواعد have to be
followed?
• How is hand disinfection performed correctly?
• What is the function of medical assessment?
• What special aspects have to be considered for
hygiene trainings?
20/06/2023
143. • Both the EU-GMP-Guide and the CFR (Code of
Federal Regulation) clearly indicate that detailed
hygiene plans must also be applied for personnel.
• In addition to requirements on protective and
working clothing, codes of conduct for personnel
and visitors are also required.
• These codes of conduct are to be fixed in the
form of work and organization instructions.
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144. • According to CFR , personnel should wear clean
clothing appropriate for the duties performed.
• As applicable, protective dress, such as head, face,
hand and arm coverings should be worn to protect
drug products from contamination.
• Personnel should practice good sanitation and health
habits.
• Personnel with apparent illness or open lesions that
may adversely affect the safety or quality of drug
products should be excluded from direct contact
with these operations.
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146. • Training on hygiene aspects should be
conveyed to employees as part of:
1. Orientation of new hires
2. Training plan for working in an area
3. Training plan for learning new procedures
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147. 11.B.1 Clothing
• In principle, working clothing must perform
different functions:
• To protect the personnel from contamination
by the product.
• To protect the product from contamination by
the personnel
• To differentiate the activity being
performed.
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148. • The function of clothing as a barrier to protect
the product is intended to keep back flakes of skin,
the body's own bacterial flora, particles & humidity
(sweat) & prevent their penetration as far as
possible.
• This function is the most relevant one from the
GMP view.
• The selection of specific colours for assigned
areas means a signal function can be achieved, e.g.
as a warning for the processing of sensitive
products.
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149. • Clothing must be changed regularly in prescribed
intervals, or even more frequently when it becomes
contaminated or damaged.
• The higher the cleanliness grade and the greater the
probability and intensity of a contamination, the
more often clothing must be changed.
(At least 1x weekly, or with grades A and B at least
1x daily).
• These intervals are based on the monitoring results,
which should provide samples of worn clothing and
fresh clothing for comparison.
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150. • Figure 11.B-1 shows a comparative overview of the
requirements and necessities of the different clothing,
depending on the cleanliness grade.
• It is recommended that an intermediate layer of
clothing be worn between the sterile room clothing &
personal underwear.
• This can help achieve a significant reduction in the
release of skin particles onto the clean room clothing &
then into the environment.
• The intermediate clothing should be Antistatic &
Autoclavable.
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151. Grade A, B (ISO 5) C (ISO 7) D (ISO 8) E * Comment
Clothing over the entire body
length (overall), sleeves &
trouser legs tucked into
gloves or boots
One or two-piece,
high collar, closed
cuffs at wrists
protective
clothing, closed
cuffs at wrists are
recommended
one or two-
piece, closed
cuffs at wrists
are
recommended
short sleeves are not
permissible
Materials synthetic fibers (e.g.
polyamide), sterilisable or
disinfectable
Cotton or blended
fabric, no particle
or fiber release
cotton or blended
fabric
cotton or
blended fabric
depending on the
permissible particle
count or particle
release
External
Pockets
Not permitted Not recommended Not recommended Not
recommended
To avoid mixes &
cross- contaminations
Change At least 1 x daily, or again
with each change of area
Periodically, at
least 1–2x per
week
Periodically, at
least 1–2x per
week
Periodically, at
least 1x per
week
More often in case of
contamination
Head Cover Integrated hood or neck
covering (connection to
over-clothing, similar
material)
Fleece material
change with each
new inward
transfer
Fleece material,
changed daily
Fleece
material,
changed daily
All hair must be
covered
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152. Grade A, B (ISO 5) C (ISO 7) D (ISO 8) E * Comment
Face mask/beard
covering
Sterile, permanent
wear or no beard,
multiple change in
each working
period
Permanent
wearing is
recommended
Permanent
wearing by men
with beards is
recommended
Face mask: only
when working with
open products
Beards: permanent
coverage is
recommended
Change when
penetrated by
humidity
Gloves Disinfectable,
wear permanently,
change with each
working period
Disinfectable,
permanent
wearing is
recommended,
change with each
working period
only when working
with open
products
Only when
working with open
products
Obligatory when
product is changed
and when
damaged
Shoes Covering shoes,
sterilisable or
disinfectable
Production shoes
or covering shoes
Production shoes
or covering shoes
Production shoes
or covering shoes
Non-slip, but
without profile due
to possible product
transfer
Cosmetics Avoid Not
recommended
Not
recommended
Not
recommended
Exception: pure
care cosmetics
Jewellery, watches Avoid Avoid Avoid Avoid For occupational
health & safety
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153. 1. Determine areas where special clothing is
required (laboratory, controlled areas, aseptic
filling areas, sterility testing areas, animal
areas, others).
