UNIT-1 PHARMACEUTICAL QUALITY AUDIT PPT/PDF

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UNIT-1
PHARMACEUTICAL
QUALITY AUDIT

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SYLLABUS

 INTRODUCTION
 OBJECTIVES
 MANAGMENT OF AUDIT
 RESPONSIBILITES
 PLANNING PROCESS
 INFORMATION GATHERING
 ADMINISTRATION
 CLASSIFICATION OF DEFICIENCIES

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INTRODUCTION

 International organization for standardization
(ISO) defines the audits as “Systematic,
independent and documented process for obtaining
audit evidence and evaluating them objectively to
determine the degree to which the verification
criteria are met”.

 In the pharmaceutical industry, audits are virtual
means for assessing compliance with the
established objectives defined in the quality system
and thus paving the way for the continuous
improvement program by providing feedback to
management.

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INTRODUCTION…
 A company that produces drugs today must be able

to demonstrate that it does so with absolute
reliability, in optimal conditions and with extreme
uniformity that allows accurate reproduction.

 Audits are conducted to ascertain the validity and
reliability of the information; also to provide an
assessment of the internal control of a system.

 It provides management with information on the
efficiency with which the company controls the
quality of its processes and products.

 The audit in simple terms could be defined as the
inspection of a process or a system to ensure that it
meets the requirements of its intended use.

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INTRODUCTION…

 Instead of considering the audit as an intrusive and
potentially threatening review, pharmacies should
consider the audit as a quality control mechanism.

 The results of the audit and the resulting corrective
actions ensure all the involved parties that a
program works in accordance with established rules
of practice.

 Pharmaceutical audit experience includes the
drafting and revision of validation policies,
guidelines and standard operating procedures
(SOP) from project qualification to performance
evaluation phases.

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TYPES OF AUDITS

 Quality audits are performed to verify the
effectiveness of a quality management system. The
quality audit system mainly classified in three
different categories:

1.Internal Audits
2.External Audits
3.Regulatory Audits

 Regulatory authority for quality audits:
ISO standards ,
Code of federal regulations [CFR] ,
ICH Q10,USFDA ,GMP

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INTERNAL AUDITS

 This type of audit is also known as First-Party Audit
or self-audit. Those auditing and those being
audited all belong to the same organization.

 Internal audit is a professional activity that consists
of advising organizations on how to achieve their
goals in a better way.

 The internal audit involves the use of a systematic
methodology to analyze business processes or
organizational problems and recommend solutions.

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EXTERNAL AUDITS

 This type of audit is also known as Second-Party
Audit. It refers to a customer conducting an audit
on a supplier or contractor.

 Although there are no strict legal requirements for
this control.

 It is always advisable to evaluate the competence of
the contractors in which we produce our products
or carry out the analysis of our products or any
other activity according to GMP.

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REGULATORY AUDITS

 This type of audit is also known as Third-Party
Audit. Neither customer nor supplier conducts this
type of audit. A regulatory agency or independent
body conducts a third party audit for compliance or
certification or registration purposes.

 International regulatory bodies such as MHRA,UK,
USFDA, Therapeutic goods administration (TGA),
Australia, Medicines control council (MCC), South
Africa ,etc. are responsible for carrying out these
checks.

 There is a team to perform the audit, it must be
composed of audit inspectors and multidisciplinary
company team.

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OBJECTIVES

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OBJECTIVES…

 Evaluating conformity of requirements to ISO 9001.
 Evaluating conformity of documentation to ISO

9001.
 Judging conformity of implementation to

documentation.
 Determining effectiveness in meeting requirements

and objectives.
 Meeting any contractual or regulatory

requirements for auditing.
 Providing an opportunity to improve the quality

management system.
 Permitting registration and inclusion in a list of

registered companies.
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OBJECTIVES…

 Qualifying potential suppliers.
 To determine the conformity or non-conformity of

the quality system in meeting the specified
requirements.

 To determine the effectiveness of the implemented
quality in meeting the specified Quality objectives.

 To provide the Audit team with an opportunity to
improve the Quality system.

 To meet the regulatory requirement .
 To permit listing of the audited organizations

Quality systems in a register.

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MANAGEMENT OF AUDIT

 An audit program may include one or more audits,
depending on the size, nature, and complexity of
the organization to be audited.

 These audits may have a variety of objectives and
may also include joint (multiple auditing
organizations) or combined (Quality management
and Environmental management systems) audits.

 Management of an audit program includes all the
activities necessary for planning and organizing the
types and number of audits, and for providing
resources for conducting them effectively and
efficiently within the specified time frames.

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MANAGEMENT OF AUDIT…

 The organization’s top management should grant
the authority for managing the audit program.
Those assigned the responsibility for managing the
audit program should:

1.Plan, establish, implement, monitor, review
and improve the audit program.

2.Identify the necessary resources and ensure
they are provided.

 The simple goal of this complex process is to
evaluate existing activities and documentation and
determine if they meet the established standards.

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RESPONSIBILITIES

 An audit will evaluate the strengths and weaknesses
of quality control and quality assurance processes,
the results of which will help us to improve
processes and build a better system for the benefit
of the company.

 Every product manufactured by a pharmaceutical
company has characteristics that must be quantified
or qualified by laboratory tests.

 Quality control and quality assurance are the
necessary processes that play the role of control and
balance system in pharmaceutical industry.

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MANAGEMENT OF AUDIT…

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RESPONSIBILITIES…
The auditor has the following responsibilities:
 Assist in the selection of the team and inform the team.
 Responsibility to plan and manage all phases of the

audit.
 Represent the audit team with the auditee.
 Control conflicts and manage difficult situations.
 Direct and control all meetings with the team and the

auditee.
 Make decisions about audit issues and the quality

system.
 Report the results of the audit without delay.
 Report the main obstacles encountered.
 Report critical non-conformances immediately.
 Possesses effective communication skills.

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PLANNING PROCESS

 In order to conduct an audit effectively and
efficiently, the work needs to be planned and
controlled.

 The form and nature of the planning required for an
audit will be affected by the size and complexity of
the enterprise, the commercial environment in
which it operates, the methods of processing
transactions and the reporting requirements to
which it is subjected.

 Audit planning is the formulation of the general
strategy for audit which sets the direction for the
audit, describes the expected scope and conduct of
the audit and provides guidance for the
development of the audit program.

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PLANNING PROCESS…

Adequate planning of an audit work aims at:
 Establishing the intended means of achieving the

objectives of the audit.
 Assisting in the direction and control of the work.
 Helping to ensure that attention is devoted to

critical aspects of the audit work.
 Ensuring that the work is completed expeditiously.
 Facilitating review of the audit work.
 Helping to assign the proper tasks to members of

the audit team and coordinates outside experts.

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PLANNING PROCESS…

The steps in planning an audit include:
 Basic discussions with the client about the

nature of the practices by sampling, reviewing the
law and testing internal rules and practices for
reasonableness.
Engagement are performed first, and the auditor
meets the key employees or new employees of a
continuing client. The overall audit strategy or the
timing of the audit may also be discussed.

 Ask about recent developments in the company
such as mergers and new product lines which will
cause the audit to differ from earlier years.

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PLANNING PROCESS…

 Ask about recent developments in the
company such as mergers and new product lines
which will cause the audit to differ from earlier
years.

 Interim financial statements are analyzed to
identify accounts and transactions that differ from
expectations (based on factors such as budgets or
prior periods).
The performance of such analytical procedures is
mandatory in the planning of an audit to identify
accounts that may be misstated and that deserve
special emphasis in the audit program.

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PLANNING PROCESS…

 Timing of the various audit procedures should be
determined.

 Outside assistance needs should be determined,
including the use of a specialist as required and the
determination of the extent of involvement of the
internal auditors of the client.

 Pronouncements on accounting principles and
audit guides should be read or reviewed to assist in
the development of complete audit programs fitting
the unique needs of the industry.

 Scheduling with the client is needed to
coordinate activities.

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PLANNING PROCESS…

 Non-audit personnel of the accounting firm who
have provided services (such as tax preparation) to
the client should be identified and consulted to
learn more about the client.

 Staffing for the audit should be determined and a
meeting held to discuss the engagement.
The purpose of all this is to ensure that the risk of
performing a poor quality audit (and ultimately
giving an inappropriate audit opinion) is reduced to
an acceptable level.

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INFORMATION GATHERING

 Information is simply the facts or knowledge
provided or learned. It can be tacit, in people’s
heads, or explicit, in documents-electronic or hard
copy.

 During the audit, information relevant to the
objectives, scope and criteria, including information
on interfaces between functions, activities and
processes, should be collected by appropriate
sampling and should be verified.

 Only verifiable information can be audit evidence
which must be recorded.

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INFORMATION GATHERING…

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INFORMATION GATHERING…

Audit evidence:
 It is any information used by the auditor to determine

if the audited information is in accordance with the
established criteria and to arrive at the conclusions
on which the audit opinion is based. Internal Audit
Evidence includes any data, information, process
flows, vouchers, bills, memos, contracts or
transactions.

Methods of gathering audit information:There
are six basic methods of gathering information during
an audit. Depending on the type of information that
needs to be obtained, the Internal Auditor will need
to determine which method, or combination of
methods, should be used.

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INFORMATION GATHERING…

Interviews:
 Interviewing is a powerful data collection

technique, which works well on its own and is often
used to support other techniques, such as
observation.

 The interviewee’s insights can guide the Internal
Auditor’s decisions about what to observe.

 The most important thing to remember when
interviewing is to always talk to the right person, as
it can save a lot of time and confusion.

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INFORMATION GATHERING…

Inspections:
 When inspecting something, it is good practice to

start with general observations and then proceeding
to the more specific elements.

 First, the Internal Auditor will have a good overall
look around the facility and then examine specific
items more closely, noting anything that does not
seem quite right.

 It is important to ask questions throughout the
inspection. If a problem is found, the Internal
Auditor must investigate (dig deeper) to explore the
extent of the finding.

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INFORMATION GATHERING…

Reviewing documents:
 Documents should be clear regardless of who reads

them. Details vary but, in general, every document
should carry a title, an owner and a revision status.
If any of this information is missing, the Internal
Auditor should ask why.

 The revisions noted should be checked against the
master record. Changes must be authorized, signed
and dated by an authorized person.

 However, one sample taken in one given period of
time is usually not enough to form accurate
conclusions. Another important aspect of record
keeping is clarity.

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INFORMATION GATHERING…

Observations:
 The simplest way to check how a process works is to

observe it in action.
 Observing a routine activity for a couple of hours

can give the Internal Auditor the opportunity to see
how something is done under normal
circumstances.

 He or she should ask questions about what they see,
making sure at all times not to interfere with the
processes they are observing, as that may cause the
personnel not to carry out their tasks as they
usually do.

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INFORMATION GATHERING…

Vertical tracking:
 This method is also referred to as “vertical auditing”

and consists of following a specific development
from the beginning until the end, simultaneously
checking all the records that are produced in the
process.

 Applying the vertical tracking technique can lead
the Internal Auditor to areas that were not initially
part of the scope, but it does facilitate a bigger
picture view, as this allows the Internal Auditor to
see how the various parts of a given program work
together.

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INFORMATION GATHERING…

Exercises:
 The aim of an exercise is to test something that is

usually done at the facility as part of the routine.
However, the Internal Auditor gets to pick the time
and the circumstances for the test.

 The subject of testing can be the personnel, the
program, or the equipment. An Internal Auditor
should not run an exercise without the knowledge
and cooperation of the auditee.

 Doing so is likely to have negative consequences as
unannounced actions may breach certain facility
specific rules or regulations which the Internal
Auditor is unaware of.

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ADMINISTRATION

Administration:
 The internal audit team must have the confidence

and trust of the key stakeholders it works with and
be seen as a credible source of assurance and
advice.

 This confidence should not be assumed and can
only be established and maintained by having an
effective working relationship, by delivering high
quality and timely advice and internal audit reports
that are seen to be contributing directly to assisting
the organisation to meet its responsibilities.

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ADMINISTRATION…

The key stakeholders of internal audit are:
1.Chief Executive
2.Board of Directors
3.Audit Committee
4.Senior management
5.External auditor
6.Other reviewers

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ADMINISTRATION…

Chief executive:
 While internal audit reports functionally to the

Audit Committee, it is important that the Head of
Internal Audit has direct access, as and when
required, to the Chief Executive.

