Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5428_Библиотеки_им_академика_М_И_Перельмана
.pdf
•
•
•
CHAPTER 3
Validation
Introduction to Pharmaceutical Validation, Scope & merits of Validation, Validation and
calibration Master plan, ICH & WHO guidelines for calibration and validation of equipment,
Validation of specific dosage form, Types of validation. Government regulation,
Manufacturing Process Model, URS, DQ,IQ,OQ & PQ of facilities.
Introduction to Pharmaceutical Validation
Validation is the process of setting up the documentary evidence to establish that a
procedure, process, or activity applied during manufacture of a product and related analysis
comply with the requirement at all stages, so that the quality of the product being consumed
is consistent.
Since mid-1970s validation has been found to be the most important power in the
manufacture and quality assurance of pharmaceutical products. The process has also been
advancing day by day. In 1976 FDA proposed a complete set of current GMP regulations
which were subsequently revised many times. Quality of a product is indicated by the
customer’s satisfaction. Quality cannot be guaranteed only by inprocess and final testing of
the product
1-3
. It is realized by all that good and documented practices can only build the
quality within a product; that is, by following GMP the quality of a product can be assured.
Validation is an essential part of Good Manufacturing Practices (GMP) in pharmaceutical
industry. It can, therefore, be considered as an important element of the pharmaceutical
quality system. Validation includes qualification and it should be applied throughout the life
cycle of a product, process, equipment, system, and utility. The guidelines were proposed by
U.S. Food and Drug Administration (USFDA) with the following definition for process
validation: Process validation is an established documented proof which provides a high
degree of assurance that a specific process (such as the manufacture of pharmaceutical
dosage forms) will consistently produce a product meeting its predetermined specifications
and quality characteristics.
According to the FDA, quality assurance of a product can be achieved by careful and
systemic attention to a number of important factors, such as
Selection of quality components and materials,
Adequate product and process design,
Involvement of skilled personnel in all activities related to a product, and
https://t.me/med1917
•
1.
2.
3.
4.
5.
6.
(a)
(b)
(c)
(a)
Statistical control of the process through in-process and end-product testing
Thus, it requires qualification and validation of both the process and its control systems so
that a high degree of confidence can be established. All individual manufactured units of a
given batch or succession of batches must meet the specifications and then, the batch
becomes approved (acceptable).
According to the FDA’s Current Good Manufacturing Practices (cGMPs) reference 21CFR
211.110(a)
4,5
control procedures should be established so that it can monitor the output and
validate the performance of the manufacturing processes that may be responsible to cause
variation in the characteristics of in-process material and the drug product‘. Such control
procedures include, but are not limited to the following, where appropriate 7 :
Tablet or capsule weight variation,
Disintegration time,
Adequacy of mixing to assure uniformity and homogeneity,
Dissolution time and rate,
Clarity, completeness of solution, and
pH of the solutions
Among these 1-6 items, the first four items 1 to 4 are directly related to the manufacture and
validation of solid dosage forms. Items 1 and 3 are normally associated with change in the
manufacturing process; the items 2 and 4 are usually influenced by the selection of the
ingredients in the product formulation. Item 3 is related to the uniformity of content and
control of unit potency. The adequacy of mixing can assure uniformity and homogeneity and
it is considered a high-priority concern. Item 5 and 6 are related to liquid dosage form,
particularly solutions.
Conventionally the quality control procedures for finished product testing include three basic
steps:
Establishment of specifications and performance characteristics,
Selection of appropriate method, equipment, and instrumentation to ensure that testing
of the product meets the specifications, and
Testing of the final product, using validated analytical and testing methods to ensure
that finished product meets the specifications.
To materialize the pharmaceutical process validation concept, the following four additional
steps can be added:
Qualification of the processing facility and its equipment
https://t.me/med1917
(b)
(c)
(d)
Qualification and validation of the manufacturing process through appropriate means
Auditing, monitoring, sampling, or challenging the key steps in the process for
conformance to in-process and final product specifications
When there is a significant change in the product or its manufacturing process,
revalidation becomes necessary 8 .
There is no specific requirement for a separate set of process validation guidelines. The
fundamentals of process validation have been included within the purpose and scope of the
present cGMP regulations. The entire cGMP document, from subpart B through subpart K,
may be viewed as a set of principles applicable to the overall process of manufacturing.
Thus, the application of the principles of qualification, validation, verification and control, in
addition to change control and revalidation, are applicable. However, the basic concept has
long been applied to other industries’. A checklist of qualification and control
documentation with respect to cGMPs is given in Table 3.1.