2. Determine what clothing is appropriate for
the duties performed (uniforms, coats, sterile
garments, head covers, beard covers, shoe
covers, gloves, or others protective apparel).
• 20/06/2023
When establishing a Policy on working clothes and safety
apparel required in various work situations, the following
items should be addressed
154. 3. Determine areas where safety apparel is required
(laboratory, warehouse, manufacturing,
maintenance, animal area, others).
4. Determine what safety apparel is needed for
areas and duties performed (safety glasses,
laboratory coats, face shields, gloves, shoes (steel
toed), hard hats, hearing protection, others).
5. Describe procedure for donning protective
apparel, provide for disposal of used protective
apparel.
6. Provide storage area for street clothing
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155. 11.B.1.1 Clothing material
Criteria for the choice of material
■Particle release (from the fabric)
■Particle retention capacity (by adsorbed
material)
■Disinfectability or sterilisability
■Wearing comfort (humidity penetration)
■Conductivity (antistatic)
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Figure 11.B-2 Work clothing: Choice of material
156. • For Sterile Forms,
• Pure synthetic fibres such as Polyester or Polyamide
(area A, B) or mixed fabrics with cotton are usually used.
• Using this material, the trapped heat & perspiration
make the material uncomfortable to wear.
• A higher proportion of cotton in fabrics makes the
material more comfortable, but releases more particles.
• It should be possible to disinfect the different fabric
types depending on their application, and clean room
clothing should be sterilisable e.g. autoclavable.
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157. 11.B.1.2 Design of the clothing
Requirements for design selection.
■Sufficient coverage (good fit).
■Practical manageability (sufficient mobility)
■Easy to put on
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The design chosen for the clothing is important for
its functionality and its acceptance by staff.
158. Cut of the clothing
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• The clothing must be appropriate for the
activity.
• For working steps in sterile preparation,
there are specific clothing requirements.
• It must cover the full length of the body (one
or two-piece) and cover the neck, e.g. as an
overall with a hood or a neck covering (see
Figure 11.B-8).
159. • For lower cleanliness grades, coverage of the
complete body area is not necessary (see Figure
11.B-9 and Figure 11.B-10).
• Only exposed areas must be covered.
• The clothing must be closed at the wrists, e.g.
through elasticated cuffs.
• The length of sleeves and trouser, legs should be
designed so that no uncovered areas remain when
gloves and shoes are worn.
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161. • Closure at the wrists enables gloves or arm cuffs to be rolled
over, so that the lower arm is not uncovered.
• In addition, this helps prevent the transfer of particles or
product that may be carried around in open sleeves (see
Figure 11.B-4 and Figure 11.B-5).
• Personnel often roll their sleeves up during cleaning work
with extensive washing activities in non-aseptic areas.
• In order to protect product contact surfaces, the use of
water-repellent materials should be provided for here, e.g.
through long-cuff gloves.
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162. •Clothing must be uniquely identifiable,
e.g. through sewn-in barcodes,
numbers or the name of the employee
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167. Putting on
• It must be possible to put the clothing on with
a minimum amount of contamination.
• In clean rooms working clothes should be
changed before re-entering.
• Surface microbial count determinations show
that the exterior and interior both become
contaminated depending on the wearing time,
intensity of movement and perspiration.
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168. • In addition, it is barely possible to remove and hang up
the clothing without contaminating the exterior.
• When putting the clothing on, it is greatly beneficial to
have a suitable mirror to ensure the correct position of
the clothing.
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169. Gloves
• In the field of sterile production, Sterile & un-
powdered gloves are used to prevent possible
particle loading.
