Seminar On

Quality Assurance and

its Importance

Presented By: Dabhi Ajay S.
M. Pharm
L. M. C. P. Ahmedabad

Dept. of Pharmaceutics and Pharmaceutical Technology





List of Contents:

Quality
- Reasons and characteristic of quality
- 5Ms of quality and factors influencing quality

Quality Assurance
- Components and Elements of QA
- QA systems
- Fundamental features and benefits of QA system
- TQM
- QA in pharmaceutical manufacturing
- Process deviations and failures
- Change controls
- QA in R&D
- Concept of SQC
- Sampling and sampling plans


Quality: represents both function and process.

Function: there are operational groups whose major
responsibilities are to assure quality creation and maintenance
(QA) and to monitor the specifications established to control
activities (QC)


Process: set of activities and operations which determine
whether a pharmaceutical product has quality.


Quality is spelled in terms of specifications which are in
language easy to understand and have methods for measuring,
determining or assessing and also for verification
Quality??



Reasons for quality consciousness in society:

Increasing consumer awareness : Expectations are growing in
consumers

Liberalization of economy : Competition is growing

Globalization of market (shrinking world)

International standards (ISO 9000)

Quality tag




Characteristic of quality:

IDENTITY
PURITY
POTENCY
STRENGTH
UNIFORMITY
SAFETY
EFFICACY
STABILITY
A drug product should comply with such requirements within
the permitted tolerance limit and that up to designated or
expected shelf life period of the drug in question. It should also
comply with legal and professional standards.
Quality is affected during the process of manufacturing on
handling and therefore required to conform with specified
quality form the beginning till they are consumed

Quality cannot be merely justified by the end product
testing and nor by manufacturing and quality control
assessment

Quality is the end product of a thoroughly understood,
properly designed, implemented and controlled
manufacturing processes.

Customary sample size alone cannot verify that the various
factors in the system intended to assure quality within and
between batches of product are functioning as they were
designed to function.
The 5Ms of Quality
Man

Material

Machinery

Manuals/Methodology ( SOP)

Motivation

Factors influencing quality:
Pre analytical Analytical Post analytical
Right specimen Laboratory
professionals
Recording
Right collection Reagents Interpretation
Right labeling Equipment Turnaround time
Right quantity Selection of test -
SOP
Report to right user
Right transport Records
Right storage Bio-Safety
Quality Assurance:

Assurance: Guarantee or promise given to inspire confidence
Quality Assurance is sum total of the organized arrangements
made with the objectives of ensuring that product will be of
quality required by their intended use.
QA is the activity of providing to all, concerned the evidence
needed to establish confidence that quality function is being
performed adequately.


Aim of QA: To ensure that each batch of a medicinal product
complies with its specifications and is fit for its intended use
in terms of safety, efficacy, and acceptability.
Quality assurance
Definition

It is the sum total of all lab activities that are undertaken to
ensure generation of accurate and reliable results.

What is the Objective?
To ensure credibility of the lab and generate confidence in
lab results

Components of Quality assurance
Internal Quality control: IQC

Nature: Concurrent
performed by: lab staff
Objective: Reliable results on a daily basis

External quality assessment: EQA
Nature: Retrospective to evaluate IQC
Performed by: Independent agency
Objective: Ensure inter laboratory comparability

Elements of QA:
Quality System Planning: A management responsibility
include strong management, facilities, equipments,
personnel, control etc.

Product development

Vendor control

Validation: Validation of process, Analytical method,
facilities, equipments, personnel, raw materials, product,
environment etc.

Documentation

Quality Audit: Periodic reviews and evaluation of
manufacture and quality control.

Quality Assurance System:

A quality assurance system is constructed by merging a
series of actions. These actions collectively ensure
product quality. The QA system must:

1) establish specific activities before production

2) control factors during production

3) evaluate results following production


Quality systems

Objectives
To prevent risks
To detect deviations
To correct errors
To improve efficiency
To reduce costs

How :
By establishing a quality manual defining
Organizational structure Staff
Responsibilities
Procedures and processes
Resources
Documentation

Fundamental features of quality system:

a quality policy which defines the purpose and objectives
of the pharmaceutical manufacturing facility, it also outlines
the ways in which these objectives will be achieved.

resources which include materials, equipments and
personnel

documentations which includes procedures and standards

an audit process to provide assurance that procedures
have been compiled with; this process can also be used to
improve the quality system.

