Quality Assurance and
Presented By: Dabhi Ajay S.
L. M. C. P. Ahmedabad
Dept. of Pharmaceutics and Pharmaceutical Technology
List of Contents:
- Reasons and characteristic of quality
- 5M’s of quality and factors influencing quality
- Components and Elements of QA
- QA systems
- Fundamental features and benefits of QA system
- 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
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
Reasons for quality consciousness in society:
Increasing consumer awareness : Expectations are growing in
Liberalization of economy : Competition is growing
Globalization of market (shrinking world)
International standards (ISO 9000)
Characteristic of quality:
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
Quality is the end product of a thoroughly understood,
properly designed, implemented and controlled
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 5M’s of Quality
Manuals/Methodology ( SOP)
Factors influencing quality:
Pre analytical Analytical Post analytical
Right specimen Laboratory Recording
Right collection Reagents Interpretation
Right labeling Equipment Turnaround time
Right quantity Selection of test - Report to right user
Right transport Records
Right storage Bio-Safety
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
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.
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
Components of Quality assurance
Internal Quality control: IQC
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.
Validation: Validation of process, Analytical method,
facilities, equipments, personnel, raw materials, product,
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
To prevent risks
To detect deviations
To correct errors
To improve efficiency
To reduce costs
By establishing a quality manual defining
Organizational structure – Staff
Procedures and processes
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
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:
Warehousing Operational protocols
Quality control Validation
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
Benefits of QA system:
Higher standards of production
Compliance with regulatory requirements
Less risk of product defects
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
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:
- 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:
End of process testing
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.
Qualification life cycle:
New Facility, Utility
Construction and installation
programme Qualification or
Preventive QA/safety approval to use
Maintain in the
Monitoring Close out qualification package
Facility, Utility and/or
Equipment retired from
- 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
- Whether specifications are being met is the process of monitoring
-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 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
GMP’s and generally acceptable practices) for water, HVAC, gases
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.
-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
-Documents are specific for the process, product, equipment etc.
-QA issues, retrieves, reviews, and stores the documents
-SOP’s 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 SOP’s, 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
-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, Staff Product
Purchase Diagrams Batch Purchase CVs Inventories
order and records orders
Diagram Floor plans Reconciliati Receiving Job Sampling,
manuals ons records description testing
Monitoring Inventories s Release
Use logs Qualificatio In process Sampling, Regulatory Master
ns and tests testing specificarti
validations on sheet
Calibration Logs Results Release Procedural Testing
logs Documents methods
Maintenanc SOP’s SOP’s SOPs Technical COA
Cleaning Monitoring Control Reconciliati Distribution
logs records charts ons and
In process Items control:
Quality Assurance before start up
Environmental and microbiological control and sanitation
Manufacturing working formula procedures
Quality assurance at start up
Raw material processing
Packing materials control
Finished product control
-Things didn’t go as planned
- Events affecting quality should be investigated in a timely
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
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
Process Materials Finished products
Process deviations Specification Product complaints
Process condition Unapproved vendors Adverse events
In-process Stability problems Specification deviation
Environmental Water, gases, etc. SQC trends
SPC trends Stability problems,
Document any and all remedial actions that may have been
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.
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 SOP’s,
changes in analytical test methods, specifications and raw
-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
- 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
- compliance to the change control policy
- assurance that adequate documentation of the change is
- 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.
- 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.
- 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.
- Necessary in 3 areas of all plant personnel: regulatory,
procedural, and technical.
- 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
Select or develop QA and QC Reporting and
Optimize Sampling preparation
QA in Research and Development
Goals of R&D
- 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, that’s submission and individual reports.
-Detailed, documented evidences of the appropriate functioning
of the controls and assurance function is necessary to prove that
the studies have quality and integrity.
The quality aspects relate to the establishment of:
The design of studies
Data that result from all tests
Gross postmortem pathology and histopathology and
Preparation of report
1. Protocol Audits
2. Procedure audits
- Study specific
- System oriented
3. Documentation audits
4. Report audits
5. Facilities audits
- 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
- 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
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
1. An acceptable quality level (AQL)
2. An unacceptable quality level (UQL)
3. Risk or error (producer’s risk): probability of rejecting a good batch
4. Risk or error (consumers risk): probability of accepting a bad batch