• The cuffs of the overalls are tucked into the
gloves to avoid leaving uncovered areas.
• For safety, additional sterile sleeve cuffs can be
used which cover the sleeve/glove connection area
(see Figure 11.B-4).
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170. • Gloves are to be changed immediately if they become
damaged, and after they have been used to touch non-
sterile objects.
• Unnecessary contamination (e.g. through scratching,
making telephone calls) is to be avoided. Entry into a
critical area always requires disinfection of the
gloves.
• For use in grade A and B, gloves should be treated
with disinfectants which are sterile at the time of
application. The use of 70% isopropanol is usually
adequate for disinfection.
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171. External pockets
• External pockets are not permitted in clean
rooms. On the one hand they hold the hazard of
accidental cross-contaminations, and on the other
hand the unintentional bringing of non-sterile or
non-disinfected objects, e.g. pen, tissues, into
the clean room.
• In principle, this requirement can also be applied
to manufacturing in lower cleanliness grades down
to non-sterile drugs.
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172. Head coverings
• The head coverings must be complete, i.e. the
hair must be completely covered.
• For work in non-sterile areas, fleece material
is usually used, while in cleanliness grade A–B
the same material is sometimes used as for
the suits. The head covering is integrated in
the suit or must be tucked into the collar (see
Figure 11.B-6).
20/06/2023
173. • People with very long hair sometimes have to wear two
head coverings (fleece fabric) at the same time to
ensure complete coverage.
• One of the management's tasks is to ensure that the
head coverings used are suitable for all employees.
Consistent execution, i.e. the same rules for managers
and visitors, is of absolute importance.
• The problem of beards and moustaches in sterile areas
is dealt with explicitly.
• The risk of releasing particles is accounted for with
the requirement to cover or remove the beard.
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174. •For non-sterile areas, the correct manner of
wearing the beard shield is also important.
•It may be that glasses are required in clean
rooms to protect the products against the
employees' uncovered eyes (e.g. eyelashes).
•Air flow control (e.g. laminar flow) may make
this unnecessary.
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175. When establishing a policy on facial hair,
the following aspects should be addressed:
Identify areas and duties whither exposed
facial hair is permitted
Identify areas and duties whither exposed
facial hair is not permitted
Identify areas where use of beard covers is
required
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176. Mouth mask/Face mask
• The mouth and nose are covered by masks.
• These masks are to be changed periodically (at the
latest when penetrated by moisture), to prevent a
critical penetration of microbes.
• As the mask is only effective when dry,
conversations in the sterile working area should be
reduced to the minimum.
• Moreover, mouth masks for sterile working areas
have to be sterile.
20/06/2023
177. •It is also important to wear the face mask in non-
aseptic areas. In these areas, it is not generally
necessary to cover the mouth, nose and hands.
•However, these measures are essential when
working on open products and on product contact
surfaces
•In this case, it is important to define these
activities clearly in the practical workflow and
demonstrate them to the staff in a
comprehensible manner.
20/06/2023
178. •The analysis of production processes or
individual working steps enables precise
specification of the measures for each
activity.
•For practical reasons, open products are to
be avoided as far as possible by using closed
containment, as this can significantly reduce
the effort required, i.e. putting on, wearing
and removing masks or gloves.
20/06/2023
179. Shoes
• In principle, the same requirements apply for
shoes as for the clothing material.
• Overshoes should be wear in the clean areas.
• The GMP requirements must be brought in line
with the safety requirements (e.g. anti-slip).
• It should be possible to clean the shoes.
• This can be done, for example, using a washing
machine or by use of Dust-Binding Mats or both.
20/06/2023
180. •For sterile areas, the leg openings of the
clothing must be as tight as possible and
must be tucked into the overshoes.
•For grade A and B, it must be possible to
sterilize or disinfect the boots.
20/06/2023
181. 11.B.1.3 Preparation/Cleaning
• Working clothing is only used as single-use
clothing in exceptional cases, as the costs for
this are usually very high.
• Therefore, processing steps are carried out to
prepare the clothing for re-use.
• The processing can be carried out within the
plant or can be outsourced as a service.
• In the field of sterile manufacturing, number of
requirements must be taken into account.