Table 3.1 Checklist of Qualification and Control Documentations
https://t.me/med1917
There is still much confusion about the process validation and the process validation
documentation. Initially, there were several different definitions for process validation,
which were taken from FDA guidelines and the CGMPs. According to Chapman the process
validation is simply an “organized, documented common sense”
10
. Others have stated that
“it is more than three good manufactured batches” and should represent a lifetime
commitment as long as the product is being manufactured. The major problem is that the
term validation is used broadly to cover the entire spectrum of cGMP. Most of these refer
primarily to the people, equipment, component, facility, methods, and procedural
qualification. The specific term, process validation should be kept for the sequence of the
product/process development. The essential steps or stages of a successfully completed
product/process development program are presented in Table 3.2
11
. The process validation
should never be designed to fail. Failure in carrying out the process validation assignment is
often the result of incomplete or faulty understanding of the capability of process. In a welldesigned, well-run overall validation program, most of the budget should be spent on
equipment, component, facility, methods qualification, and process demonstration, earlier
called process qualification. In such a program, the formalized final process validation
provides only the necessary process validation documentation required by the regulatory
authorities. The “Good Housekeeping Seal of Approval,” shows that the manufacturing
process is being continued in a state of control. Such a policy is consistent with the U.S.
FDA’s preapproval inspection program
12
. The applicant must confirm either a New Drug
Application (NDA) or an Abbreviated New Drug Application (ANDA) submission. This
must include the necessary cGMP information and qualification data (including appropriate
development reports), along with the formal protocol for the approaching full-scale, running
of formal process validation before launching the product.
Table 3.2 The Key Stages in the Product/Process Development Sequence
Development stage Pilot scale-up phase
Product design 1 × batch size
Product characterization
https://t.me/med1917
•
•
•
Product selection (“go” formula)
Product optimization 10 × batch size
Process design
Process characterization
Process optimization
Process demonstration 100 × batch size
Process validation program
Product/process certification
Definition of validation
The term validation can be defined or explained in various ways. Most commonly and well
accepted definitions of the term are:
According to the principle of good manufacturing practices (GMPs), this is to prove
that any procedure, process, equipment, material, activity or system actually in use can
lead to the expected results.
Documented evidence must indicate a high degree of assurance confirming that a
specific process will consistently produce a product meeting its predetermined
specifications and quality attributes and characteristics.
Obtaining and documenting the evidences.
Scope of Validation
The guidelines are related mainly to the overall concept of validation. These are not planned
to be regulatory in specific validation requirements. This document provides a general
guidance only and the principles may be considered very useful when it would be applied in
the business including manufacture and controlling the quality of products. In other words, it
can be said that validation is a good business practice
13,14
.
There should be an appropriate and adequate system including organizational structure
and documentation infrastructure. Sufficient numbers of personnel and financial
resources must be provided to execute the validation tasks on regular basis and within
a specified time.
It should involve the Management and related personnel responsible for quality
assurance.
https://t.me/med1917
•
Personnel marked responsible for performing validation activity should have
necessary qualifications and experience in validation.
The personnel should be from different departments depending on the validation work
to be performed.
A proper preparation and planning would be required before performing the validation
activities.
Validation activities should be performed as a specific programme.
Validation should be performed in a structured way according to the documented
procedures and protocols.
Validation should be performed at least under the following situations:
When the premises, equipment, utilities and systems, and processes and
procedures are new;
At periodic intervals; and when there is a major change is involved; for example,
at least three consecutive batches(full production scale).
Periodic revalidation or periodic requalification may be replaced, where necessary, so
that the data and information collected can be evaluated to justify whether
requalification or revalidation is required or not.
The outcome of the validation should be retained as a written report duly signed by the
members involved. The worst case situations should also be recorded.
There should be a clear (unambiguous) difference between in-process controls and
validation. In-process tests are performed during the manufacture of each batch according to
specifications and methods prepared and finalized during the development and scale-up
phase. Their objective is to monitor the process continuously.
When a new manufacturing formula or method is used, steps should be taken to demonstrate
its suitability for routine processing. The defined process, using the materials and equipment
specified, should be shown to demonstrate the consistent yield of the product of the required
quality.
Manufacturers should identify what validation work is required to prove that critical aspects
of their operations are appropriately controlled. Significant changes to the facilities or the
equipment, and processes that may affect the quality of the product should be validated. A
risk assessment approach should be used to determine the scope and extent of validation
required.
Advantages of Validation
15
Assurance of compliance to the quality,
https://t.me/med1917
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Optimization of resources,
Manufacture of products at lowest possible cost,
Reduction of failures,
Reduction of rejects,
Reduction of retests,
Reduction of reworks,
Reduction of wastage,
Advantageous for manufacturing activities,
Advantageous for distribution of products,
Advantageous for selling of products,
Advantageous for obtaining the licenses,
Makes the process more efficient for production,
Provides the in-sight of the manufacturing premises
Provides a scope to the Management to take necessary decision/measures in time
Validation and Calibration Master Plan
The validation master plan (VMP)
16
should reflect the key aspects of the validation
programme. The VMP works as the validation roadmap, setting the course, justifying the
strategy, outlining the preliminary test and acceptance criteria, and documenting the
necessary programs that ensure a continuing state of validation. It should be brief, to the
point and clear, unambiguous and should contain at least the following aspects:
A validation and calibration policy
Organizational structure of validation and calibration activities
Summary of facilities, systems, equipment and processes validated and to be validated
and calibrated
Documentation format such as protocol and report format
Planning and scheduling
Change control
References to existing documents
During almost last three decades, the legislative regulations related to GMPs, GLP and
technology have undergone major changes in metrology particularly in pharmaceutical,
biotechnology and healthcare fields. As a result, many companies have set up and are setting
up metrology to ensure uniformity, reliability, and traceability of their measurements. These
https://t.me/med1917
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
industries ensure that their systems working within the specifications are of prime
importance. Thus, before installation, the manufacturing and analytical equipment
instrumentation should be calibrated to give a known basis for subsequent analysis and
verification of proper working. One can set up such systems and procedures through
calibration and validation master plan only.
