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QA
Assoc. Prof. Dr. Mohamed
Ibrahim Bin Noordin
Pharmacy
UM
Quality?????????
• A subjective term
• Different meaning to different people
• Involved with the needs, wants and
expectation of people
• Measurable
• A competitive necessity in business
quality
• Definition 1
General: Measure of excellence or state of
being free from defects, deficiencies, and
significant variations. ISO quality as “the
totality of features and characteristics of a
product or service that bears its ability to
satisfy stated or implied needs.”
• Definition 2
Manufacturing: Strict and consistent
adherence to measurable and verifiable
standards to achieve uniformity of output
that satisfies specific customer or user
requirements.
Definition of Quality Assurance
“The sum total of the organised
arrangement made with the object of
ensuring products will be of the quality
required by their intended use”
The British Orange Guide
Quality Management
To achieve the quality objective reliably there must be a comprehensive system of
Quality Assurance which incorporates GMP and QC. It must be fully
documented and all parts of the QA system must be adequately resourced with
personnel, premises, equipment and facilities.
The British Orange Guide
Quality Management System
Core Concepts • Why?
– To satisfy Customer
– To make profit
• What? – Meeting the requirement
– Global standard (World Class)
• How? – Prevent things from going wrong
– Making Improvement
• Who? – Involved every one
The Benefits
• Control All the Processes
• Cost Reduction
• Greater Confidence for:
– The Customer
– The Management
– The Individual
Keynotes of Quality Systems
• Quality Systems are the foundation for effective management of an organization
• Quality Systems are based on philosophy of Prevention
• Quality Systems address the whole Business Process
• Quality Systems consist of structured documentation to provide control
• Quality Systems ensure complete record of what you have done and complete documentation of what to do.
A Quality Systems…………..
• Defined responsibility and authority for everyone
• A common understanding of what to be achieved
• A structured anc control documentation system
• Measurement to demonstrate effectiveness
• Policies, procedures and support documentation
A Quality Systems…………..
• A structured system to manage our
Business Process
• Application and documentation of common
sense
• Total involvement of everyone
• Springboard for effective management
control
Quality Assurance
“ The sum total of the organised arrangement made with the
object of ensuring products will be of the quality required by
their intended used.”
The British Orange Guide
QA must address:
• Design and development
• Production and control operation
• Defined managerial responsibility
• The arrangement for manufacturing, supply and use of raw materials and components are satisfactory
• There are satisfactory control on intermediates and there are satisfactory IP checks and validation
• Finish product specification
• Quality Personnel approval before sale
• Satisfactory storage arrangement
• Self audit programme
Quality Management
To achieve the quality objective reliably there must be a comprehensive system of
Quality Assurence which incorporates GMP and QC.
It must be fully documented and all parts of the QA system must be adequately resourced with personnel, premises,
equipment and facilities.
Good Manufacturing Practice, GMP
“Is the part of QA which ensure that
product are consistently produced
and controlled to the quality
standards appropriate to their
intended use and as required by
the marketing authorization or the
product specification”
GMP ensure that:
Quality is built into the product from
the first step of production.
Not merely testing at the end of the
production line
Quality Control
“Set of action to test the
acceptability of the raw material,
processed material, final product
and pakaging material”
QC is an executive arm of QA System
and it involved specific activities
QC Chemical
Physical
Biological
Micobiological
Biotechnology,
(gene therapy)
QC applies to all point of the production process IPQC
What did I learn?
Recap Session
GMP is concerned with both:
•Production
•QC
Basic requirement of GMP
• All manufacturing process are clearly
defined, systematically reviewed for
consistency of achieving medicinal
product of required quality and
specification
• Critical steps of manufacturing
processes and significant changes to
the process are validated
• All necessary facilities for GMP are
provided including:
a) Appropriately qualified and trained
personnel
b) Adequate premises and space
c) Suitable equipment and services
d) Correct materials, containers and labels
e) Approved procedures and instructions
f) Suitable storage and transport
• Instructions and procedures are written in an instructional form, in clear and unambiguous language
• Operators are trained to carry out procedures correctly
• Records are made during manufacturing which demonstrate that all steps required by the defined process proscedures and instructions and that the quantity and the quality of the product are as expected. Any significant deviation are fully recorded and investigated
• Records of manufacturing (BMR) and
distribution should enable a complete history of
a batch to be traced. These records should be
retained in a comprehensive and accessible
form.
• The distribution of the products should
minimises any risk to their quality
• A system is available to recall any batch of the
product, from sale or supply
• Complaint about marketed product are
examined, the causes of quality defects
investigated and appropriate measures taken in
respect of the defective products and to prevent
reoccurence.
QA
GMP
QC
QA
GMP
QC
Element 1:
Appropriately Qualified And
Trained Personnel
Generally Manufacturer should:
• Have an adequate number of
personnel
• Have personnel with the necessary
qualification & practical experience.
• Have an organization chart,
responsible staff with their specific
responsibility well explain by the Org.
Chart
• Ensure all personnel are aware of
GMP, by continuous training relevant
to their need.