20/06/2023
182. Processing requirements for sterile clothing:
• The preparation of the clothing must remove the
particles released by people (dandruff, etc.).
• Production dust must be removed in order to avoid
cross-contamination.
• Different items of clothing contaminated with
different products should not be cleaned together.
• Preparation must be carried out as gently as possible
so that no changes are caused in the fabric
20/06/2023
183. • A visual inspection is carried out for wear & tear:
thin spots, damage, condition of the seams.
• The preparation steps must be executed in a
defined manner.
• The exact processes (e.g. flows) are prescribed in
order to avoid secondary contamination from
external areas, for example.
Washing ˃ Drying ˃ Packaging ˃ Sterilization ˃
Storage.
20/06/2023
184. Special requirements for clean room clothing:
• Keeping a kind of log or identification and traceability
by means of barcodes, which are applied to the inside,
is recommended.
• Via single part tracking, it is possible to assign
batches to cleaning and sterilising processes with the
associated documentation.
• A usability date should be documented for sterilised
clothing in order to avoid excessive storage periods.
• This is especially important for reserve clothing with
an un-specified storage time, e.g. in visitor locks.
20/06/2023
185. • In the case of external preparation,
• The clean, decontaminated and sterilized clean
room clothing should be heat-sealed airtight and
returned in closed boxes.
• Quality control before heat sealing can be carried
out with laser particle counters.
• Disinfection of the laundry can be carried out in
washing machines in combination with drying under
a laminar flow (for clean room clothing that cannot
be sterilized in autoclaves).
20/06/2023
186. 11.B.1.4 Gowning procedure
• The hygiene procedure includes a clear, area-
specific definition of gowning. This must be
logical and consistent.
• Here, different cleanliness areas across the
plant can be identified via specific pictures or
colours on walls or doors.
20/06/2023
187. • Imprecision in terms of unclearly defined areas is
to be avoided for acceptance reasons. Passage
between areas is via personnel locks.
• The exact procedure for the transfer between
areas and the associated clothing change is
described in process descriptions.
• These processes are to be discussed in-depth in
training courses, in order to achieve the necessary
understanding and motivation of the staff.
Compliance should be permanently monitored.
20/06/2023
188. • It goes without saying that a change of activities on different
products is critical in terms of clothing.
• As re-entry into clean rooms requires a change of clothing in
any case, this is of particular importance for non-sterile
areas.
• Activities that involve such a change should be examined
separately during the risk analysis and a precise procedure
should be established.
• In addition to the production staff, visitors and service
employees must also be provided with the appropriate
clothing. For sterilised qualities, the sterility expiration date
of the stored clothing must be noted.
20/06/2023
189. 11.B.2 Code of Conduct
• In order to comply with limits for particulates and
microbial contamination in defined clean room
areas, a code of conduct has to be established.
Requirements increase with the level of the clean
room area.
• Generally, any behavior that potentially impacts
the product quality or the status of rooms and
equipment, is not tolerated.
• Supervisors should always keep an eye on the
operators’ behavior, especially in clean rooms.
20/06/2023
190. •The code of conduct should be part of
continuous training.
The following are essential for implementation:
1. Supervisors acting as a role model
2. Consistency of the sanitation program.
3. Open-minded culture where discrepancies
& deviations may be discussed in a
constructive way.
20/06/2023
191. 11.B.2.1 Personal hygiene
• Employees are expected to maintain a high level of
personal hygiene.
• Therefore, care of fingernails, hair and skin must
be defined.
• In addition to a disproportionate increase in the
microbial count if care is neglected, there is also
the hazard that fingernails could damage the
gloves and clothing.
20/06/2023
192. •Regular personnel training and testing should
make personnel aware of the significance of
personal hygiene.
•The initial conditions for the change of clothes
are dependent on the individual personal
hygiene prior to work (shower, shave, dental
hygiene, hair care, moisture cream etc).
20/06/2023
193. 11.B.2.2 General requirements
• Figure 11.B-11 General code of hygienic conduct:
20/06/2023
General code of hygienic conduct
NO eating, drinking or chewing
NO smoking
NO jewelry and watches
NO cosmetics (only for skin care)
NO critical behavior (fast movements, sneeze, cough)
Reduced number of employees in the relevant area
194. 20/06/2023
• Food, cigarettes, jewellery and other personal
objects (e.g. newspapers) must not be brought to the
place of work.