 Organisations today, recognize the advantages in
making the Head of Internal Audit directly
accountable to the Chief Executive. This not only
sends a clear signal about the importance of the
internal audit function, it also facilitates regular
contact between the Chief Executive and internal
audit.

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ADMINISTRATION…

 This contact should be used as an opportunity to
gain insights into new and emerging risks and
issues facing the organisation and to discuss the
role the Chief Executive expects internal audit to
fulfill in the company.

Board of directors:
 The Head of Internal Audit may formally report to

the Board of Directors on the effectiveness of the
internal audit function in order to exchange views
and ideas.

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ADMINISTRATION…

 As the Audit Committee is usually a sub-committee
of the Board, this responsibility is often delegated to
the Audit Committee.

 As a minimum, it is important that the Head of
Internal Audit has direct access to the Chair of the
Board and the Chief Executive, as and when
required.

Audit committee:
 Audit Committees play an integral role in the

governance framework of organizations. It assists
Chief Executives and Boards to understand whether
key controls are appropriate and operating
effectively.

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ADMINISTRATION…

 In this respect, the relationship between internal
audit and the Audit Committee is crucial and has a
number of dimensions which are mentioned below:

a. Advise the Chief Executive about the internal audit
plans of the organisation.

b. Direct or coordinate work programs relating to
internal and external audits.

c. Review the adequacy of responses to reports of
internal and external audits.

d. Utilize the internal audit function to undertake
secretariat compliance.

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ADMINISTRATION…

Senior management:
 To effectively fulfill its responsibilities, it is

important that internal audit has a professional and
constructive relationship with senior management
of the organization.

 Internal auditors should interact on a regular basis
with members of the senior management team, and
through the delivery of practical, business-focused
and useful reports and advice, build a relationship
that is based on cooperation, collaboration and
mutual respect.

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ADMINISTRATION…

 These meetings should also be used to obtain
informal feedback about the performance of
internal audit and to assist in identifying ways that
internal audit can best assist organization
management.

External auditors:
 External auditors too must help in developing

internal audit strategy and internal audit work plan.
 Both audit teams need to address the key financial

and business systems underpinning the company’s
financial statements and to avoid duplication of
compliance and assurance.

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ADMINISTRATION…

 To avoid such duplication, the external auditor
must evaluate the work of the internal audit
function to determine its adequacy for external
audit purposes.

 The Internal audit function can be made
responsible for liaising with external auditor on
behalf of the organization. Such a role can be a
useful way for an internal audit team to be aware of
planned and actual external audit coverage.

 Thus, a constructive relationship between both sets
of auditors assists in the conduct of external audits.

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ADMINISTRATION…

 Such a role can only be fulfilled when there is
healthy communication between teams which can
be achieved by establish meetings to allow for a
routine exchange of information.

Other reviewers:
 Internal audit is one of a number of internal and

external review and assurance activities that exist as
part of an organization’s governance arrangements.

 The company shall benefit when all these activities,
such as those performed by the Ombudsman and
regulators, operate in a coordinated and
complementary manner to the greatest extent
possible.

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ADMINISTRATION…

 This requires regular formal and informal contact
between review bodies to minimize duplication and
overlap.

 Some organisations see a benefit in protocols being
formalised for such activities: providing, for
example, for the regular exchange of views and
information and for the reporting of the results of
work undertaken in a coordinated manner.

 Protocols can be particularly important in
situations where internal audit needs to work
closely with other entities as a result of inter-agency
or other agreements.

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CLASSIFICATION OF DEFICIENCIES…

Nonconformities or deficiencies:
As the audit proceeds, there might arise some

situations where the facts indicate there is a failure,
either partially or wholly, of the quality management
system, such a situation is called nonconformity”.

What is nonconformity?
 a condition adverse to Quality.
 The non-fulfillment of a requirement.

The number of nonconformities that can arise
during an audit can be numerous. Following types of
defects are identified during an internal audit and
these are helpful in regulatory compliance:

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CLASSIFICATION OF DEFICIENCIES…

Critical defect:
 Critical defects have a high probability of resulting

in a product recall or in an adverse physiological
response by the consumer.

 Critical deficiencies found in internal audits that
usually produce significant effects on the strength,
identity, safety, and purity of the product that will
be considered during regulatory compliance.The
possible source of a critical defect are:

 Cross-contamination of materials of the product.
 Incorrect labeling.

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CLASSIFICATION OF DEFICIENCIES…

 Active ingredients outside of specifications.
 Product manufactured according to obsolete or

unapproved procedures.
 Open sterile products located in a non-aseptic area.
 Untrained operators working in the sterile filling

area.
 Contaminated purified water or water for injection

system.
Major defect

Major defects found during the internal audit
can reduce the usability or stability of a product, but
without causing harm to the consumer.The possible
source of a major defect are:

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CLASSIFICATION OF DEFICIENCIES…

 Major equipment not calibrated or out of
calibration.

 Inadequate segregation of quarantine components.
 Inadequate evaluation of production process

outside of action levels.
 Process deviations not properly documented or

investigated.
 Operator not trained in or familiar with the

standard operating procedures.
 Preventive maintenance on a critical water system

not conducted according to schedule.

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CLASSIFICATION OF DEFICIENCIES…

 Lack of standard operating procedures for cleaning
equipment.

 Audits of a contract manufacturer not conducted.
Minor defect

Minor defects have a low probability of affecting
the quality or usability of the product which can
help in regulatory compliance.Possible source of the
minor defect are:

 Failure to complete all batch record entries.
 Warehouse not cleaned according to schedule

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CLASSIFICATION OF DEFICIENCIES…

 Cracks in wall surfaces.
 Failures to correct documentation errors properly.
 Operator uniform not properly worn.
 Standard operating procedure review is overdue.
 Adhesive tape used on manufacturing equipment.
 Laboratory buffer solutions are obsolete.

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CONCLUSION

 Audits to be conducted at planned intervals to
evaluate effective implementation and maintenance
of the quality system and to determine if processes
and products meet established parameters and
specifications.

 An audit performed by a well trained and
thoroughly prepared auditor can be highly
beneficial by identifying areas for genuine
improvement.

 Auditing in the pharmaceutical sector serves two
different categories: regulatory compliance and
business needs.

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REFERENCE

1.Review on“Pharmaceutical quality audits” by princy
agarwal & amul misra , Nnovare;2018.

2. Vedanabhlata S, Gupta VN. “A review on audits and
compliance management”. Asian J Pharm Clin Res
2013;6:43-5.

3. Kaur J. Quality audit: Introduction, types and
procedure [Internet].Pharma Pathway; 2017.
http://pharmapathway.com/quality-audit-
introduction- types-and-procedure/.

4.Chartered Institute of Internal Auditors. How to
gather and evaluate information;2017.
https://www.iia.org.uk/resources/delivering-
internal-audit/how-/.

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“ UNIT-2
ROLE OF QUALITY SYSTEM AND
AUDITS IN PHARMACEUTICAL”

MANUFACTURING ENVIRONMENT

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ROLE

• This Chapter describes outlines and discusses the regulations
applicable to the QA function and unit, structure, , charter, and
application of the unit in the pharmaceutical manufacturing
environment.

• By regulation

• Appropriate practice,

• Common sense,

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ROLE

• quality assurance (QA) is a critical function in the pharmaceutical
manufacturing environment. The need for an independent unit to audit and
comment on the appropriate application of standard operating procedures,
master batch records, procedures approved in product applications,

• This helps assure that products are manufactured reliably, with adherence to
approved specifications, and that current good manufacturing practices
(cGMP) are maintained in conformance to regulation, both in the facility in
general
and the microenvironment of each product’s manufacturing sequence.

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ROLE

•Quality assurance personnel must have the appropriate training, experience,
familiarization with the manufacturing facility and products and the ability to
review adherence to procedures, policies, This helps to provide both an
environment and a manufactured product that can withstand Food and Drug
Administration (FDA) inspection and support a firm’s reputation for quality
products.

•The cGMP regulations establish requirements that are intended to provide
a high level of assurance that the pharmaceutical products produced satisfy
the strength, purity, potency, and other quality requirements established for
the finished product to assure that it is fit for its intended use.

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cGMP REGULATION

• The cGMP regulations for the manufacture of pharmaceutical products are
contained in Parts 210 and 211 of Title 21 of the Code of Federal Regulations (CFR)

• Part 210 specifies the scope and applicability of the cGMP regulations and defines
terms used in the regulations. Part 210 also indicates that the regulations establish
“minimum” cGMP requirements and that products that are not manufactured
under cGMP are adulterated. Adulterated products and the persons responsible for
the adulteration are subject to regulatory action by the FDA.

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cGMP REGULATION

• Part 211 contains specific good manufacturing practice requirements for finished pharmaceuticals and is divided into Subparts A–K as follows:

• A. Scope

• B. Organization and Personnel

• C. Buildings and Facilities

• D. Equipment

• E. Control of Components and Drug Product Containers and Closures

• F. Production and Process Controls

• G. Packaging and Labeling Control

• H. Holding and Distribution

• I. Laboratory Controls

• J. Records and Reports

• K. Returned and Salvaged Drug Products

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cGMP REGULATION

• The cGMP regulations are written to address the primary potential sources of product
variability.

• Subpart B establishes the quality control unit and the duties of that unit, establishes
personnel requirements and addresses personnel practices (e.g. sanitation) intended to
reduce the likelihood of product contamination.

• Sub- parts C and D establish requirements for buildings and facilities and equipment used
in the manufacture, processing, packing, or holding of a drug product.

• Subparts E through H establish controls over the major processes associated with the
production of a finished and packaged drug product that is ready to be shipped for
distribution to users.

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cGMP REGULATION

• Subpart I requires the appropriate specifications, standards, sampling plans,
and test procedures; requires instrument specifications and calibration

• Subpart J establishes documentation requirements including master and
batch records,

• Subpart K addresses the control and disposition of returned drug products
and places limitations on the salvage of drug products that have been
subjected to improper storage conditions (e.g., smoke, heat, fire, moisture).

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Duties of Quality Control Unit under
cGMPRegulations

• The cGMP regulations assign specific duties to the quality control unit. The unit is
required to have the responsibility and authority to approve or reject all
components, drug product containers, closures, in-process materials, packaging
material, labeling, and drug products

• The organization must assure that the quality control unit has adequate laboratory
facilities for the testing and approval (or rejection) of components, drug product
containers, closures, packaging materials, in-process materials, and drug products.

• In addition to duties associated with the approval of materials and finished
products, the unit is also responsible for approving or rejecting all procedures or
specifications for identity, strength, quality, and purity of the drug product.

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2 Quality Assurance Function

• The term quality is used in many industries and in everyday life and can have
various meanings depending on context.

• Quality mean the product requirements or attributes that have requirements.
• Quality assurance activities are those processes and activities conducted to assure

that a product or service consistently satisfies its requirements and is fit for its
intended use.

• In the pharmaceutical manufacturing environment, this means the activities
conducted to assure that the pharmaceutical product’s identity,strength, purity,
potency, and other quality attributes conform

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2 Quality Systems Approach

• A management commitment to quality that is communicated throughout the organization

• Identifying quality requirements using risk management and other methods as appropriate

• Developing a quality policy, plan, objectives

• Establishing an organizational structure with identified responsibilities and authorities that allows quality objectives to be met

• Providing the resources needed to meet quality objectives

• Developing the required systems and processes

• Establishing methods for the ongoing objective evaluation of the performance of systems and processes including quality auditing

• Initiating corrective and preventive actions as needed to assure that quality objectives are consistently and reliably met

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2 Quality Systems Approach

• The use of risk management techniques in identifying product
requirements, establishing processes and process control and monitoring
methods, evaluating quality data, identifying appropriate corrective and
preventive actions to address quality problems, and for other quality-related
activities can increase the overall efficiency and effectiveness of the quality
system

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2 Quality Systems Approach

• In a modern quality system, the organizational unit responsible for quality
related activities within the organization generally has a central role in the
development and management of the overall quality system.

• These activities can include quality control, quality assurance, quality
planning, and quality improvement.

• The cGMP regulations do not define or employ these terms, But the
activities the regulations assign to the quality control unit

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2 Quality Systems Approach

• Current quality system models involve quality-related activities and terms that are
not included in the cGMP regulations.