In pharmaceutical production process, with assurance is
involved in the following activities:

Purchasing Dispatching
Warehousing Operational protocols
Manufacturing Training
Quality control Validation
Packaging

The system for each the listed activities must provide:

assurance that materials, product labeling and storage
have conformed to an established programme of operations.

Monitoring to ensure that the system is completed with or
updated.

Benefits of QA system:

Higher standards of production
Compliance with regulatory requirements
Reduce waste
Less risk of product defects

Quality System:

Ensure quality
Provide evidence
Generate confidence

Total Quality Management:

Quality function is part of a team composed of research,
production Marketing/sales, and customer service.
It requires total commitment of senior-level management and
supervision of all departments, operators, suppliers and
customers.
Raw materials must be characterized and then purchased
Facilities must be designed, constructed and controlled
Equipment must be selected
Personnel must be trained
Distribution department is responsible for controlling the
shipping and handling of products, using inventory control system
based on FIFO.
Marketing department should be sensitive to customer needs
and be responsive to complaints.

QA in Pharmaceutical Manufacturing:
GMPs

- QA is ubiquitous in production
- Quality unit is responsible for ensuring that controls are
implemented during manufacturing operations which assures
drug product quality.
- The quality model that these regulations establish consists of a
sequence of events of:
Qualification
Validation
Specifications
Monitoring
End of process testing
Written instructions
Documentation and monitoring review
Decision (to approve or reject)
Qualification: includes essentially activities performed to
prove that a system does what it purpots to do
1. Design qualification
2. Installation qualification
3. Operational qualification
4. Performance qualification

- should establish and provide documentary evidence that the
premises, the supporting utilities, the equipment and the
processes will consistently produce a product meeting its pre-
determined specifications and quality attributes.

- PQ should include, but not be limited to the following:
tests, using production materials, qualified substitutes or
simulated product, that have been developed from knowledge
of the process and the facilities, systems or equipment;
tests to include a condition or set of conditions
encompassing upper and lower operating limits.
New Facility, Utility
and/or Equipment
Qualification or
Requalification
Maintain in the
qualified state
Facility, Utility and/or
Equipment retired from
Change
controls
Extensive
Monitoring
Preventive
Maintenance
Calibration
programme
Construction and installation
QA/safety approval to use
Close out qualification package
Qualification life cycle:
Specifications:
- Results of the validation and qualification exercises are specifications
- They should be derived form previous acceptable process average
process variability estimates where possible
- It separates acceptability and unacceptability
Monitoring:
- Whether specifications are being met is the process of monitoring
Documentation:
-Procedure, master production and control records
- Data recording documentation
- Review of records, retention of records and follow-up of problems
arising after production

Technology Transfer:
-Technology transfer includes quality involvement
- So QA oversights, review and approves (rejects) the transfer
Facilities and Equipments:
QA role can be review of:

Layouts and floor plans with regard to material, personnel, waste
flow, and the potential for cross contamination

Materials of construction and design of all areas

Suitability of utilities, services, and the systems (adherence to
GMPs and generally acceptable practices) for water, HVAC, gases
etc.

Suitability of equipments (design, capacity, materials of
construction, compatibility with process materials and conditions,
ability to be cleaned and/or sterilized)

Qualification and validation of facilities, equipments, utilities etc.
Materials:


-To test them to ensure that they have necessary quality attributes

- To segregate acceptable from unaccepted

-To maintain the quality of materials during their presence in the
plant and in their processing


Documentation control:
-Documents are specific for the process, product, equipment etc.

-QA issues, retrieves, reviews, and stores the documents

-SOPs and batch records must be authorized by a sign off
procedure that includes group responsible for the procedure, all
the groups directly impacted by the procedure, and QA.

-QA may be responsible for assigning batch numbers and
expiration dates as a part of issuance of batch record.

-For SOPs, calibration logs, and the like standard distribution
lists are necessary to ensure that all who need to use procedures
receive updates at the same time with instructions as to the
effective date of the new document as to the destruction or
return of the old.