• Prevent unauthorized person from
entering the production area
• Identify “key personnel” and their “Job
Description”
Eg. Org. Chart
General Manager
QA Manager
Production
Manager QC Manager
QC Manager and Production Manager have their own specific responsibilities
and some shared responsibility.
Production Manager has the
following responsibility:
• Ensure that products are produced and
stored according to the appropriate
documentation in order to obtain the
required quality.
• Approve the instructions relating to
production operations, including the in-
process controls and to ensure their strict
implementation
• Ensure that the production records are
evaluated and signed by a designated person
before they are made available to the quality
control department.
• Check the maintenance of the department,
premise and equipment.
• Ensure that the appropriate process validation
and calibrations of control equipment are
performed and recorded and the report made
available.
• Ensure that the required initial and continuing
training of production personnel is carried out
and adapted according to need.
QC Manager has the following
responsibility:
• Approved or reject starting material, packaging material and intermediate, bulk and finish products
• Evaluate BMR
• Ensure that all necessary testing being carried out
• Approve sampling instructions, specification, test method and other QC procedures
• Approve and monitor analyses carried out under contract
• Check maintenance of the department, premises and equipment
• Ensure that appropriate validations, including those of analytical procedures and calibration of control equipment are done
• Ensure that the required initial and continuing trainning of QC personnel is carried out and adapted according to need
Their possible shared responsibility
• Authorization of written procedures and other documents including amendments
• Monitor and control of the manufacturing environment
• Ensure plant hygiene
• Process validation and calibration of analytical apparatus
• Training, including the application and principles of QA
• Approval and monitoring of supplier of material
• Approval and monitoring of contract
manufacturers
• Designation and monitoring of storage
conditions for materials and products
• Ensure and monitor retention of records
• Monitoring of compliance with cGMP
requirements
• Inspection, investigation and taking of samples
in order to monitor factors that may effect
product quality
Element 2:
Premises
Principle:
Premises must be located, design,
constructed, adapted and maintained to
suit the operation to be carried out. Their
layout and design must ain tominimize the
risk of errors and permit effective cleaning
and maintenance in order to avoid cross-
contamination, build-up of dust or dirt, and
in general any adverse effect on the
quality of the products.
General requirement: proper and
adequate Premises space
• Situated in an environment which protect the
manufacturing process and present minimum
risk of contamination
• Suitably designed and constructed to reduce
contamination and facilitate work and good
sanitation
• Premises should be maintained and clean
according to written procedures
• Electrical supply, lighting, temperature, humidity
and ventilation should be appropriate
Penicillin Production Area
• Have to be separated totally from general production area
• Having dedicated (separate) air Handling Unit (AHU)
• Penicillin waste should be channeled into a disintegration tank for treatment
• Fully automatic machine should be used to minimize contact of penicillin with personnel
• Penicillin gaunt to be wash in-house
The Malaysian Drug Control Authority (DCA) requires the Plan Layout of
pharmaceutical manufacturing facilities to be submitted along with the “Site Master
File”
All Building of new factory ater 1986 should be consulted with the authority, where the
company concern has to submit their factory plan layout for approval before the
start the building of the factory
The Factory: The manufacturing
facilities should be equipped with
various flows:
• The Personnel Flow
• The Raw Material Flow
• The Finish Product Flow
• The Air Flow
Premises Separation Concept
WHITE GRAY BLACK
Black Are
Eg. Store, office,
canteen
No linkage with White
area at all
Grey Area
Changing Room
Buffer/Clean Down Area
White Area
PRODUCTION
Anything entering
the Production
Area (white area)
should first enter
the Black area
and through the
Grey area.
Personnel Flow in the
Manufacturing Premises
Material Flow in the Manufacturing
Premises
Air Flow in the Manufacturing
Premises
Within the production area there should
be a clear dedicated area for
internal(tabs., Caps.), Internal liquid prep.
(Syrup, Mixt. Etc) and External prep.
(Cream, oint., lotion, etc)
Multi dosage Forms Manufacturing Premises
Production area general principles:
In order to minimize the risk of a serious
medical hazard due to cross-
contimination, dedicated and self-
contained facilities must be available for
the particular pharmaceutical products,
such as highly sensitizing materials (e.g.,
penicillins) or biological preparations (e,g.,
live microoganisms).
The production of certain other products,
such as some antibioties, hormones,
cytotocix substances, highly active
pharmaceutical products, and non-
pharmaceutical products, should not be
conducted in the same facilities.
The manufacture of technical poisons, such
as pesticides and herbicides, should not
normally be allowed in premises used for
the manufacture of pharmaceutical
products. In exceptional cases, the
principle of campaing working in the same
facilities can be accepted provided that
specific precautions are taken and the
necessary vadlidations are made.
General principles Quality Control area.
Quality control laborataries should be
separated from production areas. Areas
where biological, microbiological, or
radiosotope test methods are employed
should be separated from each other.
Control labolotaries should be designed to
suit the operation to be carried out in
them. Sufficient in space should be given
to avoid mix-ups and cross-contamination.
There should be adequate suitable
storage space for sample, reference
standards (if necessary, with cooling), and
records.