• important for organizations adopting a quality systems approach to
unambiguously define the terms and quality concepts they will be using

• include these definitions as appropriate in training all staff in the organization who
will be involved in quality-related activities.

• This will help assure effective communication throughout the organization and
with vendors and others

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2 Quality Systems Approach

FDA guidance on the quality systems approach the following definitions:

• Quality Assurance (QA) Proactive and retrospective activities that provide confidence that requirements
are fulfilled.

• Quality Control (QC) The steps taken during the generation of a product or service to ensure that it meets
requirements and that the product or service is reproducible.

• Quality Management (QM) Accountability for the successful implementation of the quality system.

• Quality System (QS) Formalized business practices that define management responsibilities for
organizational structure, processes, procedures, and resources needed to fulfill product/service
requirements, customer satisfaction, and continual improvement.

• Quality Unit (QU) A group organized within an organization to promote quality in general practice.

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2 Quality Systems Approach

Other cGMP-assigned responsibilities of the QU that are consistent with modern
quality system approaches include the following:

• Ensuring that controls are implemented and completed satisfactorily during
manufacturing operations

• Ensuring that developed procedures and specifications are appropriate and
followed, including those used by a firm under contract to the manufacturer

• Approving or rejecting incoming materials, in-process materials, and drug products
• Reviewing production records and investigating any unexplained discrepancies

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FDA has designed and implemented
quality system can do the following

• Reduce the number of (or prevent) recalls, returned or salvaged products, and defective products entering
the marketplace

• Harmonize the cGMP regulations to the extent possible with other widely used quality management
systems, which is desirable because of the globalization of pharmaceutical manufacturing,

• When the use of effective risk management practices, handle many types of changes to facilities,
equipment, and processes without the need for prior approval regulatory submissions

• Potentially result in shorter and fewer FDA inspections by lowering the risk of manufacturing problems

• Provide the necessary framework for implementing quality by design , continual improvement, and risk
management in the drug manufacturing process

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2 Quality Systems Approach

• The major elements of the quality system model described in the FDA’s pharmaceutical QS
guidance document,These elements are as follows:

• Management responsibilities

• Resources

• Manufacturing operations

• Evaluation activities

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Management responsibilities

Current quality system models assign management a major role in operation of a successful quality system

• Provide leadership ,communicated throughout the organization

• Create an organizational structure with clearly defined responsibilities and authorities to perform quality
functions associated with achieving quality objectives

• Building and documenting a quality system to meet specified quality and regulatory requirements and
achieve quality objectives

• Establishing a quality policy and objectives, and quality plans and communicate this throughout the
organization

• Assure that appropriate corrective and preventive actions are taken in response to quality problems using
effective change control procedures and documented

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Management responsibilities

• Under a comprehensive quality system the QU can expect an expanded and more
visible role within the organization with greater accountability to and interaction
with upper management.

• the QU should be structured to reflect management’s strong commitment to
quality and to facilitate achieving quality objectives.

• The structure (e.g., organizational relationship to other organizational units,
reporting relationships) should provide clear lines of responsibility and authority
that support the production, quality, and management activities necessary to
achieve quality objectives.

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Management responsibilities

• The cGMP regulations require quality-related activities to be conducted during all
phases of manufacturing from the acceptance of raw materials through batch
release, packaging, and labeling.

• the role of quality personnel can be significantly expanded to include internal
quality auditing, expanded review and analysis of quality data, investigation of
nonconformance, root cause analysis, risk analysis, and other quality-related
activities.

• Quality staff should have sufficient scientific and technical knowledge and training
(e.g., statistical methods, risk analysis)

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Resources

• Inadequate staffing, training, manufacturing equipment and facilities,
environmental controls, analytical equipment, and other resources can be
sources of variability leading to the production of product that does not
meet specified requirements

• Modern quality system standards specifically address the issue of resources
by requiring the organization to determine and provide the human,
infrastructure, and work environment resources necessary for the quality
system.

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Resources

• The cGMP regulations address the resource issue in the adequacy of
personnel (including consultants), manufacturing facilities including
contract facilities, equipment, and laboratory facilities. The QU has
significant responsibility in this regard.

• The FDA, in its pharmaceutical QS guidance document, discusses the need
for adequate resources in developing, implementing, and managing a
quality system that complies with the cGMP regulations.

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Resources

• Management is responsible for identifying resource requirements and providing
resources accordingly, including providing training that is appropriate to the
assigned activities

• Personnel should understand the impact of their activities on their assigned duties
and be familiar with cGMP requirements and the organization’s quality system.

• Management should establish a working environment that encourages problem
solving and communication in identifying and acting upon quality-related issues.

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• the QU and other organizational units should be involved in the
identification of the resources required to achieve quality objectives,
including regulatory compliance, evaluating the effect of personnel, facility,
product, process, regulatory

• The FDA notes that the cGMP regulations place as much emphasis on
processing equipment as testing equipment and contain specific
requirements for the qualification, calibration, cleaning, and maintenance of
production equipments

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• the specification of facility and equipment requirements may be performed
by technical experts (e.g., engineers)

• The cGMP regulations require the QU to be responsible for reviewing and
approving all initial design criteria and procedures pertaining to facilities
and equipment and any subsequent changes

• A requirement of both the cGMP and current quality system models is that
such review and approval be conducted by persons who are qualified by
education, training and experience to do so.

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• the control of outsourced operations, the cGMP regulations require that the
QU approve or reject products or services provided under a contract.

• Under current quality system models, the organization must follow a formal
vendor qualification process to qualify outsource providers and verify
through inspection or other To comply with the regulation, these operations
should be conducted by the QU

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MANUFACTURING OPERATIONS :

This requirements contained in current quality system models
such as ISO 9001-2000 and the GMP regulation requirements for
manufacturing.

The FDA has identified four major elements of QS approach to
manufacturing operations.

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CFR cGMP REGULATIONS RELATED TO
MANUFATURING OPERATIONS

Quality system elements Regulatory citation

Design and develop product and Production :§211.100(a)

process

Examine inputs Material:§§210.3(b),211.80-
211.94,2110110,211.111,211.113

Perform and monitor operations Production:§§211.100,211.103,211.110,211.111,211
.113

Address nonconformities Discrepancy
investigation:§§211.22(a),211.100,211.115,211.192,
211.198 recalls 21 CFRpart7

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Design, Develop and document product and
process

In a modern quality system manufacturing environment, the significant

characteristics of the product being manufactured should be defined and verified as

meeting requirements from design to delivery, and control should be exercised over

all changes.

This is consist of the cGMP regulations.

That require quality and manufacturing process and procedures, and changes to

them to be defined approved and controlled.

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Document is required and can include the following :-

Resource and facilities used

Procedures to carry out the process

Identifications of the process owner who will maintain and
update the process as needed

Identification and control of important variables

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Quality control measures, necessary data collection, monitoring,

and appropriate controls for the product and process

Any validation activities, including operations ranges and

acceptance criteria

Effect on related process, functions, or personnel

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labling controls.

So packaging and labelling requirements, process and controls
should be included in a QS based approach to product and
process design and development.

The FDA acknowledges that the reluctance to pursue
potentially innovative changes in pharmaceutical manufacturing
can be undesirable from a public health perspective and has
published a process analytical (PAT)guidance document.

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This guidance is intended to address this by promoting the use of

analytical tools to gain process understanding and meet regulatory

requirements for validating and controlling manufacturing process.

The FDA has published the guidance document and other

pertinent PAT information on its website at www.fda.gov.

companies interested in PAT methods should contact the FDA.

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FDA internal implementation of PAT include the following:

A PAT team approach of CMC review and cGMP inspections

Joint training and certification of FDA PAT review, inspection,

and compliance staff

Scientific and technical support for the PAT review, inspection,

and compliance staff

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EVALUATION ACTIVITIES :

The evaluation component of a QMS is intended to provide

objective information and data that allow the organization to assess

the conformity of the product, evaluate the performance of its

quality system, and maintain and improve its effectiveness.

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CFR cGMP REGULATIONS RELATED TO
EVALUATION ACTIVITIES

Quality system element Regulatory citation

Analyse data for trends Annual review:§211.180(e)

Conduct internal audits

Risk assessment

Corrective action Discrepancy
investigation:§§211.22(a),211.192

Preventive action

Promote, improvement §211.110

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TREND ANALYSIS

Trend analysis is one statistical tool specifically recommended by the FDA in
its pharmaceutical QS guidance document.

That can be very valuable monitoring process and quality system
performance to identify emerging problems and to assess the effectiveness of
improvement efforts.

Traditional statistical process control and other methods also provide
valuable support in the objective and ongoing analysis of quality data and can
be helpful in implementing real-time quality assurance practices as
recommended by the FDA.

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CONDUCT INTERNAL AUDITS

Internal audit is not specifically required by the cGMP
regulations, but manufacturers have traditionally used internal
audits as a self-assessment tool and to prepare for FDA
inspections.

International standards provide guidance on auditing.

Audits procedures should be developed and documented to ensure
that the planned audit scheduled takes into account the relative
risks of the quality system activities.

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Factors that can incorporated into a risk-based approach to
planning audit frequency and scope include the following :

Exiting legal requirements (e.g., cGMPs)

Overall compliance status and history of the company or facility

Robustness of a company’s quality risk management activities

Complexity of the site

Complexity of the manufacturing process

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Complexity of the product and its therapeutic significance

Number and significations of quality defects (e.g., recall)

Result of previous audits/inspections that can include prior
internal audit results as well as regulatory (e.g., state, federal, or
other regulatory agencies) and third-party audits.

Major changes of building, equipment, process and key personnel

Experience with manufacturing of a product (e.g., frequency,
volume, number of batches )

Test results of official control laboratories

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Different audit approaches may be applied depending on the

intended purpose and scope of the audit.

A top-down approaches first evaluates the overall structure of the

quality system and its subsystem.

Subsystem may be chosen for review.

Systems identified and developed by the FDA in a SIX-

SYSTEM inspection model for the inspection of drug

manufacturers.

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Overall quality system

Facilities and equipment

Materials system

Production system

Packaging system

Laboratory controls

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[COMPANY NAME ] QUALITY SYSTEM AUDIT CHECKLIST

FROM: REV: DATE: APPROVED :

AUDIT DATES (S): Refs:

Auditor: TITLE SIGNATURE :

REQUIREMENT cGMP SECTION CROSS CONFORMS (Y/N/NA) OBJECTIVE
REFERENCE EVIDENCE AND

COMMENTS

SUBSYSTEM 1

REQUIREMENTS 1.1

REQUIREMENTS 1.2

SUBSYSTEM 2
RREEQUREMENTS 2.1

REQUIREMENTS 2.2

SUBSYSTEM 3

REQUIREMENTS 3.1

REQUIREMENTS 3.2

SUBSYSTEM N
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CORRECTIVE AND PREVENTIVE ACTION

A corrective and preventive action may be initiated based on

reviewed and analysis of quality data from a verity of sources

including adverse experiences, product complaints, quality audits,

FDA inspection, third-party inspections, nonconforming materials

reports, process control information, trend analyses, and other

sources.

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A firm’s CAPA system and process should be designed to analyse
and respond to quality issues in a systematic way that is
commensurate with the risk.

The system should provide for the verification or validation of
corrective and preventive actions to assure their effectiveness and
to assure that actions do not adversely affect the finished product.

The system should also assure that pertinent CAPA information is
appropriately disseminated throughout the organization as
necessary to assure the effective operation of the quality system
and for management review.

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TRANSITIONIG TO QUALITY SYSTEM
APROCH

The GMP regulations assign significant responsibilities to the
organizational unit responsible for quality-related activities.

Organizations implementing a quality system model will be
responsible for additional quality-related activities including but
not necessarily limited to, conducting quality audits, analysis of
quality data, risk assessment, and preventive actions based on
review and analysis of quality data to prevent the occurrence of
product nonconformities.

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Some points to consider in planning the
transition :-

Create a transition team: A cross functional team should be
developed involving key managers and staff from throughout the
organization to plan and execute the transition.

The transition team should have a clear understanding of its
mission and the organizational objectives associated with the
transition.

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Train the transition team: management should assure that all individuals on
the transition team receive proper training on quality systems requirements,
risk management, and FDA ‘s recommended approach to quality system.

Develop a transition plan: a transition plan, based on clearly defined
objectives, should be developed by the transition team.