• Eating, chewing, drinking and smoking is strictly
forbidden in the production areas.
• Suitable recreational rooms must be provided for
this purpose.
• The transition between areas is to be consistently
via a lock, in which the production clothing is changed
or (depending on the production cleanliness grade) at
least sufficiently covered.
195. • Before entering the production area, openly worn
jewellery and watches must be removed.
• This is also required for safety at work.
• Coughing and sneezing must not be directed towards
the product. This can result in direct contamination.
• Raising awareness during training can clarify the hazard
potential.
• Clothes and gloves should be controlled regularly in
order to detect damages or contaminations.
20/06/2023
196. • If different products are handled
simultaneously at different locations (e.g.
manufacturing of tablets or capsules),
measurements have to be defined in order to
avoid cross-contamination, such as change of
gloves and cleaning of shoes before entering
the production rooms.
20/06/2023
197. 11.B.2.3 Special requirements for clean
rooms
• Employees working in clean rooms should – at least
during their total working time – not smoke.
• The time dependency between particle release with
exhaled air and the rest time since smoking has been
proven. Only approx. 20 minutes after finishing
smoking the average particle release value of
nonsmokers is achieved.
• This is demonstrated very effectively in training
courses.
20/06/2023
198. • Cosmetics must be used sparingly or preferably not at
all by people who work in clean rooms. The hazard of
contamination through particle release must not be
underestimated.
• A stipulation of the absence of any cosmetics avoids
the differentiation between permissible and non-
permissible quantities.
• In clean rooms, speaking should be kept to an absolute
minimum in order to prevent accelerated
humidification of the mask with a penetration of
microbes.
20/06/2023
199. • Gloves should be disinfected regularly. In order to
facilitate compliance, application systems should be
provided in a sufficient number.
• Only the absolutely necessary number of people
should work in clean rooms at any one time.
• Operators who are not involved in the manufacturing
process should leave the clean room.
• The most effective way to minimise the number of
employees in the sterile area is to execute only the
absolutely necessary production steps in clean
rooms.
20/06/2023
200. • Activities such as coding ampoules or visual
checks on products can be carried out
outside the clean rooms in lower cleanliness
grades.
20/06/2023
201. • The movement of people in clean rooms should be
calm and uniform as this will have the least negative
effect on flow ratios and causes the lowest release
of particles.
• In any case, movement should be as minimum as
possible.
• Simply folding your arms can lead to contamination of
your gloves.
• The hands are placed near the armpits which, even on
the outside of the fabric, are the areas with the
highest microbial count.
20/06/2023
202. 11.B.2.4 Policies to be
established
• Policy for storage of food and drink
• Identify specific areas where food and drink
can be stored or consumed (lunch room,
specially designated area for storage)
• Identify areas where food and drink can not be
stored or consumed (laboratory, manufacturing,
aseptic filling area, sterility testing area,
warehouse area, animal area, other)
20/06/2023
203. • Policy on the use of cosmetics
• Identify areas where cosmetics can be worn.
• Identify areas where certain cosmetics are
restricted
• Identify areas where cosmetics can not be
worn (aseptic filling area, sterility testing
area, animal area)
• List what cosmetics are restricted for specific
work areas (eye makeup, rouge, face powder,
hair spray, fingernail polish, others as listed)
20/06/2023
204. • Policy on the wearing of jewelry
• Identify when and where wearing jewelry is
not permitted (areas with machinery with
moving parts, controlled areas, aseptic filling
areas, sterility testing area, animal area)
• Identify what jewelry is not permitted for
wearing (watches, rings, ear rings, bracelets,
necklaces)
20/06/2023
205. • Policy on smoking or eating in facility
• Identify areas where smoking and eating can
be done
• Identify areas where smoking and eating
cannot be done
20/06/2023
206. 11.B.3 Hand disinfection
• Before starting any activity in the production area,
the hands or gloves must be disinfected regardless of
the type of production.
• As microbes are continuously reproducing, periodic
disinfection must also be carried out.
• The frequency of this measure depends on the
cleanliness grade, the activity and the technical
circumstances (closed or open systems).