The design of the laboratories should take into account the suitability of construction
materials, prevention of fume, and ventilation. Separate air-handlings units
and other provision are needed for biological, microbiological, and
radiosotope laboratories.
.
A separate room may be needed for
instruments to protect them against
electrical interference, vibration, contact
with excessive moisture, and other
external factors, or where it is necessary
to isolate the instruments
Element 3
Equipments
Equipment.
• Principle:
– Equipment must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out.
– The layout and design of equipment must be aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build- up of dust or dirt, and, in general, any adverse effect on the quality of products.
PPM: Plan Preventive Maintenance
• Having service log book
• Repair to be recorded
• Calibration to be done as needed
(annually, Monthly…..)
• Calibration shall be recorded
• The use of calibration sticker is mandatory
• Validation and revalidation should be
recorded
Element 4:
Materials
Principles on materials
• All incoming material should be first
quarantined
– Only to be release by QC department
– QC should ascertained that the incoming
material satisfy all documented specification
• Reject material should be stored
separately
• Approved material should be immediately
move to the general store
Type of Material
• Starting material/Raw material
• Packaging material (Labels and Packages)
• Intermediates
• Finish Product
• Reject material
• Rework material
• Recall product
• Returned goods
• Reagent and culture media
• Reference standards
• Waste materials
• Miscellaneous (insecticide, detergent and sanitizing material)
3 types of labels should be used by the QC
so that all personnel can identify the status
of all material
QUARANTINE
REJECT
PASSED
Element 5
Documentation
GMP:
Document What You Do
Do What You Document
Prove that the system work for QSE
Built the Quality into the product not only testing Qualiti on Finish Product
Ensure:
Reproducibility, Repeatability, Traceability
Constantly Monitoring the Product
Types of Document
• Specifications:
–Specification for starting Materials
–Specification for Packaging
Materials
–Specification for Intermediates and
Bulk Products
–Specification for Finish Products
• Master Formulae
• Packaging Instruction
• Batch Manufacturing Records
• SOP
• Manufacturing Method and Processes
• Job Description
• Analysis and Test Method
• Record of Premises
• Site Master File
• Labels
• ect.
BMR
Batch
Processing
Records
QC
Batch
Packaging
Records
content:
• Name of Product
• Batch No.
• Check on equipment, work station, clear of previous product, cleaning of equipments and working area.
• Dates and time of commencement of significant steps
• Name of person who does the steps and who counter check
BMR
• Batch no of material used or analitical control number of such material.
• QC certification of materials
• Actual weight of each material
• Any relevant processing operation or event
• Major equipment used
• Status of equipment before use and what are they use for
• The IPQC performed, who does the sampling, testing and what are the results
• The record of “Theoretical Yield” and “Actual Yield”
• Records of any deviation and action taken
• Samples of the printed packaging material used, eg. Labels bearing the batch number, expiry date, etc.
• The indication of quantities and reference number or identification of all printed packaging material and bulk product used, destroyed or returned to stock and the quantity of finish product obtained, to permit and adequate “Reconciliation”
• Sampling of Finish Product by QC, Test
Done, Results (to also archive the results
specimens such as the HPLC peaks)
• Who release the Final Products and when
released
Sample of each released product has to be
kept as “Retension Sample” for future
reference.
Standard Operating
Procedures (SOP)
SOP: Examples
• Materials;
– Receiving and Inspection
– Storage
– Sampling by QC
– Distribution of Finish Product
– etc
• Production;
– Gowning Procedure
– Machine and equipment operation
– Cleaning (Machine/Premises
– Calibration
– Maintenance
– Validation
– etc
• QC;
– Preparation of reagents
– Sampling
– Testing methods
– Release of material and product
– Batch numbering
– etc
The purpose of a standard operating
procedure is to describe the performance
of a controlled process.
If it is written to fulfill only that purpose
efficiently and effectively, it becomes a
rugged, flexible, and valuable quality
assurance tool.
• Once a pharmaceutical manufacturing
process has been fully designed,
developed, and demonstrated, the
standard operating procedure (SOP) can
be finalized and approved.
Consider the following type of
information, discovered during
process design and
development, that are required
to accurately describe a
processing event and its control.
• A list of materials and components required for processing, with minimum quality characteristics and/or vendors; specifically cite the part numbers that are approved for use.
• A full description of any reagent, component, or sample preparation/handling that must be performed before process initiation; describe compounding or formulation of reagents specifically or reference appropriate part numbers.
• A list of equipment required and the relevant characteristics of that equipment (capacities, precision, compatibilities, and limitations); indicate equipment specifically by name or equipment number when appropriate.
• Technician training requirements.
• A step-by-step description of the processing event to include the scale or capacity of the operations.
• Processing control parameters and the techniques or methods that ensure their control.
• Test methods or observations that ensure the effectiveness of process controls and documentation requirements associated with this testing.
• Process control effectiveness testing limits or acceptance criteria.
• Data-handling requirements with example calculations.
• Reporting and documentation requirements.
SOP FORMAT AND MANAGEMENT
• Requirements for:
– document identification and control,
– accountability and traceability,
– responsibilities,
– etc.,
This can be accomplished by providing a
consistent format and consistent document
management requirements for every
procedure.