-review of documents after the completion of the process and
testing. The batch record should be reviewed for completeness,
proper sequencing, appropriate dates, acceptable yields,
meeting of all in-process specifications, and explained and
unexplained deviations.


-Final test results must be reviewed to ascertain whether all the
specifications are met. If any results are not within
specifications, the SOP to handle this must be implemented.


- After all these QA decides the releasibility of the final product.

Equipments Facilities Process Containers,
Closures,
Labeling,
Raw
materials
Staff Product
Purchase
order
Diagrams
and
drawings
Batch
records
Purchase
orders
CVs Inventories

Diagram
manuals
Floor plans Reconciliati
ons
Monitoring
Receiving
records
Inventories
Job
description
s
Training
Sampling,
testing
Release
documents
Use logs Qualificatio
ns and
validations
In process
tests
Sampling,
testing
Regulatory Master
specificarti
on sheet

Calibration
logs
Logs Results Release
Documents
Procedural Testing
methods
and
procedures

Maintenanc
e logs
SOPs SOPs SOPs Technical COA

Cleaning
logs
Monitoring
records
Control
charts
Reconciliati
ons and
accountabil
ity
Distribution
In process Items control:
Quality Assurance before start up
Environmental and microbiological control and sanitation
Manufacturing working formula procedures
Raw materials
Manufacturing equipments

Quality assurance at start up
Raw material processing
Compounding
Packing materials control
Label controls

Finished product control

Quality Events:

-Things didnt go as planned

- Events affecting quality should be investigated in a timely
manner
under the auspices of QA.

-Technical service dept. is responsible for performing the studies
but QA must access the impact upon the affected batches and
other
potentially affected batches

- Annual review of products
Process Validation Deviations and Failures:
-It is foolhardy to begin process validation without an assurance
that the process is under control
- Recognize validation failure
- well documented investigations for less clear deviations

The following steps should be performed as soon as possible
after the problem is discovered:
Document clearly what occurred and when it occurred.

Interview personnel as soon as possible (before memories
can get clouded) and document the interview.

Collect any additional data (as is relevant).

Describe a sequence of events of when and what happened,
review batch records, and corroborate events through data and
records.

Process Materials Finished products
Process deviations Specification
deviations
Product complaints
Process condition
deviation
Unapproved vendors Adverse events
In-process
specification
deviations
Stability problems Specification deviation
Environmental
excursions
Water, gases, etc.
deviations
SQC trends
SPC trends Stability problems,
recalls, reworks,
returns
Document any and all remedial actions that may have been
taken.

List all possible causes for the event.

After investigating, eliminate causes that do not fit the data.

Establish a cause or most probable cause based upon the data.

List corrective actions that need to be implemented.

Only events that are not process-related could be written off as
not negatively affecting the validation (e.g., power failures, natural
disasters, human error, etc.).

Even if a process validation failed and the cause was not
process-related, the validation should be replaced with a fresh run.


Change control:
A basic change control system should cover:

Planned changes: change in equipment, facilities, utilities, and
computer systems, temporary changes or emergency changes
against permanent ones, changes in batch records and SOPs,
changes in analytical test methods, specifications and raw
materials.
-planned changes are intentional and pre-approved and can be
either permanent or temporary.

Unplanned changes: They are actually deviations
-A change control SOP defining terms, levels of justification and
approval needed, and the specific responsibility of approvers,
must be written approved and followed.

-There should be a documented change control system
-A technical review by qualified personnel should review the
- adequacy of the justification
- whether validation or revalidation is needed
- the adequacy, accuracy, and usefulness of any requested
drawings
- the potential risk(s) (including cost and downtime), and
whether those risks are adequately addressed.

-QA normally reviews proposed changes for the
- adequacy of the rationale for the decision to make the
change
- compliance to the change control policy
- assurance that adequate documentation of the change is
present
- the impact on internal or external customers or GMPs,
and the required changes to other procedures,
specifications, batch records, and so on.

- A Financial review
- Follow up

- Emergency changes
Emergency or quick changes still require writing the change
down and getting the approval of one technical area manager
(such as Development) and QA.

How to do change control?