Identify staffing requirements: The transition will likely affect individual job
descriptions and create additional duties that will have to be addressed
through the reassignment of staff, and providing necessary training to all
affected staff.

 Define roles and responsibilities: The plan should clearly define the roles
and responsibilities of those responsible for development and execution of
the plan for quality system implementation as well as staff roles and
responsibilities under the quality system.

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 consider organizational structure requirements: In order to function
properly, person responsible for quality-related activities must have the
responsibilities and associate authority defined and appropriately
communicated within the organization.

Consider benchmarking: If possible, arrange with other organizations
that have successfully made the transition to meet with them, review their
system , and discuss transition issues and how they were solved.

Communicate regularly: clear and ongoing communication within the
transition team and with management is essential to effectively coordinate
plan activities, report progress, resolve issues, and identify evolving resource
needs

validate the system

Maintain regulatory compliance.

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REFERENCE :-

• Active Pharmaceutical Ingredients Committee (APIC). Auditing guide; 2016.
Available from:
http://apic.cefic.org/pub/Auditing/APIC_CEFIC_AuditingGuideAugust2016.
pdf. [Last accessed 19 Mar 2018] Place Unknown: Word Press; 2008.
Available from: https://drpotdar.wordpress.com/2008/04/30/audit/.

• BSI standards publication: European committee for standardization.
Guidelines for auditing management systems; 2011. Available from:
http://qic-eg.com/wp-content/uploads/2015/08/BS-EN-ISO-19011-2011.pdf.

• Roger CPA Review Blog. The 10 steps in planning an audit; 2009. Available
from: https://www.rogercpareview.com/ blog/10-steps-planning-audit.

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UNIT-3
AUDITING OF VENDORS AND
PRODUCTION DEPARTMENT

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BULK PHARMACEUTICAL VENDOR AUDIT :

INTRODUCTION :
• Manufacture of medicinal products and the active pharmaceutical

ingredients {APIs} , bulk pharmaceutical ingredients {BPIs } used as
starting materials in the production of these products is subject to
strict good manufacturing practice regulations that are dissigened
ensure their quality , safety, and efficacy .

• This ensures that patients worldwide and at any time can have
confidence in the quality ,safety ,and efficacy of medicines .

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WHY VENDOR AUDIT :

• The quality system requirements to idenity , select , approve and
quality vendors of all materials used in the manufacture of BPIs and
medicinal products are clearly defined in the GMP guidelines .
 Non critical raw materials
 Critical raw materials
 Registered intermediates
 APIs

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CONTINEUED ……
In addition to GMP regulatory the excipient vendor qualification is

particulary important .
To provide adequate assurance of drug product performance .
To aviod the potential risks mentioned below.
• Presence of extraneous matter e.g., metal , paper , particles
• Cross contamination with other chemicals [ either excipients or APIs or

breakdown products ]

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CONTINEUED…..
• Contamination with melamine risk materials which is not permitted by

legislation .
• Inconsistent manufacture such that the quality of final products cannot

be assured .
• Mislabeling of containers leading to product mix –up
Concept of quality by design {QbD} involves understanding of product

variability in which contribution of excipient also needs special
consideration

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AS PER GMP THE GUIDELINES FOLLOWED FOR
AUDITS .
• Registered intermidiates usually involve custom synthesis or process

development by the supplier .
• The quality system requirements to identify , select , approve and

qualify suppliers of all materials used in the materials used in the
manufactutr of APIs and medicinal products are clearly defined in the
GMP guidelines .

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TERMS WHICH FOLLOWED ….

• We are also referring to existing APIC quidance documents whenever
applicable to futher clarify expectations and provide consistency to
the processes .

• E.g :
• Quality agreements
• Auditing guide ,
• APIC audit programme

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DIMENSIONS ….

• Following different dimensions could be assessed :
 Assurance of suppy
 Quality and regulatory compliance
 Cost / procurement aspects
 Technical /innovation
 Communication capabilities and responsiveness

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AUDITING PACKAGING MATERIAL VENDORS :

• Goals :
Perform a packaging component supplier audit .
Understand which worldwide requirements apply to packaging

component suppliers .
Use a range of information tools , including the contents of this

module , in support of a packaging component supplier audit .

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DEFINITIONS :

1. GANG – PRINTED LABELLING :
• Labeling derived from a sheet of material on which more than one

item of labeling is printed .{ see example below } . Gang printing is
considered to be an un acceptable practice for some industry since it
increases the potential for label mix –up .

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2 .PACKAGING MATERIALS :

• Any material employed in the packaging of a medicinal product ,
excluding any other packaging used for transportation or shipment.

3.PACKAGING COMPONENT –CRITICAL {PCNC}:
• Is any printed packaging component ,primary {product contact }

component or device , futhermore any secondary packaging
component critical to the microbiological intergrity ,stability and /or
administration of the product { e.g alumninium pillow packs around
semi permeables }

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4. PACKAGING COMPONENT –NON CRITCAL {PCNC} :
Is any non–printed or secondary {non contact }packaging component

or device that does not fall with in the defintion of a pcc .
5. PRINTED PACKAGING COMPONENT :

Packaging materials that are printed and /or otherwise decorated .
Examples would include cartons ,lables ,leaflets .

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AUDITING PACKAGING MATERIAL VENDOR :
a. LINE CLEARANCE : Line clearance is an essential in product mixup

prevention and needs to focus on :
i. Input materials on the line from the previous batch
ii. Samples and waste from the previous batch
iii. Documents on the line from the previous batch
iv. Verification that any electroinc data is wiped from consoles etc.

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• CONTAMINATION CONTROL :
• The facilities should be designed and laid out to appropriately reduce

the risks of contamination from the environment and permit effective
cleaning .

• Personnel growning and hygiene practies are part of contamination
control efforts that may be applicable .

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• The supplier should define the appropriate environmental conditions
for handling and storage of the component (s) being manufactured .
Guidance for minimum conditions can be found in PS 9000
pharmaceutical packaging materials , as well as programs such as ISO
9001 : 2000 and ISO 9004: 2000 for pharmaceutical packaging
materials .

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• VALIDATION AND QUALIFICTION :
• Ensure the process are adequately validated ,qualified and /or

demonstrated according to the quality critical parameters of the
component being manufactured .this may be demonstrated in the
form of capability studies.

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• SAMPLING :
• There should be an SOP that definies package components sampled

be representive of the batch and sampling should be conducted to
prevent contamination from the sampling mathod .

• Any packaging materials that meet appropriate written specifictions
should be formally approved and released for use . Any components
fail to meet such specifications must be rejected to prevent
distribution .

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• DOCUMENTATION :
• The appropriate SOPs and batch records must be followed when

documenting any information or data associated with a component
manufacture . Other pertinent types of documentation include :

• Records of how and who set up a particular machine .

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AUDITING WAREHOUSE AND DISTRIBUTION
SYSTEM :
• GOALS :
• Perform an audit of warehouse and distribution .
• Assess and understand warehousing and distribution requirements ,

including licensing requirements .
• Use a range of tools and information , including the contents of this

module and the internet , in support of auditing warehousing and
distribution

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DEFINITIONS :

• FEFO : an inventoory management system where the products
expired first are the ones sold first known by the abbreviation “FEFO ,
first expire ; first out .

• FIFO : an inventory management system where the products received
first are the ones sold first or the oldest inventory is the first to be
distributed . Known by the abbreviation “FIFO , first in ; first out .

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FINISHED PRODUCT :
 A product which is packaged and labeled for supply to a wholesaler .

hospital pharmacy , docter or patient .
 The use of this definition in the document includes medicinal products

/prescription drugs

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• INVESTIGATIONAL MEDICINAL PRODUCT :
• A pharmaceutical from of an active substance or placebo being tested

or used as a reference in a clinical trial , including already with a
marketing authorization but use or assembled [formulated or
packaged] in a way different from the authorized form or when used
for an unauthorized indication or when used to gain futher
information about the authorized form.

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TABLETING
General:

•Whether the unit has provide effective air extraction
systems with discharge points to avoid contamination of
other.

• products and process. Filters to be installed to retain
dust.

•Whether the unit has taken precaution to avoid
contamination of fiber shedding materials like wood.

• The unit is monitoring environmental conditions of
pressure differential between rooms.

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The unit is monitoring environmental conditions of pressure
differential between rooms.

Temperature and humidity is controlled while processing of
aspirin , ferrous sulphate ,tablets etc.

Whether metal detector provided.

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Sifting, Mixing and Granulation

oWhether mixing , sifting and blending equipment are fitted
with dust extractors unless operated as a closed system.

oWhether filter bags fitter to fluid bed drier are used for
different products without being washed in between used.

oWhether air entering in to the drier is filtered.
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Compression (tablets)

• The tablet compressing machine are provided with effective
dust control facilities and installed in separate cubicles.

•Whether tablets are being de-dusted and monitored for the
presents of foreign materials and collected in clean labeled
containers.

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•Whether tablets are being inspected and checked for suitable
Pharmacopeia parameters like appearance weight variation ,
disintegration , hardness , friability and thickness and record
maintained.

• The compressed tablets are stored properly.

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Equipment and area in the tablet section

1. Mass Mixer
2. Drum Mixer
3. Rotary tablet machine
4. Hot air oven
5. Multi mill
6. Coating pan
7. Sifter
8. Polishing

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AUDIT CHECKLIST

Edition no Approved Effective Date

Dry
Department Production :

Tableting
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Date of
audit

Purpose
of audit specify

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A . Documents Reviewed:

1. SOP
2. Personnel

B . Data Reviewed:
1.Facilities
2.prevention of cross –contamination
3.Equipment and facility cleaning

4.In-process control

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SOP

• Is a complete index and a complete set of application sop
available in the department.

•Are the index and the SOP current.

• Is the set of SOP correctly organized according to the index.

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Personnel

• Select three employees working in the department. Are their
training records up-to-date.

•Have the employees undergone training in the following area
during the last year.

1. GMP
2. SOP

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Facilities

Is the department maintained in a good state of repair.

Is the department neat and orderly with sufficient space for
equipment and operation.

Are all work areas clearly labeled with the name and the batch
number of the product being processed.

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Prevention of cross-contamination

• The doors closed at all time.

• Is personnel clothing clean , unstained and dust free including
shoes.

• Is there a shoe-cleaning device in the department.

• Is there a record of the pressure.
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Equipment and facility cleaning

• The pallets and drums brought into the area clean and free
from powder or dust.

• Is the equipment neat clean and rust free.

•Are there specific procedures for the cleaning of tableting
machines.

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In-process control

• Is there an approved SOP for in-process control.
•Do all test result conform to specification.
•Are there printouts available for all in-process test result

labeled .
1. Product name
2. batch number
3.Date and time of testing
4. Signature of the tester

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Coating

Edition no

Approved

Dry
Effective Date Department Production :

coating
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A . Documents Reviewed:

1. SOP
2. Personnel

B . Data Reviewed:
1.Facilities
2.prevention of cross –contamination
3.Equipment and facility cleaning
4.In-process control

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SOP

• Is a complete index and a complete set of application sop
available in the department.

•Are the index and the SOP current.

• Is the set of SOP correctly organized according to the index

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Personnel

• Select three employees working in the department. Are their training
records up-to-date.

• Have the employees undergone training in the following area during
the last year.

1. GMP
2. SOP
3.Coating techniques

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Facilities

Is the department maintained in a good state of
repair.

Is the department neat and orderly with sufficient
space for equipment and operation.

Are all work areas clearly labeled with the name and
the batch number of the product being processed.

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Prevention of cross-contamination

• The doors closed at all time.

• Is personnel clothing clean , unstained and dust free including
shoes.

• Is there a shoe-cleaning device in the department.

• Is there a record of the pressure.
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Equipment and facility cleaning

• The pallets and drums brought into the area clean and free
from powder or dust.

• Is the equipment neat clean and rust free.

•Are there specific procedures for the cleaning of coating
machines.

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In-process control

• Is there an approved SOP for in-process control.

• Do all test result conform to specification.

• Are there printouts available for all in-process test result labeled .
1. Product name
2. batch number
3.Date and time of testing
4. Signature of the tester

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Capsules

Edition no Approved Effective Date

Dry production :
Department

capsules

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A . Documents Reviewed:

1. SOP
2. Personnel

B . Data Reviewed:
1.Facilities
2.prevention of cross –contamination
3.Equipment and facility cleaning
4.In-process control

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SOP

• Is a complete index and a complete set of application sop
available in the department.