• Company name and pagination.
The company name and pagination (e.g.,
"page 3 of 7") must appear on every page
of the document.
It should always be apparent which
company is responsible for the document.
• Title.
The title should be descriptive. Because a procedure describes how to do something, the title should use directive language to declare what is being done to what.
An SOP titled "Water for Injection Still" is not descriptive of the procedure's content; a more appropriate title would be, "Operation of Water for Injection Still."
• Identification and control.
• Procedures must be uniquely identified. This identification supports accountability and traceability of the document throughout the facility and over time as it changes.
• The accountability and traceability of procedures are based on assigning them identification numbers or codes and control numbers or codes (e.g., revision or edition numbers).
• Purpose.
The purpose or objective of a procedure
should restate and expand a well-written
title.
Expand or qualify the directive language
used in the title (e.g., operation,
monitoring, and routine maintenance
associated with ABC Corporation and XYZ
Company WFI systems).
• Scope. The scope should provide limits to the
use of the procedure. Are there certain samples
• that are appropriate to test by this method? Do
these operations apply only to certain equipment
• or to certain departments? Is there a limit to the
capacity, volume, or throughput of the
• procedure? State to what areas this procedure
does and does not apply.
• Responsibility.
Who is responsible for performing the
work described? Who is responsible for
reporting the work? Are there special
training or certification requirements? As
discussed below, this section defines the
procedure's audience, i.e., who will be
qualified to perform the work described. It
will set the stage for the amount of detail in
the document that follows.
• Procedure.
Describe the procedure in a step-by-step,
chronological manner. Use active verbs
and direct statements, e.g., "Weight 5.00 g
of sodium chloride, PN3244" or "Add
100.0 ml of Purified Water, PN 0128.“
This can be follow-up with a flow chart
showing the full process with references
and interfaces
• Calculations / data handling /
documentation requirements.
Describe how the raw data are managed
and reported. Provide examples of
calculations, when appropriate.
• SOPs are often subdivided into types of
procedures with specific format and design
requirements;
– Manufacturing Procedures (MPs),
– Quality Test Methods (QTMs), or
– Test Methods (TMs),
– Calibration Procedures or
– Preventive Maintenance procedures
• Categorization of procedures is useful, but
it is best to categorize them based on the
types of activity they describe. Use
directive language in the titles of
procedures, and the list will begin to
subdivide itself naturally (e.g., "Testing
of...," "Operating of...." or "Maintenance
of...").
WHAT DOESN'T REQUIRE A SOP?/HOW
MANY SOPS ARE ENOUGH?
• Are SOPs required for "Operation of a hand-held
calculator," "Operation of a balance,“ "Operation of the coffee pot," "Operation of the copy machine," or "Measuring liquids in a graduated cylinder"? When can the writing stop? What needs to be established in writing and what can be left to training?
• The consistency of operations must be ensured for all activities that directly affect the product or the decisions about product quality. What types of activity, if performed inconsistently, could affect product safety, performance, and quality? The answer is different for every manufacturer.
HOW MUCH DETAIL IS ENOUGH?
• The level of detail required in a procedure is affected directly by the level of expertise of the individuals performing the work and the rigor of training associated with the task. There are no rules about the level of detail in SOPs that apply to all companies.
• Procedures must be written to communicate effectively with the individuals who perform the work routinely. Every procedure should describe this audience and its required level of expertise and training in the responsibility section of the SOP.
• How does one write an SOP that has enough detail to be useful to the technician without having so much detail that it triggers meaningless deviation reports? One way is to focus on the purpose of the procedure (procedure defines a process, process controls, and process control effectiveness testing criteria).
• For example, if a processing step requires centrifugation of a sample, then the process design and controls associated with this step are: "Spin at 10,000 X g; 20-25 min; 2-8 °C". This directive is fundamental to consistent processing, but it is useless to the technician who routinely stands in front of a centrifuge and simply needs to know what settings to choose. "Setting #5 on refrigerated centrifuge Beckman BJ-15; 22 min" might routinely achieve the directive by providing the information the technician needs to know, but it does not adequately establish the process design or control parameters (10,000 X g, etc.) and it unnecessarily limits the processing event to a particular brand of centrifuge. Instead, consider the following: "Spin at 10,000 X g; 20-25 min; 1-8 °C; for example, setting #5 on refrigerated centrifuge Beckman BJ-15; 22 min."
WHO SHOULD WRITE THE SOP
• When a test method or process has been developed in-house, the individual who has designed the process and its controls, as described above, should write the procedure. – The more knowledgeable the author, the more accurate the
procedure will be.
– If the author is directly familiar with the work, the procedure will communicate effectively and the requirements of the work will be user-friendly.
• Many procedures, however, are not designed or developed. Some test methods, for example, are standard methods from the U.S. Pharmacopoeia or the Association of Official Analytical Chemists; some equipment operation procedures are copied from vendor manuals.
• In conclusion, the procedures should be written by an individual who performs the task routinely or someone who is directly responsible for the performance of the task.
What did I learn?
Recap Session
Master Document
MASTER DOCUMENT.
• Prepared in advance of production.