• The frequency and exact method of execution are to
be specified in an operating procedure.
20/06/2023
207. Carrying out hand disinfection
■Wet the hands
■Squirt of soap – wash
■Rinse thoroughly
■Dry
■Squirt of disinfectant – rub in for approx. 30
seconds
20/06/2023
Figure 11.B-12 Hand disinfection (example)
The disinfectant manufacturer's specifications
are to be taken into account (for example, see
Figure 11.B-12).
208. • In any case (even for non-sterile production), the
hands must be disinfected after going to the
toilet or eating, drinking or smoking.
• Hand cleaning and disinfection solutions are
available individually and as combined products.
• The design of the facilities in the washing area
should enable operation without using the hands.
• This means considering the process with all
individual elements:
20/06/2023
209. • Control of the water supply (e.g. activation
via motion sensor, foot operated switch),
dosage of the cleansing agent (elbow lever),
drying (paper towels or hot air dryer), waste
disposal (pedal bins), etc.
20/06/2023
210. • The use of hand towels and bars of soap should be
avoided.
• Most disinfectants are applied as rub in disinfections.
• This means that the disinfectant is rubbed into dry
hands for a certain period of time.
• The disinfectants used should be approved by the
respective national test centre.
• There must be an adequate number of dispensers for
disinfectant solutions.
• This will avoid long waiting times in the current work
process and will increase acceptance levels.
20/06/2023
211. • As part of monitoring, the microbial status of
the cleansing agent and disinfectant
dispensers must be regularly reviewed.
• Pictograms or clear instructions are helpful.
• This is important for visitors or external
workers who are not familiar with these
procedures.
20/06/2023
212. When establishing a policy on hand washing, the
following items should be addressed:
• Identify specific causes for hand washing (visit to
restroom, after manufacturing, laboratory analyses,
animal area, controlled/classified rooms, other).
• Identify duties and tasks requiring hand washing
(preparation for gowning for entry into aseptic filling
areas, others )
• Identify acceptable hand sanitizing compounds
(cleansers, bacteriocidal agents, chlorine solutions,
quaternary ammonium compounds, iodinebased
compounds, alcohols, others)
20/06/2023
213. • Specify whether sanitizers must be sterile or
nonsterile
• Identify requirements for signage
(lavatories, at entry to controlled areas,
reminder/instruction posters, gowning areas,
others)
20/06/2023
214. 11.B.4 Health requirements
• Only persons who do not have any infectious diseases
at the time of production may be employed to
manufacture drugs. This is ensured through health
monitoring. (See Chapter 2.B.2 Health
requirements.)
• In a medical fitness policy for employees, work areas
have to be identified where physical requirements
and/or psychological characteristics are important,
e.g. aseptic filling area, animal area.
20/06/2023
215. • Furtheron it has to be specified what
examinations or tests are required for
employment, e.g. health history questionnaire,
physical examination, laboratory tests, abuse
drug screening program. When doing so, privacy
aspects, local laws and labor- management
agreements have to be considered.
20/06/2023
216. • As a crucial aspect for health monitoring, a
system has to be established that ensures
reporting of all health related conditions of
employees to the company medical officer.
• A procedure should be established which
adderesses the following aspects:
• Identify illnesses which restrict employee from
working in certain areas
• Identify injuries which restrict employee from
working in certain areas
20/06/2023
217. • Identify cuts and abrasions which restrict
employee from working in certain areas
• Identify work areas where employees with
illness, injuries or cuts and abrasions can not
work (aseptic filling area, sterility testing
area, animal area, others)
20/06/2023
218. • When determining the need for monitoring the
health of personnel by physical examinations, a
differentiation between the following areas is
reasonable:
• Areas and jobs where physical examination may be
needed before employment or start of work (animal
area, aseptic filling area, others)
• Areas and jobs where periodic physical
examinations may be needed (animal area, aseptic
areas)
• Areas where exposure to hazards may occur
20/06/2023
219. 11.B.5 Training
• For the field of hygiene in particular, training courses
represent an essential basis for the necessary measures.
• Without correct explanation, sufficient compliance with
the guidelines by the employees cannot be counted on.