•Are the index and the SOP current.

• Is the set of SOP correctly organized according to the index.

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Personnel

• Select three employees working in the department. Are their
training records up-to-date.

•Have the employees undergone training in the following area
during the last year.

1. GMP
2. SOP

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Facilities

Is the department maintained in a good state of repair.

Is the department neat and orderly with sufficient space for
equipment and operation.

Are all work areas clearly labeled with the name and the batch
number of the product being processed.

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Prevention cross-contamination

• The doors closed at all time.

• Is personnel clothing clean , unstained and dust free including
shoes.

• Is there a shoe-cleaning device in the department.

• Is there a record of the pressure.
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Equipment and facility cleaning

• The pallets and drums brought into the area clean and free
from powder or dust.

• Is the equipment neat clean and rust free.

•Are there specific procedures for the cleaning of tableting
machines.

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In-process control

• Is there an approved SOP for in-process control.
• Do all test result conform to specification.
• Are there printouts available for all in-process test result labeled .

1. Product name
2. batch number
3.Date and time of testing
4. Signature of the tester

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Granulation

Edition no Approved Effective Date

Dry
Department production :

Granulation

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Date of
audit

Purpose specify
of audit

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A . Documents Reviewed:

1. SOP
2. Personnel

B . Data Reviewed:
1.Facilities
2.prevention of cross –contamination
3.Equipment and facility cleaning

4.Lubricants

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SOP

• Is a complete index and a complete set of application sop
available in the department.

•Are the index and the SOP current.

• Is the set of SOP correctly organized according to the index.

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Personnel

• Select three employees working in the department. Are their
training records up-to-date.

•Have the employees undergone training in the following area
during the last year.

1. GMP
2. SOP
3. Granulation tecwwhw.nDuiloqMixu.coem s

 

Facilities

Is the department maintained in a good state of repair.

Is the department neat and orderly with sufficient space for
equipment and operation.

Are all work areas clearly labeled with the name and the batch
number of the product being processed.

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Prevention of cross-contamination

• The doors closed at all time.

• Is personnel clothing clean , unstained and dust free including
shoes.

• Is there a shoe-cleaning device in the department.

• Is there a record of the pressure.

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Equipment and facility cleaning

• The pallets and drums brought into the area clean and free
from powder or dust.

• Is the equipment neat clean and rust free.

•Are there specific procedures for the cleaning of major
equipment.

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Lubricants

• Is there a written procedure for the receipt and approval of
such lubricants.

• Is a record made of the catalog number of the lubricant used
when maintenance is performed.

• The lubricants available in the department. They clearly
labeled and stored in a sanitary manner.

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Sterile Production

Edition no Approved Effective Date

Dry production:
Department sterile

production
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A . Documents Reviewed:

1. SOP
2. Personnel

B . Data Reviewed:
1.Facilities
2.Batch records
3.Monitoring

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SOP

• Is a complete index and a complete set of application sop
available in the department.

•Are the index and the SOP current.

• Is the set of SOP correctly organized according to the index.

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Personnel

• Select three employees working in the department. Are their
training records up-to-date.

• Have the employees undergone training in the following area during
the last year.

1. GMP
2. SOP
3. sterile manufacturing techniques

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Facilities

Is the department maintained in a good state of repair.

Is the department neat and orderly with sufficient space for
equipment and operation.

Are the cleaning and sanitizing solution labeled with an
expiration date according to the relevant SOP.

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Monitoring

• Is there a valid calibration label affixed to monitoring sensors
for pressure , temperature , and relative humidity.

•Are records according to the relevant SOP.

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Packaging

Edition no

Approved

Effective Dry
Date Department production :

packaging
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Date of
audit

Purpose
of audit specify

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A . Documents Reviewed:

1. SOP
2. Personnel

B . Data Reviewed:
1.Facilities
2.cleaning procedures
3.In-process control

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SOP

• Is a complete index and a complete set of application sop
available in the department.

•Are the index and the SOP current.

• Is the set of SOP correctly organized according to the index.

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Personnel

• Select three employees working in the department. Are their training
records up-to-date.

• Have the employees undergone training in the following area during
the last year.

1. GMP
2. SOP
3. Packaging techniques

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Facilities

Is the department maintained in a good state of repair.

Is the department neat and orderly with sufficient space for
equipment and operation.

Are all work areas clearly labeled with the name and the batch
number of the product being processed.

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Cleaning procedures

• Is there a written procedure for the cleaning of the
packaging facility.

• Is there documented evidence that the cleaning
procedure is being followed.

• The procedure specific to a particular machine.

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Reference

1.Kumar S, Tanwar D, Arora N. The role of regulatory GMP audit in
pharmaceutical companies. Int J Res Dev Pharm Life Sci 2013;2:493-8.

2. Kaur J. Quality audit: Introduction, types and procedure [Internet]. Place
Unknown: Pharma Pathway; 2017. from:
http://pharmapathway.com/quality-audit-introduction-types-and-
procedure/.

3. Biswas P. ISO 9001. Internal audit [Internet]. Place Unknown: Word Press;
2015. Available from: http://isoconsultantpune.com/iso-90012015-
internal-audit-by-pretesh-biswas-apb-consultant/.

4. Bernacchi T. The pharmacy audit: what is it and are you prepared? J
Managed Care Pharm 1999;5:94-8.

5.Vedanabhlata S, Gupta VN. A review on audits and compliance
management. Asian J Pharm Clin Res 2013;6:43-5.

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UNIT-4
AUDITING OF MICROBIOLOGICAL

LABORATORY

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Definition:

Quality audit is defined as a systematic and independent examination
to determine whether activities and related results comply with
planned arrangements and whether these arrangements are
implemented effectively and are suitable to achieve objectives.

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Scope and Objectives:

To ensure quality of the Product

To assess effectiveness of QA system

It permits timely correction of problems

It established high degree of confidence

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Auditee :
An organization, facility or person being audit.

Auditee’s Responsibility

Inform relevant employees about the objectives and scope of the audit

Appoint responsible members of staff to meet with members of the audit
team

Provide all resources needed for the audit team in order to ensure an
effective and efficient audit process

Determine and initiate corrective actions based on the audit report

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What is the process for audit?

A process audit is an examination of results to determine whether
the activities, resources and behavior that cause them are being
managed efficiently and effectively.
A process audit is not simply following a trail through a department

from input to output – this is a transaction audit.

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How to Audit a Manufacturing Process

An audit of a manufacturing process is a comprehensive examination
of the process to verify that it is performing as intended.
Processes generate results, and process audits determine if the

results are accurate and being generated by an effectively managed
process…

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Manufacturing process audits should ensure that procedures are
properly followed, problems are quickly corrected, there is
consistency in the process, and there is continuous improvement and
corrective action as needed.

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There are many reasons for conducting a manufacturing
audit:

Assures procedures reflect actual practice (what we say is what we
do);
Uncovers inaccuracies so they can be quickly corrected;
Reveals the consistency of a process (from person to person, or day

to day);
Demonstrates a proactive approach to process improvement; and
Encourages ongoing corrective action

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A good manufacturing audit requires:

Announcement in advance. Manufacturing audits are not meant to
catch people doing something wrong. On the contrary, during an
audit you hope to catch people doing things right.
A rating scheme to classify problems discovered. A rating scheme

allows you to rank problems in order to prioritize corrective actions.
Trained auditors. Auditors should be familiar with both the area they

are observing and with auditing techniques.
Planning and clear procedures. A manufacturing audit is more than

just walking into a work area and looking for trouble

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The steps listed below can help in planning and
conducting an audit.

Select a process to be audited. Prioritize the processes that can be
audited in terms of importance and risk to the overall operation.
Begin auditing the highest-risk areas first.

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Select a team to conduct the audit. The audit team should be
familiar with the process being audited. They should also be familiar
with audit techniques such as sampling and analyzing results. They
must have the necessary expertise to identify problems and
determine the corrective actions needed.

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Decide how often the process should be observed (the frequency of
the audit). If there are significant problems or noncompliance, the
process should be observed more often until the situation is under
control.
 Announce the audit in advance so there are no surprises. The

objective is to improve the process, which will require the cooperation of
everyone involved

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Set up an audit schedule for the entire shift and follow the
established audit schedule. The number of observations will be your
sample of the work for that shift. The audit schedule should be
determined in advance and should be as random as possible. Once
established, the audit schedule should be followed to provide results
based on a random sample.

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Document any problems discovered and inform all those affected. The
idea is not to assign blame but to find a solution. The problems
discovered become the basis for corrective actions and follow-up.
Everyone affected by the problem should be informed so they are aware
and can provide input to the resolution. Also, the process being audited
will likely affect other processes in the over-all operation.

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Determine and perform corrective actions. Let employees make
suggestions for corrective actions and select any that are appropriate,
but management should make the final decision as to which
corrective actions to implement.

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Monitor corrective-action results. Perform follow-up monitoring to
determine if the corrective actions have actually eliminated the
problem or if further action is required. Also verify that no new
problems have developed or entered into the process.

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Product and Process
Information

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Contents

Process audit

Product audit

Quality goals

Process audit vs Product Audit

Reference

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What is Process Audit

A process audit is an examination of results to determine whether
the activities, resources and behavior that cause them are being
managed efficiently and effectively.

 A process audit is not simply following a trail through a department
from input to output – this is a transaction audit.

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In contrast with rear-facing product inspections, process audits focus
on how your team prepares, produces, packages and distributes
those products.
This approach provides a more comprehensive view of the value

stream than product audits, which only sample the finished output.

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Process audits look at details of manufacturing process such as:

Fabrication steps
Safety measures
Temperature settings
Pressure readings
Calibration of gauges

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What is Product Audit

The product audit is the assessment of the final product/service and
its qualification for use evaluated versus the intent of the purpose of
the product/service.
It ensures a thorough inspection of a final product before delivery to

a supplier or a customer.

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PRODUCT AUDIT…

Product audits take place after manufacturing is complete, but
before the product reaches the customer.
If a product doesn’t meet standard requirements or specifications,

the auditor documents the findings and logs a non-conformance.

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While each company will have its own procedures for addressing non-
conformances, the process typically includes:

Identifying the problem
Containing the non-conformance
Reworking or repairing the products, if possible
Disposing of nonconforming products if you can’t rework or repair

them
Determining the necessary countermeasures for preventing

recurrence

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PRODUCT AUDIT…

Product audits can help a manufacturer improve quality, profits,
customer satisfaction, and loyalty.

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Product and Process Audits Go Hand-in-Hand

An effective manufacturing process audit program that ensures the
highest level of quality requires both product and process audits.
Though nearly all manufacturers conduct product audits, fewer of
them have defined process audit procedures in place

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Process audits are critical to quality goals that
include:

Standardizing processes to ensure compliance with specific
requirements such as time, components, accuracy or temperature

Continuously reducing risk through systematic identification and
correction of process errors

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Monitoring key metrics for evaluating overall process performance

Assessing effectiveness of process controls such as procedures,
instructions and specifications

Reviewing production resources, work standards and the
manufacturing environment itself

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What is the difference between Process audit & Product audit

Process Audit Product Audit

Auditor will concentrate on Auditor will concentrate only on
process at each stage & its output of the process & its
relevant parameters process relevant parameters.
parameters like temperature,
pressure, speed etc

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CONTENT

1.General areas interest in the building:

i. Walls and celling’s

ii. Floors and drains

iii. Doors ,windows and fittings

iv. equipment

v. pipelines

2.RAW MATERIALS

3.WATER

i. Microbiological results

ii. Essential document

iii. PQ is divided into 3 phases

iv. Microbiological procedure reviewed

4.PACKAGING MATERIALS

5.EFFECTIVE VENTILATION www.DuloMix.com

 

GENERAL AREAS OF INTREST IN THE BUILDING RAW MATERIALS

GENERAL AREAS INTREST IN THE BUILDING

1.WALLS AND CELLINGS:

 moulds are most commonly encountered microbes on walls celling’s ,

particularly when poor ventilation, temperature, and relative humidity control

lead to high level of moisture.

 contamination may be excessive where damaged surfaces expose the

underlying plaster.

 surfaces should be smooth ,impervious and cleanable; damaged surfaces

should be repaired promptly.
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2.FLOORS AND DRAINS:

 Flours should be impervious to water, cleanable and resilient to day to day

wear and tear.

 flours should be laid flat to minimize the risk of excessive surface water(e.g.

washing bays) or ,ideally should slope towards drain.