• Master document are kept to confirm that the requirement have been met.
• There are 7 master documents required for manufacture and control of a drug product:
• Product Authorization
• Master formula
• Master manufacturing instructions
• Specification
• Test method
• Sampling procedure
• Packaging instruction
MASTER DOCUMENT HAVE TO
BE PREPARED BEFORE A DRUG
CAN BE MANUFACTURED.
WITHOUT THEM THERE IS NO
PRODUCT, BECAUSE THEY
DISCRIBE THE PRODUCT.
Specifications.
• Define a material-differentiation from other material
• Identification
• Test-list to be conducted
• Limit
-Quantitative (upper & lower limit)
-Qualitative
-Discriminating
• Test method
• Approval date & signiture
Test Method
• Detailed description of the method used to
perform tests of specification.
– E.g., Physical examination of packaging
material
– Raw material, specific detailed tests
• Instruction for Chemical, Physical or
Micobiological.
• This document should contain: • Title
• Summary
• List of Equipments
• List of Reagents
• Procedure
• Calculation
• References
Sampling procedure
• It is impractical to test every/all labels, cartons, bottles, caps & raw material
• Therefore a sample is taken from every batch for testing
• Size of sample varies with type of material
• Each sampling procedure has to be in writing, include: • Identification
• Scope
• Preparation for sampling
• Sample size
• Sampling procedure
• Sampling retention
Batch Control Records
• From a QC pt of view, if the product has to be tested, then a set of doc. That constitute the Bach Records, required
• This record should contain: • Receiving report
• Quarantine report
• Sampling frequency
• Sampling taken
• Testing
• Certificate of analysis
• Disposal
• Certificate of disposal
• Sticker
Packaging Instructions
1. Name of Product
2. A description of its pharmaceutical form, strength and method of application where applicable
3. The pack size expressed in terms of the number, weight, or valume of the product in final container
4. A complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types, with the code or reference number relating to the specifications for each packaging material
5. Where appropriate an example or reproduction of the relevent printed packaging materials and specimens, indicating where the batch number and the expiry date of the product have been marked
5. Special precautions to be observed, including
a careful examination of the packaging area
and equipment in order to ascertain the line
clearance before the operation begin
6. A description of packaging operation, including
any significant subsidiary operations, and
equipment to be used
7. Detail of in-process controls with instructions
for sampling and acceptance limits
Specification for starting and
packaging materials
Specifications for starting and primary or printed packaging materials should provide, if applicable, a description of the materials including:
– The designated name (if applicable, the International Nonproprietary Name)
– The reference if any, to a pharmacopoeial monograph
– Qualitive and quantitative requirements with acceptance limits
Depending on company’s practice other
data may be added to the specification,
such as:
– The supplier and the original producer of the
materials
– A specimen of printed materials
– Directions for sampling and testing, or a
reference to the procedures
– Storage conditions and precautions
– The maximum period of storage before re-
examination
• Packaging materials should conform to specifications, with emphasis placed on the compatibility of the material with the drug product contains. The material should be examined for critical and major physical defects as well as for the correctness of identity marking.
• Documents describing testing procedures should state the required frequency for re-assaying each starting material, as determined by its stability.
Specification and Testing
Procedures
• Testing procedures described in
documents should be validated in the
context of available facilities and
equipment before they are adopted for
routine testing.
• There should be appropriately authorized and dated specifications including tests on:
– Identity
– Content
– Purity
– Quality
for staring and packaging materials, intermediates and finish products and any other material involved in production such as water, solvents and reagents
• Each specification should be approved
and maintained by the quality control unit
• Periodic revisions of the specifications
may be necessary to comply with new
editions of the pharmacopoeia or other
official compendia.
• Pharmacopoeias, reference standards,
reference spectra and other reference
material should be available in the QC lab.
Specifications for Intermediates
and Bulk Products
• Specifications for Intermediates and Bulk
Products should be available if these are
purchased or dispatched, or if data
obtained from for Intermediates Products
are used in the evaluation of the finish
product.
Specifications Finished Products
• Specifications Finished Products sholud include: – The designated name of the product and the code
reference where applicable
– The designated name(s) of the active ingredient(s)
– The formula or a reference to the formula
– A description of the dosage form and packaging details
– Directions for sampling and testing or a reference to procedures
– The qualitative and quantitive requirement, with acceptance limits
– The storage conditions and precautions, where applicable
– The shelf-life
Master Formula
• A formally authorized master formula should exist for each product and batch size to be manufactured
• A master formula should include: – name of the product and the code reference relating
to pecification
– A description of the dosage form, strength of production and batch size
– List of starting material to be used, with the amount of each, described using the designated name and a reference that is unique to that material ( mention should be made of any substance that may disappear in the course of processing)
– A statement of expected final yield with the
acceptable limits and of relevant
intermediates yields, where applicable
– A statement of the processing location and
the principle equipment to be used
– The methods and reference to the methods,
to be used for preparing the critical
equipment, e.g., cleaning (especially after
change of product), assembling, calibrating,
sterilizing
– Detailed stepwise processing instructions, e.g.,
• Checks on materials pretreatments
• Sequence for adding materials
• Mixing time
• temperature
– The instructions of any in-process controls and their limits
– Where necessary the requirement of the storage of the products, including the container, the labelling and other special storage conditions
– Any special precaution to observed
Labels
• All finish products should be identified by
labelling, required by the national
legislation, bearing at least the following
information:
– The name of the drg product
– List of active ingredients, showing the amount
of each present and the statement of the net
contents
– The batch number assigned by the
manufacturer
– The expiry date in an uncoded form
– Any special storage conditions or handling precaution that may be necessary
– Direction for use, and any warning and precautions that may be necessary
– The name and address of the manufacturer or the company or the person responsible for placing the product in the market.