• This results in inconsistent, partly incorrect handling of
the requirements.
• In the field of sterile production in particular, the smallest
microbial contaminations are extremely critical by
nature.
20/06/2023
220. • In this respect, dialogue between the
management and production employees must
be encouraged. In cases of doubt, unclear
description in the requirements and unclear
labelling of rooms can lead to different
interpretations by the employees.
20/06/2023
221. • In this dialogue, the principles of microbiology
can be communicated and the requirements can
be explained.
• The involvement of the staff in the selection of
working clothing, e.g. as part of a test phase, can
give an indication of the practical suitability of
the clothing.
• In addition, a high level of acceptance by the
staff can be achieved. (See Chapter 2.C Training.)
20/06/2023
222. Summary
• The working clothing requirements are directly linked
to the cleanliness grade in which production is being
carried out. Cleanability, particle release, suitability
and wearing comfort must be taken into account when
selecting the clothing.
• The clothing must be cleaned (prepared) in
accordance with an established procedure in order
not to affect the quality of the material.
20/06/2023
223. • For each cleanliness area, there should be a
gowning procedure which is taught
intensively.
• Personnel hygiene includes the health check
and training on special codes of conduct.
20/06/2023
225. 3.B Material flow, personnel
flow and layout
Dr. Majed R. Feddah
Schwarzat, Dr. Ralph Gomez
226. Here you will find answers to the following
questions:
1. What is the significance of the personnel
flow and material flow in production?
2. Which principles governing the material
flow are applied in pharmaceutical
production?
3.Which design concepts does FDA
recommend for an aseptic processing
facility?
20/06/2023
227. 3.B.1 Material flow
• Material flow refers to the interlinking of all
operations.
• This involves:
1. Processing.
2. Handling.
3. Transportation.
4. Testing,
5. storage.
20/06/2023
228. • Material flow is the sequence of
individual manufacturing,& storage steps,
starting with the raw material & ending with
the finished product.
20/06/2023
229. Functions and characteristics of material flow
Functions • Suitable for preventing the omission of
quality- manufacturing and control
steps
• Elimination of confusion.
• Compatibility with other manufacturing
procedures in other rooms
Characteristics • Clear.
• Unambiguous.
• Characterized by short routes.
20/06/2023
230. • The material flow eventually, represents the
manufacturing process in the building, which must
be broken down into individual steps and
presented in a flow diagram.
• Each processing step must be assigned to a
machine, and each machine assigned to a room.
• The rooms in the building must then be grouped in
a manner that reflects the material flow.
20/06/2023
234. Horizontal and Vertical Flow
•There are two main principles governing
the material flow that will obviously be
influenced by the building structure as
well as the products:
These are:
1. Horizontal Flow.
2. Vertical material Flow.
20/06/2023
235. Horizontal Flow
•The horizontal flow is determined by the
transportation of materials using
conventional methods.
•Production takes place at one level.
•The horizontal material flow is widespread
in the case of sterile dosage forms
production.
20/06/2023
236. Vertical Flow
•A vertical material flow, use of gravity for
the transportation of products.
•The production equipment operates at several
connected levels.
•Transport and production take place at
different levels wherever possible.
•This procedure is mainly used in solids and
liquid production.
20/06/2023
238. • In addition to the two principles of material flow.
• An interlinking of facilities is desirable from the
GMP standpoint, particularly for Vertical material
flows but also for Horizontal material flows.
• The facilities are joined together using fixed
connections such as pipes, tubes, coils, etc.
• The product may be transported from one machine
to the next via these connecting elements without
having to be transferred to intermediate
containers.
20/06/2023
240. Comparison of principles of material flow
Advantages Disadvantages
Horizontal ■No connection with
other levels
■Clear production sequence
■Simple tried-and-tested
transportation systems
■Large hygienic areas
■Transport and production not
separated ■Transportation systems
(stackers) often not compatible with
GMP
Vertical ■Transport& production separ
ated
■Small hygienic areas
■High degree of automation
■Closed systems
■Technically complex
■Greater need for validation
■No visual check possible
■Special architectural design
required
■Complicated cleaning process
Interlinked ■Flexible transport
■Closed systems to a large
extent
■Large hygienic areas
■Transport and production not
separated 20/06/2023
242. 3.B.2 Personnel flow
•Material flow also apply to personnel flow.