1. Keep it simple: use an approved from and SOP
2. Hold regular change control meetings
3. Distribute proposed changes electronically
4. Train your employees
5. Follow up
6. Publish a report on outstanding change request forms
7. Be careful how you agree to handle temporary changes
8. Enlist a powerful ally and assign responsibility for
tracking/monitoring changes to one individual / department.
Monitoring:
- Process and environmental monitoring
- testing and issuance of results
- Imp: results of testing is reviewed by QA. Thus QA must receive all
notices of deviations and monitoring excursions on an on-going
basis in such a way that it can make determinations as to product
quality and what steps may need to be take.
Inspection Control:
- These are online QA staff responsible for container and label
accountability, online statistical process control of critical
processing steps, online checking of labels lines for expiration
dates, batch no., and proper labels as well as line clearance
before and after labeling run, filled vial inspections for
particulates, tablet weight variation and other functions.
Training:
- Necessary in 3 areas of all plant personnel: regulatory,
procedural, and technical.
Auditing:
- The essence of audit is comparison. The essential question of
any audit are:
1) Has the system been established?
2) Is the system reasonable and appropriate?
3) If so, is it being followed?

- Manufacturing audit program should include:
Vendors and contractors
Plant inspection
Procedures
Batch records
Submissions (pre-approval)
Quality systems
QA and QC
Formulate the
question
Draw
Conclusions
Select or develop
analytical
procedure
Optimize
procedure
Conduct analysis:
Sampling
Sampling preparation
Analysis
Reporting and
Interpretation
QA in Research and Development
Goals of R&D

Effective drugs
- data should be real, accurate, complete, consistent and reasonable
- results of attendant analyses are the basis for companies and
regulatory agencies decisions, must be unbiased, inclusive of all
appropriate data, and in correct with the predetermined protocols
and/or analytical plans.

assess the acceptability of and minimize the errors in products
of R&D, thats submission and individual reports.
GLPs:
-Detailed, documented evidences of the appropriate functioning
of the controls and assurance function is necessary to prove that
the studies have quality and integrity.
Preclinical QA:
The quality aspects relate to the establishment of:
The design of studies
Investigational materials
Test subjects
Data that result from all tests
Observations
Gross postmortem pathology and histopathology and
Preparation of report
Audits:
1. Protocol Audits
2. Procedure audits
- Study specific
- System oriented
3. Documentation audits
4. Report audits
5. Facilities audits
SQC:
- Monitoring of quality by application of statistical methods in all
stages of production
- Used for estimating parameters, for performing test of
significance, for determining the relationship between factors,
and for making meaningful decisions on the basis of
experimental evidence
- SQC has been used to serve
1. as a basis for improved evaluation of materials through more
representative sampling techniques and
2. as a means of achieving sharper controls in certain
manufacturing process

Objective: determine whether the major source of observed
variation is due to chance variation which is inevitable during
the manufacturing process, or to assignable cause which is
usually detected and corrected
-For this normal frequency distribution curves and quality control
charts have been used

Sampling and sampling plans:
-Process of removing an appropriate number of items form a
population in order to make inferences to the entire population
- proper methods of sampling and adequate number and size of
samples are needed for an effective QA program, as judgment of
accept or reject lies in it
- the number of unacceptable units are controlled to rigid standards
by the stringency of the sampling plan
-Sampling plans based on data from measurement of attributes or
variables may be constructed
-Govt. sampling plans such as MIL-STD-414 for variable sampling and
MIL-STD-105D for attribute sampling is used
-Acceptability of a batch is determined by the use of sampling plans
associated with the designated acceptable quality level


- A sampling plan indicates the no, of units of product form each
batch to be inspected and the criteria for determining the
acceptability of the batch
- Inspection level determines the relationship between the batch size
and the sample size
- Single sampling: specified sample is selected
- Double sampling: a second sample for inspection is permitted if
The first fails, and two acceptance numbers are used- the first
Applying to the observed number of defectives for the first sample,
And the second applying to the observed number of defectives for
First and second samples combined
- Statistical sampling plan requires that four basic quality standards
Be specified:
1. An acceptable quality level (AQL)
2. An unacceptable quality level (UQL)
3. Risk or error (producers risk): probability of rejecting a good batch
4. Risk or error (consumers risk): probability of accepting a bad batch