For reference standards thec label or accompanying document should indicate concentration, date of manufacture, expiry date, date the closure is first opened and storage condition where appropriate.
VALIDATION A powerful Tool to QA
Definition of Validation; US, FDA
Establishing documented evidence
which provide a high degree of
assurence that a specific process will
consistanly produce a product
meeting its predetermined
specification and quality attributes.
Definition of Validation; EU
Action of proving, in accordance with
the principles of GMP, that any
procedures, process, equipment,
material, activity or system actually
lead to the expected result.
Definition of Validation;
Asean/Auatralia
The action of providing that any
material, process, procedures,
activity, system, equipment or
mechanism used in the manufacture
or control can and will reliably achieve
the desired and intended results.
Basic Principle of Validation
• Establish that the process equipment has
the capability of operating within required
parameters
• Demonstrate that controlling, monitoring
and/or measuring equipment and
instrumentation are capable of operating
within the parameters prescibed for the
process equipment.
• Perform replicate cycles (runs) representing the required operational range of the equipment to demonstrate that the processes have been operated within the prescribed parameters for the process and that the output of product consistently meets the predetermined specification for quality and function.
• Monitor the validated process during routine operation. As needed, requalify and rectify the equipment.
Validation; step by step
Design Specification
Installation Qualification
Operational Qualification
Process Validation
Design Specification
Validation Master Plan
•Prospective Validation
•Restrospective Validation
•Concurrent Validation
•Revalidation
Installation Qualification (IQ)
Establishing documented evidence of
performance and test done to ensure that
equipment (such as machine, measuring
equipment) used in a manufacturing
process are appropriately selected,
correctly installed and work in accordance
with establish specification.
Installation Qualification (IQ)
• Engineering task
• Documentation and record
• Test and acceptance criteria
• Plant functional specifications
• Tagging of equipment and gauges
Operational Qualification (OQ)
Establishing documented varification that
the system or subsystem perform as
intended throughout all anticipated
operation range.
Operational Qualification (OQ)
• Critical variable studies to ensure
compliance with specific operating range
• Simulated product
• Test method and predetermined
acceptance criteria
• Finalization of SOPs related to equipment
Performance Qualification (PQ)
• Product qualification
• Process Validation
PROCESS VALIDATION (PV) Establishing by documented evidence that a process consistently
Produce a result or product meeting its predetermined specification
PROCESS
PERFORMANCE
QUALIFICATION Establishing by documented
evidence that a process is
Effective and Reproducible
PRODUCT PERFORMANCE
QUALIFICATION Establishing by documented evidence
through appropriate testing that finish product
produced by a specific process meets all
release requirement for functionality and safety
Production
Manufacturing Packaging
Process
Control
minimise the possibility of producing
substandard products and
extraneous contamination, cross-contamination,
mislabelling or incorrect packaging
Adulteration Misbranding
Controlled
Process
Environment
Personnel
Methods
Equipment
Materials
Measurement
Consistent
Product
Quality
Factors Which Influence Process Control
Documentation Methods
Deviation &
Change
Contamination
Materials
Process
Control
Personnel
Equipment
1
2
3
4 5 7
6
Ways of doing validation
• Having a Validationa Master Plan: Know
what to validate and when to validate
• Validation can be done by way of:
•Prospective Validation
•Retrospective Validation
•Concurrent Validation
•Revalidation
Prospective Validation
Validation conducted prior to the
distribution of either a new product or
product made under a revised
manufacturing process, where
revision may effect the product
characteristics
Retrospective Validation
Validation of a process for a product
already in the distribution based on
accumulated production, testing and
control data
Concurrent Validation
• Validation carried out during routine
production of product intended for sale
New product
formulation
Modified product
formulation
Existing product
formulation
New
Equipment IQ, OQ, PV IQ, OQ, PV IQ, OQ, PV
Modified
Existing
Equipment
IQ (abbrv.),
OQ(abbrv.),
PV
ReV,
IQ(abbrv.),
OQ(abbrv.),
PV (Cpk)
ReV,
IQ(abbrv.),
OQ(abbrv.),
PV (Cpk)
Existing
Equipment
PV ReV,
PV(Cpk)
Retrospective
Validation
(base Cpk)
Eg, Process Validation:
Manufacturing of microdose tablet
Triboelectrification
Dispensing
Premixing
Machine capacity
Initial Blending
Granulating
Drying
Tablet
Dry Granules
Final Blending
Granules for tableting
Tab. Comp. Machine Vibration in hopper outlet
Lubricant
Granulation Solution
Particle size
Step Discription Equipme
nt
Test Sample
Preparation of granule
solution
Bucket
Stirer
- -
Preblending mixer - -
Trituration Bag - -
Initial Blending mixer Content uni 10
Add. Granulation Solution mixer - -
Blending Mixer - -
Oven Drying Oven Moisture content 10
Final blending mixer Con. Uni.