 The auditor should pay particular attention to joints, seals and floor to wall

coving to ensure that surfaces should be repaired promptly.

Where floor drainage channels are needed , they should be open shallow easy

to clean drain effectively.

 The auditor must be aware that any ‘static’ water can act as reservoirs for gram

negative organisms , particularly pseudomonas species.
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3.DOORS ,WINDOWS AND FITTINGS

 These should be flush-fitting whenever possible. Wood readily absorbs

moisture and can generate high number of moulds; where present, it should

be sealed with a high –glass paint and any surface damage repaired

immediately.

4.EQUIPMENT

 The ability of bacteria to attach to surfaces such as stainless steel and plastic

and survive should not be under estimate.

 Every piece of equipment has its own particular nooks and crannies where

microbiological contamination can reside; internal threads and dead legs

cause particular problem. www.DuloMix.com

 

5.CLEANING OF EQUIPMENT
 Cleaned equipment can be readily recontaminated before use .
 The auditor should review :the quality water used in final rinsing stage

 and how equipment is dried and stored to minimize the risk of contamination
by pseudomonas and other gram –negative bacteria .
6.PIPELINES

 Pipeline must be completely drainable to ensure that trapped fluid does not
provide a hospitable environment for growth of bacteria.

 Internal surfaces should be smooth and polished to min imize pits where
microbes may lodge.

 Joints and welds should be kept a minimum, since they may provide a
protective haven for a microorganism. Its sealed with lagging material.

 If the protective outer seal is damaged and may provide a rich source of
mould contamination.

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RAW MATERIALS
 Raw materials pose a major contamination threat to the product and the

production environment, and warrant special attention from auditor.

 Untreated raw material of natural origin contain an extensive and varied

microbial population ,including potentially pathogenic organisms, such as E.coli

and salmonella species .

 In case of excessively high bioburden , pre-treatment may be needed to reduce

the bioburden to an acceptable level , using process such as heat filtration,

irradiation ,recrystallization from a biocidal solvent or ,where compatible

,ethylene oxide gas.

 Irrespective of the type raw material used, the auditor should confirm that the

material is provided by an ‘approved ‘suwwpwp.DluileoMr…ix.com

 

 Confidence in the supplier ‘s manufacturing process and their quality system, which have

been challenged through audit. likewise the sampling programme used should be satisfactory

,based upon the nature of the raw material(natural /synthetic),the history and performance

of the supplier ,and end use of raw material.

 Sampling procedure should be reviewed.

 Reduce the risk of contamination both sample and bulk.

 Sampling equipment should be dedicated and clean. Samples should be properly trained in

aseptic techniques.

 Warehouse storage condition should also be reviewed: temperature control should be

satisfactory ;pest control should be effective; and containers should be positioned so that

they do not come into contact with damp ,cold surfaces such as walls and floors.

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Water
 Water is principle of raw material used in pharmaceutical industry. When

reviewing water systems usually as part of a ‘product based audit’, the

auditor must establish quickly an understanding of the system and how it

performs.

 Key facts to know include whether water is used directly manufacture ,and

what’s grades of water used .

 Management and operational issues include who owns the system, its

complexity(one or multiple plants).

 A schematic of the system should be provided.

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MICROBIOLOGICAL RESULTS

 In establishing whether an adequate system of control operates ,data from samples

taken from user points over the past 6 to 12 months should be reviewed noting user

points sampled , the range of results and underlying trend ,whether action and alert

limits are visible and appropriate, and whether trend analysis has been applied to

improve interpretation and reporting of results .

 The time of monitoring should also be noted with reference to when the system

was sanitized.

 Even in the event of zero counts, the microbiological sampling practices and test

procedures should be challenged .

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ESSENTIAL DOCUMENTS
 Validation documents relating to design qualification ,installation

qualification ,operational qualification and performance qualification
(DQ,IQ,OQ AND PQ) should be complete , available and current fir the water
system concerned.

 Only when this has been thoroughly reviewed and approved may any
microbiological considerations be addressed.

 protocol should be prepared and approved.

 final reports should have been completed, reviewed and approved
highlighting areas of non compliance together with justifications and
recommendations for corrective action.

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performance qualification should have been spread over an extended period divided into three

phases.

Phase 1 ; all parameters should have been reviewed and approved at all sample and user points

during every day of a 20 to 30 day period .

Phase 2 ; all user points and worst case locations should have been examined using a reduced

sampling scheme over a 2 to 3 month period …..

Phase3:The final phase should have investigated similar sample points on a rotational basis for
a period of 6-12 months.
microbiological procedure to be reviewed include following:

1.media preparation and fertility testing

2.methods used

• filtration ,plate counted,etc..

3.incubation conditions (temperature/time)
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PACKAGING MATERIALS
Cardboard ,paperboard and pulpboard, unless sealed or treated , can provide a

rich source of contamination, particularly moulds and gram positive bacteria ,

often as resistant spores .

Materials become moist through poor storage ,levels of microbiological

contamination can increase significantly .

Material such as glass, synthetic rubbers, plastics and laminates have minimal

surface microbial counts.

However ,if stored with limited protection in dusty or damp conditions and

packed for transportation in cardboard boxes ,often on damp ,dirty wooden

pallets, they may contain moulds awnwdw .DbualocMtixe.croimal spores…

 

EFFECTIVE VENTILATION
The aerial route of contamination is common and can be significantly reduced by

an effective heating ventilation and air conditioning system.

Humidity and Temperature control is important , since this not only provides a

pleasant working environment ,but also reduces the risk of mould contamination.

CLEANING AND DISINFECTION

Although routine sanitization of surfaces is key to controlling environmental

contamination ,its importance is often over looked . The sanitization programme

and procedure should be reviewed to confirm the frequency and precise method

of cleaning and their scientific basis ….
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The cleaning records should confirm procedural compliance (when , where , and

by whom).

The activity of any disinfectant used should be appropriate for the wide range of

environmental contaminants likely to be present .

The manufacturers instructions should be followed and fresh disinfectant

solutions should be made up before use.

Mops, sponges and cloths can provide an ideal environment for rapid and

extensive growth of water –bone organisms such as pseudomonas species.

Inadequately stored and maintained cleaning equipment can be highly efficient

vehicles for spreading micro-organisms throughout the environment.
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Reference

• Quality assurance of pharmaceuticals, volume -2; second updated
edition, world health organization, chapter:17, page no.:54.

• QA Manual,D.H.Shah; chapter:12, page no.:184-190
• Ruud Lighting, Inc , 2003; wisqa.org
• www.elsar.com accessed on Nov.2011
• Guidelines for quality and/or environmental management system

auditing, 1st Edition, 2002
• www.cityu.edu.hk, Internal Quality Audit Scheme.
• Handbook of microbiological quality control, edited by Rosamand

M.Barid Norman A .Hodges and Stephen P.Denyer.

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UNIT-5
QUALITY ASSURANCE
MAINTENANCE,
CRITICAL SYSTEMS

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Critical systems
1. overview qualification
2. HVAC Qualification
3. Water System qualification

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General principles and Practices

• Guidance to industry issued by the FDA in
January 24 ,2011 .

• Inline with the principles advanced in ICH Q8
, ICH Q9 , ICH Q10 and in ASTM E2500 .

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FDA Guidance :
General principles and practices
• Replaces the guidance issued in 1987
• Quality of the product cannot be assured by

simply inspecting or testing in process and
finished products . It must be built into the
product –process a-prior

• Focusing exclusively on the qualification
effort without understanding the process and
ensuring the process is maintained in a state
of quality.

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Product
Pharmaceutical Technology Commercial

discontinua
Development Transfer manufacturing

nce

FDA Guidance To Industry January 2011
Three stages of process validation
• Process design stage ( process is defined based

on development and scale up)
• Process qualification stage ( design is confirmed

as being capable of reproducible production)
• Continued verification and improvement

(continuously gaining assurance the process
remains in a state of control )

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The Design Stage
• Understanding the science
• Understanding the risk
• Building quality into the process
• Establishing control strategy
• Proper design of the facility and utility serving

the process

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Implementation and process
qualification
• Qualification of utilities and equipment

(“….design of the facility and qualification
of the equipment and the utilities)
• performance qualification and PQ protocol

(..PQ combines the actual facility , utilities ,
equipment , and the trained personnel with the
commercial manufacturing process , control
procedures , and components to produce
commercial batches .)
Protocol execution and report

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Continued process verification
• Monitoring appropriate parameters to ensure

process in a state of control , including the
performance of the utilities (e.g
Environmental monitoring for HAVC and
water system verification )

• Use CAPA , PAT and change control as well as
data collected in monitoring to continually
improve the process .

• Proper maintenance of the facility , utilities ,
and process equipment

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Science and Risk Based compliance :
An Overview

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Risk to What ?
 In GMP Compliance

-Risk to product quality
-Risk to the patients well being

 In Manufacturing
– Risk to personnel
-Risk to the environment

 In Business
-Financial risk to the company

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Focus for this workshop

 Risk is always present
 You need to know what it is and how it

manifests itself a priori
 We will focus on risk to product quality during

manufacturing and the patients wellbeing
 Thus we will focus on GMP issues

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FDA Initiative August 2002

Pharmaceutical CGMP for the 21st century : A
Risk –based approach
A science and risk –based approach to product
quality regulation incorporating an integrated
quality system approach

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FDA Guidance August 2002

• Early adoption of new technology .
• Adoption of modern quality management

techniques and implementation of the quality
system approach .

• Focus on understanding the science &
technology associated with what you are
making .

• Priority to mitigating the highest risk elements
of the manufacturing operation.

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FDA Guidance August 2002
• Take home :

– You must understand what you are doing .
-You must focus on critical areas (highest

risk to product ) of
your operation

– You should utilize automation and data
collection to reduce

risk associated with the operation and
allow for

continuous improvement .
-You must build the quality into your

operation. www.DuloMix.com

 

ICH Q8 –Pharmaceutical Development
• Deals with product development and its

manufacturing process .
• Defines the need for good Design Of

Experiments(DOE).
• Use data from product development studies to

manage the risk associated with the product (Quality
cannot be tested in the product but rather built into it
).

• Managing quality through out the product life cycle
from initial development through discontinuation .

• Defines continuous process verification as an
alternative to process validation .

• Defines the knowledge space , the design space and
the normal or cwownw.DturlooMilx.csopm ace.

 

ICH Q8 –Pharmaceutical Development
• Benefits :

-Manufacturing knowledge
-Manufacturing improvement within DS are not

changes
– Operational robustness
– Reduce Post –approval submissions
-Real time release and reduced product testing
-Continuous process / product improvement

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ICH Q8 (R1)-Pharmaceutical Devoplopment
• Introduces the concept of quality by design

(QbD)
• Emphasize use of design of experiments and

prior knowledge to define the design space.
• Identifies critical quality attributes (CQA) of the

product and critical processing parameters
(CPP) That would affect it .

• Defining a control strategy based on
CQA =(CPP)

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ICH Q8 (R1)
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 .

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ICH Q8 (R1)
Critical quality Attribute (CQA):
It is a physical , chemical , biological or
microbiological property or characteristic that
should be within appropriate limit, range , or
distribution to ensure the desired product
quality . CQAs are generally associated with the
drug substance , excipient , intermediates , and
drug products .

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ICH Q8 (R1)
Critical Processing parameter (CPP):
A process parameter whose variability has an
impact on a critical quality attribute (CQA) and
there fore should be monitored , “alarmed “ ,
and controlled to ensure the process produces
the desired quality.

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ICH Q9
• Outlines quality risk management principles

for product lifecycle .
• Phases of QRM include risk assessment , risk

control , and risk review .
• Defines risk and how to measure it.
• Outlines the principle of focusing on the

critical aspects of the drug manufacturing
based on the level of risk .

• Use of change management to reduce risk.