The contents of a typical validation master plan are
17,18
:
Introduction: validation policy, scope, location and schedule.
Organizational structure: personnel and their responsibilities.
Plant/process/product description: rational for inclusions or exclusions and extent of
validation.
Specific process considerations that are critical and those requiring extra attention.
List of products/ processes/ systems to be validated, summarized in a matrix format,
validation approach.
Re-validation activities, actual status and
Key acceptance criteria.
Documentation format.
Reference to the required SOP’s.
Time plans of each validation project and sub-project.
Calibration Master Plan
Most of the companies calibrate the manufacturing, laboratory instrumentation, measuring
and test equipments to comply with the governments’ regulation.
To ensure the quality assurance of a product right from the design stage, calibration is
equally important. It must be established that uniformity and reliability of a product, the
equipments and instruments used to monitor at each stage of development are appropriate
and accurate to required degree of confidence. After start of the commercial production, the
role of calibration continues and monitors the raw materials, production processes, inprocess testing, finished product testing and storage of the products. Although most of the
companies establish the calibration program to satisfy the regulatory requirements, the
quality of the product depends on a rigid monitoring system on regular basis. The
productivity is simultaneously improved. The structure and content of calibration master
plan is provided in Table 3.3 and explanation of each characteristic follows.
Table 3.3 Content of calibration master plan
Section Title
https://t.me/med1917
1 Purpose
2 Responsibilities
3 Terminology and definitions
4 Guidelines
5 Calibration Quality
6 Environmental controls
7 Personnel requirements
8 Computer software
9 Sources of information
Purpose
Purpose of the calibration master plan is to define why an effective calibration control
program is necessary to be established. The calibration control program is necessary to
ensure that all the Measuring and Test Equipments (M&TE) being used or to be used are
calibrated and meet the manufacturer’s accuracy specifications or tolerances. Measurements
and recording should be traced either by the National Institute of Standards and Technology
(NIST) or by other suitable and appropriate agency.
Responsibilities
Responsibilities of the QA personnel
19,20
, Metrology personnel, and Instrument users are
briefly mentioned below point wise:
Responsibilities of the QA personnel
QA Personnel is/are supposed to establish a mechanism for assuring the adequacy of
the calibration program.
Re-evaluation of the acceptance criteria of all products using the equipments or
instruments is found within the tolerance.
Reviewing and approving the decision taken on inclusion or exclusion of M&TE into
the calibration and/or service program.
Reviewing and approval of the calibration and/or service interval.
Reviewing whether the accuracy of the measurements is adequate for acceptance
limits of product/process for process acceptance and adjustments, or other actions are
https://t.me/med1917
necessary to be taken to assure adequate measurements.
Audit of the calibration system and M&TE usage are done to ensure the compliance
with this document.
Reviewing whether changes in specifications of the product, new accuracy
requirements, and requirements to current good manufacturing practices have been
included in the calibration program.
Reviewing whether the performance of the calibration contractor can assure the
appropriate technical levels.
Responsibilities of Metrology Personnel
Implementation of calibration program.
Development and control of metrology standard laboratory to support the ongoing
GMP processes at the premises.
Development and maintenance of computerized calibration scheduling system.
Providing support to all departments, using M&TE, within the company, wherever
possible.
If the calibration is done through a suitable contractor, it is to be preaudited and found in
conformance with this document, and the calibration contractors may be used outside at the
discretion of the corporate metrology.
The production and QA personnel should be notified for any discrepancies found in
instrumentation during routine maintenance and calibration. All discrepancies must be
recorded on GMP incident report, and the same must be forwarded immediately to the
Manager, QA.
Evaluation of the procedures outlined in this protocol annually along with QA personnel.
The evaluation shall include monitoring and updating to ensure compliance with GMPs.
Supervising whether production equipment and calibration programs have been strictly
followed and the equipment downtime has been kept to a minimum.
Instrument users would be responsible for:
Ensuring whether all instruments used in a GMP process are included in the metrology
department’s computerized calibration scheduling system. Any instruments that do not
have a calibration label affixed should not be part of the system. The user must fill up
completely the instrument form and forward to the metrology department for entry
into the system. The instrument will then be studied for calibration and a calibration
label shall be affixed. The instrument will then be automatically tracked, and the user
will be notified when recalibration would be due.
https://t.me/med1917
Соседние файлы в папке Библиотека им академика М.И. Перельмана