Particle size
Density
10
1
1
Tablet compression Tableting
machine
Con. Uni., Weight
Uni., Disintegration,
Hardness, Fribility,
Thickness
Aim of Validation in PV
• Validation to show achievement of
the set specification
• Validation of critical stages in the
process
• Validation of worst case scenario
Validation to show achievement of
the set specification
• Reproducibility
• IPQC tests for specification at all stages of
production
• Review procedures or steps
Validation of critical stages in the
process
• Eg. 1: Triboelectrification
– Electrical charges related to equipment
surfaces may cause changes in homogeneity
of mix
– To overcome – change in material of
construction – increase in certainquantities of
component such as Mg. Stearate (static
changes-reduction…Quality of final product..?
• Eg. 2: Vibration
– Vibratory feeds may also destabilized
homogeneity of mix, eg. KCl powder become
dislodged from active constituent
– Constituents segregation
– Particle size segregation
Validation of worst case scenario
• Eg. 1:
– The max. capacity of mixer is 80kg and
itsminimum capacity is 20kg. So validation
have to be done for both sizes
• Eg. 2:
– Speed of mixer, validation at highest speed
and lowest speed
• Eg. 3:
– Sampling of granules from mixer. Sampling to
be done all over at strategic area and worst
case area where to homogeinity is suspected
to be low.
1
4
3
5 6 8
7
9
10
2
2 4
1 8
5 9
6
10
7
3
Confidence
• Achievable if the process is Under Control (Stable
& Predictable) and Capable (Cp > 1) of producing
a product meeting its predetermined specifications
and quality attributes
• Achievable if the process is Validated
• Needed because of Process Variation* Everything varies - no two outcomes are exactly alike
* Process Variation can be calculated if the system is
stable - control limits can be set (LSL and USL)
Process Capability (Cp) and Specifications
Is the process “capable” of reliably meeting limits set by management?
Capability Ratio (Cp) = Specification Limits
Process Variation
Cp = USL - LSL
6
USL = Upper Specification Limit
LSL = Lower Specification Limit
= Standard Deviation
if Cp > 1.33 Process is qualified
if Cp = 1.0 maybe investigate
if Cp < 1.0 investigate to center process
Process Capability (Cp) and Specifications
Natural Limits (± 3 )
Specification Range
Process
Average Defect
Zone
Defect
Zone
This measure presumes
the following:
• both USL and LSL apply
• process mean lies midway
between spec. limits
• process is stable &
predictable
• the output is normally
distributed
Process Capability Index or Confidence Index
• Process Capability Index (Cpk) can be calculated with QC data
for key tests (eg. Assay, dissolution, dose uniformity)
• Calculate the mean (X) and SD () for the data set (use
> 20 points if possible)
Cpk = 3
X - LSL or Cpk =
USL - X
3
Your company has been producing TIRU Tablet for the past 5 years and you
have set the hardness specification 485 ± 25 N.
But now you have replaced the blender with a new one. This blender is able to
take a minimum load of 20 kg and maximum 80 kg. The following are the
results of tablets’ hardness from the batch of 20 kg and 80 kg. Sample size
is 50 tablets.
For 20 kg batch: For 80 kg batch
n = 50 n = 50
X = 485.84 N X = 512.92
= 5.25 = 8.17
USL = 485 + 25 = 510 N
LSL = 485 - 25 = 460 N
For 20 kg batch:
CpL = 485.84 - 460 = 1.01
3 (5.25)
CpU = 510 - 485.84 = 2.17
3 (5.25)
Cpk = 1.01
Therefore, the blender can be used
for the minimum load of 20 kg
For 80 kg batch:
CpL = 512.92 - 460 = 2.16
3 (8.17)
CpU = 510 - 512.91 = - 0.12
3 (8.17)
Cpk = < 1
Therefore, the blender cannot be
used for load of 80 kg
Another trial (of 20 runs) for batch size lower than 80 kg is required to
determine the blender’s maximum capacity
VALIDATION
IQ OQ
PV
Cleaning
Sterilization
Analytical Method
Validation
Packaging
Air-flow
Computer
System
Aseptic
Technique
Validation of Analytical
Methods
Method validation is the
process to confirm that the
analytical procedure employed
for a specific test is suitable for
its intended use.
Methods need to be validated or
revalidated
• before their introduction into routine use
• whenever the conditions change for which
the method has been validated, e.g.,
instrument with different characteristics
• whenever the method is changed, and the
change is outside the original scope of the
method.
Parameters for Method
Validation
Selectivity/Specifity
• The terms selectivity and specificity are
often used interchangeably.
• specific generally refers to a method that produces a response for a single analyte only
• selective refers to a method which provides responses for a number of chemical entities that may or may not be distinguished from each other. If the response is distinguished from all other responses, the method is said to be selective.