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What is Risk ?
The combination of the probability of
occurrence of harm and the severity of that
harm *.
Risk is always present :
• Risk to the patient / public (Drug side Effects

, Adulterated Drugs)
• Risk to the product (Contamination )
• Risk to the personnel
• Risk to the neighbors and environment
• Risk to the company (regulatory recalls )

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Defining Level of Risk
Function of :
-severity
-Frequency
-Detectability
• These three factors determine the numerical

Risk Priority Number (RPN)
• Qualitative risk (low , medium ,high

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ASTM E-2500 Consensus Standard
published in august 2007
What is it ?
-A consensus standard developed with input
from industry and FDA
-it is called “standard Guide for Specification ,
Design , and verification of pharmaceutical and
biopharmaceutical manufacturing systems and
Equipment “
-Applies to elements of manufacturing systems
of biopharmaceutical products including facility
equipment , utilites , control , etc .

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ASTM standard E2500
Objective
– Insure that manufacturing systems are fit for

the intended use and while reducing work
duplication and cost of the required
validation .

– Accomplish through building quality into the
design , specification and construction of
such systems .

– Verify and certify suitability.

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ASTM Standard E2500
Tools :
– Use of User Requirements Specification (URS).
– Use of Good Engineering Practice (GEP).
– Use Scientific and Technical Knowledge and

enlist Subject Matter Experts (SME).
– Relating Critical Quality Attributes (CQA) to

Critical Processing parameters (CPP).

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Overall Approach to Verify Manufacturing
Systems
• Define user requirements
• Conduct risk –and science –based analysis to

define critical aspects of the operation
• Ensure that quality was designed into the

operation a priori
• Ensure that quality was designed into the

operation a priori
• Ensure that Good Engineering Practices were

used in the design , specification and
construction of the operation .

• Utilize subject matter experts (SME) to plan and
define verification strategy.

• SME to executweww.tDhuloeMix.tcoemsts and review the results.

 

Overall Approach to Verify Manufacturing
Systems (cont.)
• SME to define acceptance criteria and selection

of appropriate test methods .
• SME to review and accept the verification testing

and certify the systems is “Fit For Intended Use”
• Utilize vendor documents and testing

information to support the verification effort .
– confirm acceptable vendor quality system

and technical
capability

• Avoid duplication of effort / testing by using GEP
commissioning data to support the verification .

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The Process
Good Engineering Practices

Product
Knowledge

A
Process Re Sp cc

knowledge qu eci ept
Ver

ire fic anc
ific e & Opera

Regulatory me ati ati tion
Rel

requirements nt on on &Conti
eas nuous

s e Impro
Company vemen

Quality Reg . t

Risk Management
Design Review

www.DuloMix.com Change Management

 

Qualify / Validate Verified System

• Provide documented evidence that the process
will consistently produce product which meets
predetermined characteristics and quality
attributes . Ensure system remains in a
validated state .

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Heating Ventilation Air Conditioning (HVAC)
System
 HVAC or “aitch-vak” systems are mechanical

arrangement that treat outside air to produced
cleaned (from dust and microbes) and
conditioned air (temp. & Humidity )for use in
controlled and critical areas within the
pharmaceutical manufacturing space .

 The systems normally consist of filtration ,
heating , cooling , dehumidification , and
humidification steps .

 It is the technology of indoor environmental
control and /or comfort.

 The most important utility in the manufacture of
drug products .

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HVAC
 Controls the environmental conditions in the

manufacturing space , which may affect
product quality , safety , and Efficacy
(temperature and Humidity).

 Control the cleanliness of the manufacturing
space (room classification –particle number
both viable and non viable ).

 Prevent cross contamination (relative
pressurization between spaces).

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Regulatory Imperatives
• Control Temperature , Humidity , pressure , Dust

(particulate ), and Microbial load (21 CFR 211.46)
• The need to filter the air coming into

manufacturing space (21 CFR 211. 46)
• Protect product from extraneous contamination

by microorganisms or their byproducts . Most
intermediates and materials used in the industry
are excellent promoters of microbial growth.

• The need to ensure that the product is not cross
contaminated by other products being
processed in adjacent space .

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Process Validation and HVAC Systems
An HVAC system can be viewed as a process
using outside air as a raw material and
producing conditioned air . The conditioned air
comes into contact with the drug product and
hence has a direct impact on the drug product.

Additionally , HVAC is a system that is a utility
and part of the facility in which production
occurs and as such must be qualified and
maintained as part of stage 2 of the proposed
FDA guidance on process validation.

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HVAC System consists of
1. AIR Handling Unit (AHU)

-Air filtration and conditioning .
-Pump and meter the air into the distribution

system.
2. Air Distribution System –Duct Work

– Distribute the air to the various areas .
– Temperature , humidity and smoke detection

controls
– Final filtration and heating if necessary
-Returning or exhausting the air .

3. Use Areas
-Manufactwuwrw.iDnulogMix.scopm aces & support spaces

 

Typical HVAC System for a Biotech Facility
(schematic ) AHU

METE Humi
R differ Coolin Pre Outside

g coil heat Filte air
rs

Reheat
coil

Therm
Fermentatio

Buffer Prep al
Return n suite class

gfgt66r Poc-o- HEPA
corridor 100k Clean

corridor

www.DuloMix.cHomOO
D

 

Schematic of Biotech Facility
(Air flow pattern for cleanliness and contamination control )

Air flow

Clean Wash Soiled
storag storage
e

Return
corridor

Buffer & Fermentati
Dego Isolatio

Media prep on
wn n

Purificatio
Clean

Gown n
corridor

Storage Packag Finishing
& ing
Staging

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Schematic of Biotech Facility
(Air flow pattern for cleanliness and contamination control )

Typical Air flow / Relative
Layout pressure

Class FILL & Cold
Packaging 100 Finish Room

Purification
& Shipping

Class 10,000 Gown / Class
RH 50% +/- Degown 100,000
10%

Gown &
degown Corrid Class

100,000
or

Buffer & Air lock Isolation
media prep Class 100,000

Wash Fermentati
room on class

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100,000

 

Design stage
• User requirements :

-Defines , temperature , humidify , cleanliness requirements
for the product as

defined by the design organization and others .
• Risk assessment :

-Identifies issues associated with maintaining the user
requirements such as

required levels of cleanliness and air flow parameters .
• Functional specifications :

-Identify how conditions can be reached using the
appropriate technology and

technical knowledge .
• Control strategy :

-how will the conditions .

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What to Qualify ?
• The mechanical system

– its installation and operation
-The controls

• The air distribution system
-Installation
-Adequacy
-safety issues

• The conditions prevailing in the room
-Temperature and humidify
-Air changes

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Documents you need
• User requirements

• Engineering specifications

• Contractors submittals

• Engineering drawings

-Mechanical drawings

-Architectural layout drawings

• Test and Balance Report

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Qualification of the HVAC system
• First step is to confirm that the system has

been installed per the design and is capable of
operating within the required parameters .

• Second is to verify that the system is capable
of providing the needed conditions within the
space and maintain them.

• Finally a report summarizing the effort and
reaching the condition that the system is
acceptable for the intended use has to be
developed.

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Performance Qualification
Particulate count
USP 23 and FDA guidance on sterile Drug products
, 2004

Room classification Particles /ft3* cfu/ft3
100(M3.5; ISO 5) 100 <0.1
10,000(M5.5; ISO 7) 10,000 <0.5
100,000 (M6.5; ISO 8) 100,000 <2.5

*Less than the indicated number of particles of
diameter < 0.5 micron/ft3

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Air changes

Based on : ISO Standard 14644 and IFEST-RP-
CC012.1

Room classification Air changes per
hour

– 100(M3.5) -500-700

– 10,000(M5.5) – 60-90

– 100,000(M6.5 ) – 12-40

*Relative pressurization standard is 0.05 of water
relative to adjacent les clean areas .

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Temperature
Based on USP ; 8th supplement , dated May 15 ,1998

Room (condition )description
Temperature Range

Freezer 25⁰ C to
– 10⁰ C
Cold 2⁰ C

to 8⁰ C
Cool 8 ⁰ C

to 15⁰ C
Controlled room temperature 20⁰ C to 25⁰

C
Warm 30⁰ C

to 40⁰ C
Excessive Heat over 40⁰ C

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Instruments use
• Data Loggers for temperature and humidity

monitoring .
• Particle counters for particulate monitoring
• Smoke sticks or magnahelic gauges for airflow/

relative pressurization.
• Active microbial sampling techniques
• Possibly use data from BAS and its instruments .

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Why Monitor ?
 It is the law (21 CFR 211.42 -10 )
Identify and correct potential environment control

equipment problems
Complete the validation effort by collecting DATA

which takes into account the seasonal variations
Validate cleaning of environment / manufacturing

area
 Establish alert and action levels ( by establish

baseline conditions and identifying hot spots )
 Insure that the manufacturing space is always in a

validate state and GMP compliant
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Why Monitor ?
Insure conditions within the manufacturing

space remain within the appropriate ranges
required by the product

a. No biological contamination for sterile space
b. No cross contaminating particles from other

manufacturing operations or
due to re-circulation of air .

c. Appropriate temperature and humidify conditions .

Use information collected from the
monitoring program / system to control the
operation of the HVAC system

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Where to Monitor ?
• All production areas ( including corridors and

airlocks )
• Storage areas for product , intermediates , and

raw materials
(especially if affected by environmental

conditions ,
especially in critical areas near doors , ceilings

, etc .)
• Clean rooms and laminar Flow Hoods
• Critical surfaces
• Environmental controlled rooms / chambers
• Freezers, Refrigerators , Incubators

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What you should Monitor ?
• Temperature
• Humidity
• Pressure
• Particulate
• Microbial / Biological Load

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How to Monitor ?
• Temperature probes , thermocouples , chart

recorders
• Humidity probes , chart records
• Temperature and humidity mapping devices and

data loggers
• Magnahelic gauges
• Building Automation systems (BAS) when several

HVAC systems are used (T, RH , pressure deferential
)

• Particle counters
• Active microbial air sampling
• Settling plates *

– use appropriate media for organisms to be
detected ,

e.g .TSA for bacteria , SDA for mold and yeast
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Validation of Pharmaceutical
Water Systems

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Pharmaceutical Water System
• Water in the pharmaceutical industry

must be treated prior to use . Treating
the water ensures that bit would have
consistent quality and be free of
contaminations that may negatively
impact product quality , safety and / or
efficacy.

• Water systems normally consist of
filtration , deionization , microbial
removal / reduction , conditioning of
water , and distribution to use points .

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Water in the pharmaceutical industry
• One of the most important if not the

most important utility in the
manufacturing of the drug products .

• Water systems control the quality of the
water , which may affect product quality
, safety , and efficacy ( chemical content
, solids , microbial content , etc ).

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Where is water used ?

• In manufacture .

• In formulation .

• In cleaning of equipment .

• In cleaning of the facility.

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Problems with untreated water
• Chemical content

• Dissolved Gases and odour

• Microbial and endotoxin content

• Inconsistent quality

• Seasonal variation

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Regulatory Imperatives
• The introduction of undesirable

chemicals or other contaminants
through the use of water in the
manufacture of drugs would result in
adulterated product .

• Water should be supplied in a fashion
that would not contribute to
contamination of drug (ICH Q7a)

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Regulatory Imperatives
• Potable water (this should apply to any

water supply) shall be supplied under
continuous positive pressure in a
plumbing system free of defects that
could contribute contamination to any
drug product (21 CFR 211.48(a))

• Where water used in the process is
treated by the manufacture to achieve a
defined quality , the treatment process
should be validated and monitored with
appropriate action limits (ICH Q7 a)

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Water systems consist of

1 . Water Conditioning
– Water filtration and removal of inorganic .
– Microbial content

2 . Water Treatment
-Deionization
-Distillation
-Microbial control .