•Most importantly, personnel flow serves to
protect the product in addition to
considerations of economy and labor
legislation.
•To optimize the material flow, the appropriate
number of personnel required to operate,
monitor & maintain the machines and facilities
must be determined.
20/06/2023
243. • The functions of individuals must then be
described, and the routes transferred to the
layout.
• The personnel flow and its repetitive, optimization
are assessed together with the layout and material
flow based on the following assumptions:
1. Access to pharmaceutical areas only
via locks/changing rooms
2. Separate routes for pharmaceutical
and non-pharmaceutical personnel
3. Short routes
20/06/2023
244. Layout
• “Layout” refers to the visual representation of
machines inside rooms and also the arrangement
and shape of rooms within a building.
• When finding a suitable layout, personnel and
material flow are also factors to consider in
addition to the necessary areas or volumes and
room planning.
• The layout shows functions that ensure a safe
manufacturing process and so when designing the
layout it is recommended that quality assurance is
also considered.
20/06/2023
245. Layout Information
■Type and size of rooms
■Room layout and arrangement of machines
■Traffic routes (personnel flow and material flow)
■Locks for material and personnel
■Staff rooms (short break areas, toilets)
■Zone classification
20/06/2023
246. Recommended facilities design concepts from the U.S.
Sterile Drug Products Produced by Aseptic Processing
guideline:
• Optimize material and personnel flow.
• Optimize personnel movement and comfort.
• Minimize frequency of entries and exits to & from the
processing room.
• Minimize the number of people in the room.
• Minimize the number of transfers into the cleanroom
or isolator.
20/06/2023
247. •Restrict movement adjacent to the critical areas.
•Automate whenever possible.
•Sterilize equipment using Sterilize-in-place (SIP)
technology.
•Transfer product under appropriate cleanroom
conditions.
20/06/2023
248. •Transfer partially closed sterile product only
in critical areas.
•Provide for Class 100 (ISO 5) protection in
the area between a filling line and
the lyophilizer
•Protect the sterile product and container-
closures by equipment of suitable design.
20/06/2023
249. • Use carefully designed curtains and rigid plastic shields
to act as barriers. Use an isolator system to further
enhance product protection.
• Define and control the dynamic interactions permitted
between. Cleanrooms.
• Install airlocks between the aseptic area & lower
classified areas .
• Install airlocks in interfaces between personnel
transitions & material staging areas.
• Safeguard uncapped stoppered vials until completion of
the crimping step.
20/06/2023
250. • Employ devices for the on-line detection of improperly
seated stoppers
• Use construction materials for cleanrooms that are
easy to clean and sanitize
• Install seamless and rounded floors and easily
accessible corners in cleanrooms.
• Design cleanrooms and HEPA filter banks to protect
sterile products from contamination .
• Eliminate unnecessary equipment, fixtures and
materials from cleanrooms .
20/06/2023
251. • Equip processing equipment and systems with sanitary
fittings and valves.
• Insure that any drain installed in an aseptic facility is
of proper design.
• Design equipment to facilitate ease of sterilization
(CFR 211.63).
• Design equipment to ensure ease of installation to
facilitate aseptic setup.
• Address the effect of equipment design on the
cleanroom environment .
20/06/2023
252. • Avoid horizontal surfaces or ledges that accumulate
particles
• Design of equipment should be such that it does not
obstruct airflow nor, in critical areas, disturb
unidirectional airflow.
• Insure that deviation or change control systems
address atypical conditions posed by shutdown of air
handling systems or other utilities and the impact of
construction activities on facility control .
• Prepare written procedures which address returning a
facility to operating conditions following a shutdown.
20/06/2023
253. • Summary:
• Material & personnel flow influence GMP and the
economic efficiency of an operation.
• Horizontal material flow is predominantly used in the
pharmaceutical industry.
• Vertical material flow are becoming increasingly common
– particularly in the production of solid dosage forms.
• It is recommended that quality assurance be included
when determining the layout.
• FDA’s revised Aseptic Processing guideline recommends
many design concepts that can be applied to an aseptic
facility. 20/06/2023