• Since there are very few methods that respond to only one analyte, the term selectivity is usually more appropriate.
• The USP defines selectivity of an analytical method as its ability to measure accurately an analyte in the presence of interference, such as synthetic precursors, excipients, enantiomers and known (or likely) degradation products that may be expected to be present in the sample matrix.
• Selectivity in liquid chromatography is obtained by choosing optimal columns and setting chromatographic conditions, such as mobile phase composition, column temperature and detector wavelength.
Precision and Reproducibility
• The precision of a method is the extent to
which the individual test results of multiple
injections of a series of standards agree.
• The measured standard deviation can be
subdivided into three categories:
– repeatability,
– intermediate precision and
– reproducibility
• Repeatability is obtained when the
analysis is carried out in one laboratory by
one operator using one piece of
equipment over arelatively short time-
span. At least
– 5 or 6 determinations of
– three different matrices at
– two or three different concentrations
should be done and the relative standard
deviation calculated.
• The acceptance criteria for precision depend very much on the type of analysis.
– For compound analysis in pharmaceutical quality control precision of better than 1 % RSD is easily achieved,
– For biological samples the precision is more like 15% at the concentration limits and 10% at other concentration levels.
– For environmental and food samples, the precision is very much dependent on the sample matrix, the concentration of the analyte and on the analysis technique. It can vary between 2% and more than 20%.
• Intermediate precision is a term that has been defined by ICH as the long-term variability of the measurement process and is determined by comparing the results of a method run within a single laboratory over a number of weeks.
• A method’s intermediate precision may reflect discrepancies in results obtained by different operators, from different instruments, with standards and reagents from different suppliers, with columns from different batches or a combination of these.
• The objective of intermediate precision validation is to verify that in the same laboratory the method will provide the same results once the development phase is over.
• Reproducibility as defined by ICH represents the precision obtained between laboratories.
• The objective is to verify that the method will provide the same results in different laboratories.
• The reproducibility of an analytical method is determined by analyzing aliquots from homogeneous lots in different laboratories with different analysts and by using operational and environmental conditions that may differ from but are still within the specified parameters of the method (interlaboratory tests).
• Validation of reproducibility is important if the method will used in different laboratories.
Typical variations affecting a method’s
reproducibility
Accuracy and recovery
• The accuracy of an analytical method is the extent to which test results generated by the method and the true value agree.
• The true value for accuracy assessment can be obtained in several ways. – One alternative is to compare results of the method with results
from an established reference method. This approach assumes that the uncertainty of the reference method is known.
– Secondly, accuracy can be assessed by analyzing a sample with known concentrations, for example, a certified reference material, and comparing the measured value with the true value as supplied with the material. If such certified reference material is not available, blank sample matrix of interest can be spiked with a known concentration by weight or volume. After extraction of the analyte from the matrix and injection into the analytical instrument, its recovery can be determined by comparing the response of the extract with the response of the reference material dissolved in a pure solvent.
Linearity and calibration curve
• The linearity of an analytical method is its ability to elicit test results that are directly, or by means of well-defined mathematical transformations, proportional to the concentration of analytes in samples within a given range.
• Linearity is determined by a series of three to six injections of five or more standards whose concentrations span 80-120 percent of the expected concentration range.
• A linear regression equation applied to the results should have an intercept not significantly different from zero. If a significant nonzero intercept is obtained, it should be demonstrated that there is no effect on the accuracy of the method.
• Frequently the linearity is evaluated graphically in addition or alternatively to mathematical evaluation. The evaluation is made by visual inspection of a plot of signal height or peak area as a function of analyte concentration.
Range
• The range of an analytical method is the interval between the upper and lower levels (including these levels) that have been demonstrated to be determined with precision, accuracy and linearity using the method as written.
• The range is normally expressed in the same units as the test results (e.g. percentage, parts
• per million) obtained by the analytical method.
Limit of Detection and
Quantitation • The limit of detection is the point at which a measured
value is larger than the uncertainty associated with it. It is the lowest concentration of analyte in a sample that can be detected but not unnecessarily quantified. In chromatography the detection limit is the injected amount that results in a peak with a height at least twice or three times as high as the baseline noise level.
• The limit of quantitation is the minimum injected amount that gives precise measurements , in chromatography typically requiring peak heights 10 to 20 times higher than baseline noise.
• A number of samples with decreasing amounts of the analyte are injected six times. The calculated RSD% of the precision is plotted against the analyte amount. The amount that corresponds to the previously defined required precision is equal to the limit of quantitation.
Robustness • Robustness tests examine the effect operational
parameters have on the analysis results.
• For the determination of a method’s robustness a number of chromatographic parameters, for example, flow rate, column temperature, injection volume, detection wavelength or mobile phase composition are varied within a realistic range and the quantitative influence of the variables is determined.
• If the influence of the parameter is within a previously specified tolerance, the parameter is said to be within the method’s robustness range.
• Obtaining data on these effects will allow to judge whether a method needs to be revalidated when one or more of parameters are changed, for example to compensate for column performance over time.