3. Water distribution
– Storage of treated water
– Pump and meter to use points
– Condition water at use point
– Microbial control
– Recycle the wwwawt.eDurloMix.com

 

Types of Water
• Potable Water
• Deionized Water
• USP purified water ( DI – RO)
• Water for injection (WFI)

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Water Properties
• Water properties :

-Organic chemical content (TOC)
-Inorganic chemical content ( conductivity )
– Microbial and endotoxin content
– Dissolved gases

• Water system variables
-Flow rate
-Pressure

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Schematic diagram for purified water
production in Biotech

Facility ( possible example )
To WFI Production /

Return
Distribution

Distribution

Purified For distribution in
Ozone water

RO / Final facility
inject storage

Filter (0.45& UV Ozone
0.2 µ) destruct

UV conditioning
Sterilizer

Pre-filter
UV Sterilizer Municipal Water

Ion
exchange
Beds

Resin trap www.DuloMix.com Meter
Carbon
Filter

 

Water system Design Issues
• Sanitary piping , valves and fittings requirements (

design)

• Materials of construction and passivation
requirements ( design –ss vs PVDF , PVC )

• Dead legs and loop design consideration ( design)

• Regular cleaning and sanitization (Maintenance –design )

• Hot vs cold system (Energy consideration , material of construction –
design )

• Purification methods to be used ( design ; DI-RO ,DI only ,etc )

• Control of microbes and endotoxin ( include and ozone
generators , etc )

• Operating procedure of the system ( design and initial testing )
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What to Qualify ?
 The treatment system

-its installation and operation
-the controls

 The water distribution system
-Installation and operation of use points
-Adequacy
-cleaning and sanitization issues

 Water quality at the use points
-flow rate
-Ph
-chemical content
-Microbial wawnwd.D uelonMidx.cootmoxin content

 

Documents you need
• User requirements
• Engineering specifications
• O&M Manuals
• Engineering drawings and

documentation
-System Description
-Mechanical drawings showing mechanical

components (M series )
-plumping drawings showing sampling points

(P series )
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-Architectural layout drawings (A series )

 

Sampling Requirements
• Sample daily after each step in the

process
• Continue sampling for a minimum of 2

to 4 weeks
• Samples at use points should reflect how

the use points will be used ( e.g . If hose
to be used sample with hose in place )

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Instruments to use
• Mass flow meters .
• Stop watches and graduated containers .
• Pressure meters .
• Temperature

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Example Data Sheet Attachment
Stage : 2 Measured conductively not to be greater than 2.1
µs/cm .

Use point Location : Use
point ID :
TItiemme : AM/PMR e s u l t
DTeamtpee r:ature of sample @25º C YES
-/+ 1 C⁰ ? NO
Conductivity of sample

Acceptance Criteria Met YES
NO

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Where to Monitor ?
• Incoming feed water
• Water quality at all use points .
• Critical processing parameters (CPP) within

the system ( e.g. Temperature of the still , UV
intensity , etc .).

• Storage tanks ( e.g . Temperature , Microbial
content , etc .)

• Filter integrity .
• Water quality at critical processing /

purification points within the systems .
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What you should Monitor ?
• Chemical content ( TOC , Ph , Conductivity , etc .)
• Microbial / biological load .
• Endotoxin content .
• Flow .
• Dissolved gases ( Chlorine –for RO protection ).
• Solids , colour , odour .
• CPP ( temp , pressure , Ozone concentration, etc .)
• Other ( e.g , failures , deviations , maintenance issues

, OOS ,etc .)
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How to Monitor ?
• TOC analyzers ( on– line and in the

laboratory )
• Conductivity meters ( Laboratory and on –line

)
• PH Meters and mass flow meters
• Turbidity meters
• Temperature sensors and indicators
• In-line pressure and flow meters
• Sampling for microbial (plating ) and

endotoxin (LAL)content
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 WATER FOR INJECTION

 ❏ A clear and colourless liquid and odorless

 ❏ Water for injection is pyrogen free .it contain no added substance

 ❏ Water for injection is obtained from potable or purified water by
distillation in

 an apparatus

 ❏ The distillate is collected and stored in conditions designed to prevent
growth

 of microorganisms and to avoid any other contaminations

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 MANUFACTURING OF WATER FOR INJECTION

 ❏ USP specified distillation and reverse and osmosis as methods to prepare

 water for injection

 ❏ Only these two methods is it possible to separate adequately various
liquids ,

 gas and solid containing substances from water

 Preparation methods are very similar to a particular point however water
for injection preparation process in pharmaceutical must include distillation
or double pass reverse osmosis techniques

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 FACTORS INFLUENCE PRODUCTION OF WFI

 The quality of feed of water for distillation will effect the quality of distillate

 The size of the eveporator

 The baffles (condensing surface ) determine the effectiveness of refluxing

 Volatile impurities

 Contamination of vapor and distillate from the metal part of the still can
occur

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 FACTORS INFLUENCE PRODUCTION OF WFI

 The quality of feed of water for distillation will effect the quality of distillate

 The size of the eveporator

 The baffles (condensing surface ) determine the effectiveness of refluxing

 Volatile impurities

 Contamination of vapor and distillate from the metal part of the still can
occur

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 Dechlorination

 This refers to the removal of chlorine from the water

 There are several ways to dechlorination

 This include injection of a reducing agent like sodium metabisulfite and
exposure

 to a high dosage of UV rays can dechlorinate .

 However the most common one is filtration through activated carbon
media

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 Water for injection preparation process in pharmaceutical is dechlorinated
by

 carbon .

 Carbon dechlorinates by chemically reacting with the free chlorine in
water to form

 hydrochloric acid carbon monoxide or dioxide

 High doses of UV light rays are widely used in water purification system for
both

 disinfection and TOC reduction

 Another use of UV is dechlorination though it is relatively new process

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 Ion removal

 There are basically three types of ion reduction processes

 ❖ Membrane processes

 ❖ Ion exchange processes

 ❖ Distillation processes

 Membranes are used in water purification systems to remove ions ,

 particulate,organic compounds and living organisms

 Membranes are different from one another in terms of pore size , molecular

 weight and even on ion rejection .

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 Ion removal membranes include membranes such as reverse osmosis

 membranes and nanofiltration membranes

 These are used in ion reduction processes

 The ion exchange system provide additional ion reduction processes
making the

 water much lower in conductivity than required and it also provides a back
up for

 membrane processes

 Distillation can also be used to remove ion however it is very expensive

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 Bacteria control is usally applied during processing storage and even
distribution

 UV light is an exellent non chemical method of disinfecting water for
injection

 Thermal sanitization involves the used since it is a very strong oxidizing agent
it

 can there fore oxidize bacteria

 Chemical can also ne used to kill bacteria as a means of bacterial control

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 Removal of specifc impurites

 There are various different sources of water for injection used during
preparation

 process in pharmaceuticals

 Every source is different and therefore the possibilities of specific
contaminant

 problem are possible

 These contaminants include iron , maganeese ,hydrogen , sulfide ,hardness
ions ,

 particulate matter , and high conductivity

 Filtration can be used to remove any heavy loads .

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ETP

ETP (Effluent Treatment Plant) is a process design for
the industrial waste water for its reuse or safe disposal to the
environment

 Influent :Untreated industrial waste water

 Effluent :Treated industrial waste water

 Sludge :Solid part separated from waste water by ETP

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Need of etp

 To clean industry effluent and recycle it for further use

 To reduce the usage of fresh / potable water in industries

 To cut expenditure on water procurement

 To meet the standard for emission or discharge of environmental pollutants
from various industries set by the government and avoid hefty penalties

 To safeguard environment against pollution and contribute in suitable
development

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Design of etp

The design and size of the ETP depends
upon :

 Quantity and quality of the industries discharge effluent

 Land availability

 Monetary consideration for construction , operation
and maintenance

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Area dimension depends on:
Quality of waste water to be treated

 Flow rate

 Type of biological treatment to be used

In case of less available land
CETP(Common Effluent Treatment Plant) is preferred

over ETP

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TREATMENT LEVELS & MECHANISMS
OF ETP

Treatment levels
 Preliminary

 Primary

 Secondary

 Tertiary

Treatment mechanisms
 Physical

 Chemical

 biological

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Mjor treatment units in etp

PRELIMINARY TREATMENT

 Screens

 Scrapers

 Grit chamber

 Skimming tanks

 Aeration

PRIMARY TREATMENT

 sedimentation

 Clarifloculator

 Equalization tank

 Neutralization tank

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SECONDARY TREATMENT

 Activated sludge process

 Trickling filter

 Aerated lagoons

 Multiple evaporated

TERTIARY TREATMENT

 Sand/membrane filter

 Activated carbon filter

 Disinfection

 Ion exchange

 Nutrient removal

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Preliminary treatment level

 Physical separation of big sized impurities like cloth
,plastics ,wood logs ,papers and etc…..,

Common physical unit operations at preliminary level
are

 Screening :a screen with openings of uniform size is used
to remove large solids such a plastics ,cloth etc.

 Sedimentation : physical water treatment process using
gravity to remove suspended solids from water

 Clarification : used for separation of solids from solids

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PRIMARY TREATMENT LEVEL

 Removal of floating and materials such as suspended solids and organic
matter

 Methods : both the physical and chemical methods are used in this
treatment level

 Chemical unit processes

 Chemical unit processes are always used with physical operations
and may also be used with biological treatment processes

 Chemical processes use the addition of chemicals to the waste
water to bring about changes in its quality

 Example : PH control , coagulation , chemical precipitation and
oxidation

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Secondary treatment

 Secondary treatment is a biological treatment of effluent which is
typically performed by indigenous, water borne ,micro organism
managed habitat

 Secondary treatment removes dissolved and suspended organic
matter by consuming food and covert into new cell mass ,energy
and co2

 The most common micro organisms are bacteria(areobic ,
anaerobic) protozoa and rotifers ;common algae or fungi

 after secondary treatment almost 70-80%of BOD and 80-90%
dissolved solid are removed from effluent.

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Tertiary treatment

 Tertiary treatment is the final treatment meant for polishing the effluent and
removal of pollutant not removed in primary and secondary treatment.

 These pollutant may include soluble in organic compounds such as
phosphorous or nitrogen which is support to algae growth in support
receving waters.

 Also removes organic material contributing BOD ,COD color, taste, odour ,
bacteria ,viruses , colloidal solids with subsequent reuse of the water.

 prefered when treated water is ne to be reuse or discharge is into a highly
sensitive or fragile ecosystem(low flow rivers ,coral reefs.ss

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 Tertiary treatment additional cost to the treatment process but quality
effluent which can be refuse further for commercial and industrial
application.

 Treated water can be refuse for the irrigation of golf course green way or
park, industrial process etc.

 if it is sufficiently clean it can also be used for ground water recharge .

 Treated water is sometimes disinfected chemically or physically depending
upon the discharging location.

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Process description

 Sludge treatment : the under flow from clarifier and the secondary clarifier
having the sludge consistency of around 1-1.5% is pumped into centrifuge
for dewatering . the dewater sludge is disposed off suitably while the
concentrate is taken back to the equalization tank.

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Process description

 BIOLOGICAL TREATMENT: the neutralized effluent will this the treated
through the bio tower with aeration tank and clarifier the liquid over flow
from the lamella clarifier is taken to the chlorination tank .the sludge
underflow from the lamella clarifier is partially returned to the inlet of the
aeration tank for maintaining the desired level .the excess sludge is treated
through a basket type centrifuge

 FILTRATION: chlorinated water will be passed through a multigrade sand
filter further reduction of suspended solids to less then 20ppm and then
passed through a activated carbon filter for the polishing of BOD ,COD
values.

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Process description

Equalization :the waste from main plant is first collected in the equalization
tank through screening the equalization tank is designed for the hydraulic
retention time is around 6 hours and with avoided air grids connected to a
air blowers for maintaining the solid is suspension

Effluent solid mixer flocculation tank& clarifier: the equalized waste is then
pumped of f into the flash mixer compartment of flash the flocculation
compartment is aid the process of setting. The over flow of the
flocculation compartment is taken into the clarifier for further treatment
while the under flow is taken for sludge compartment.,

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REFERENCE:

 Professional Development Committee, the Institute of Cost Accountants of
India. Exposure Draft: Guidance Note on Internal Audit of Pharmaceutical
Industry; 2013. Available from:
http://icmai.in/upload/Institute/Comments_Invited/ED-IA-Pharma.pdf.

 Vedanabhlata S, Gupta VN. A review on audits and compliance
management. Asian J Pharm Clin Res 2013;6:43-5.

 Sharma S, Kohli S, Potdar M. Current good manufacturing practices: Audit.

 Active Pharmaceutical Ingredients Committee (APIC). Auditing guide; 2016.
Available from:
http://apic.cefic.org/pub/Auditing/APIC_CEFIC_AuditingGuideAugust2016.pdf.
[Last accessed 19 Mar 2018] Place Unknown: Word Press; 2008. Available :
https://drpotdar.wordpress.com/2008/04/30/audit/.

 BSI standards publication: European committee for standardization. Guidelines
for auditing management systems; 2011. Available from: http://qic-eg.com/wp-
content/uploads/2015/08/BS-EN-ISO-19011-2011.pdf.

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