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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5670_Библиотеки_им_академика_М_И_Перельмана
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These parameters are interrelated and should be determined to ensure that the atomized
coating solution reaches the tablet surface and then is dried quickly.
Coating solution
The concentration and viscosity of the coating solution should be determined. The solution
should be sufficiently diluted so that uninterrupted spray can be done on the tablets. The
concentration of the coating solution will also determine the amount and volume of solution
to be applied to the tablets. The stability of the coating solution should be investigated to
establish its shelf life.
Coating weight
There should be a minimum and maximum coating weight for the tablet; this should be
established. Sufficient coating material should be applied to the tablets so that a uniform
appearance is obtained; however, it should not be high enough to cause fill-in of the
embossing.
Residual solvent level
If organic solvents are used for tablet coating, the residual solvent level will have to be
determined. Testing of appearance of the tablets is critical during the coating operation. The
following points with respect to appearance should be observed:
Cracking or peeling of the coating,
Embossing fill-in,
Surface roughness
Color uniformity
Coating efficiency should be determined for the coating operation. The efficiency will
determine the amount of coating solution overage that may be required.
In-process control tests
Following tests should be conducted as ‘in-process’ control tests:
Moisture content of “dried granulation”
Granulation particle size distribution
Blend uniformity
Individual tablet/capsule weight
Tablet hardness
Tablet thickness
Disintegration
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Impurity profile
Finished product tests
Appearance
Assay
Content uniformity
Tablet hardness
Tablet friability
Impurity profile, and
Dissolution
These key test parameters are the indexes by which the major processing variables in solid
dosage forms can be evaluated. Process validation testing is generally performed on the first
three batches of product prepared in production-size equipment. Revalidation testing is only
done when a ‘significant’ change has been noticed. A significant change is one that will alter
the in-process or final product specification established during the validation program or a
change in formula, process, or equipment.
Types of Validation
The word validation simply means assessment of validity or action of proving effectiveness
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. Validation is a concept. It has been continuously developing. It was first appeared in
1978 in the United States of America. Thereafter, the concept started expanding through
years to include a wide range of activities including analytical methods. These activities
should take place at the conclusion of product development and at the start of commercial
production. Validation is the confirmation by examination and provision of evidence of
objective that the requirements for a specified intended use are fulfilled.
Primary objective of any pharmaceutical plant is to manufacture the products of requisite
attribute and quality consistently, at the lowest possible cost. Validation studies have been
conducted in the pharmaceutical industries since long for the purpose of quality assurance.
Validation is being conducted by the manufacturers, but it is not made compulsory by the
regulatory authority. However, it is considered an important and integral part of the cGMP.
Validation is a team effort involving people from various disciplines and departments of the
plant.
Importance of validation
It can assure the quality of a product,
Time-bound program,
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Useful to optimize a process,
Reduces the cost of quality,
Results nominal mix-ups, and reduces bottle necks,
Results minimal batch failures,
It can improve the productivity efficiently,
Reduces the quantity of rejections,
Increases the output,
It can avoid unnecessary capital expenditure,
Reduces process related failures,
Testing during processing and of finished products are reduced,
New equipment can be rapidly and reliably started-up,
Scaling-up of developmental process becomes easier,
Maintenance of equipment becomes easier,
It improves the process of employee awareness,
Automation becomes more rapid,
Government approval becomes easier.
Documentation
The method should be established and written down. The method must specify which, when
and how to qualify and validate
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. The method should be reviewed and approved. The
method should mention the critical steps and acceptance criteria. A report on cross-reference
the qualification and/or method of validation should be prepared, the results obtained are
summarized, and remarks on any deviation should be noted and the changes necessary to
correct the deficiencies. Any changes to the method should be documented with necessary
justification.
Validation team
A multidisciplinary team is basically responsible for performing and supervising validation
studies. The studies should be conducted by personnel who are qualified, trained and has
experience in the relevant discipline.
Responsibilities of validation team
The basic responsibilities of a validation team are:
Creation of updates reviews and approves individual project validation plans and
deliverable validation.
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Ensuring compliance with the validation of company according to the validation
master plan and project validation plan.
Coordinating, implementing, and verifying the elements of VMP.
Consultation, evaluation and approving the changes.
Reviewing and approving the IQ/OQ/PQ procedures and plans.
Reviewing test results and recommending with respect to release of the product.
Assessing risks and developing the contingency plan.
Types of validation
There are mainly four types of validation
Prospective validation,
Concurrent validation,
Retrospective validation, and
Revalidation (Periodic and after Change)
Prospective validation
Prospective validation
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can be defined as the established document proving that a system
does what it is expected to do based on a preplanned protocol. This validation is conducted
before the distribution either of a new product or a product made under a revised
manufacturing process. The validation is performed on at least three successive production
batches.
In prospective validation program the validation is conducted is conducted before the
process is used for commercial production. During the product development phase, the
production process should be categorized into individual steps. Based on experience or
theoretical knowledge the critical parameters of each step should be evaluated. These
parameters that can affect the quality of finished product are evaluated. A number of
experiments should be designed to determine the criticality of these factors. Each experiment
should be planned and documented completely in an authorized method. All equipment,
production environment and the methods used for analytical testing should be completely
validated. The Master Batch Documents such as Master Validation Plan (VMP) can be
prepared only after identification of the critical parameters of the process, machine settings,
specification of different components, and environmental conditions. Various batches of the
same product can be prepared by using this defined process. Theoretically, the number of
processes runs should be carried out and the observations made should be sufficient to allow
the normal extent of variation and the tendency of such variation should be established to
generate sufficient data for evaluation.
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The method of manufacture or process is generally considered acceptable and validated
when three consecutive batches/lots produce the product of desired quality would be
considered as proper validation of the process. In practice, it may require some considerable
time to accumulate these data. Some considerations should be implemented when selecting
the plan for the process validation. Among all these, different lots of dug substance (active
raw materials) and major excipients, batches produced in different shifts, the use of different
equipment and facilities used for commercial production, operating range of the critical
processes, and a thorough analysis of the process data in case of requalification and
revalidation are to be validated. During processing of the validation of batches, extensive
sampling and testing should be performed on the product at different stages, and the results
of these experiments should be documented comprehensively. Detailed testing should also
be done on the final product in its final package. On completion of the review,
recommendations should be made on the extent of monitoring and the in-process controls
necessary for routine production. All these data should be incorporated into the Batch
Manufacturing and Packaging record or into appropriate standard operating procedure.
Limits, frequency, and action should be taken when the limits exceed should also be
specified.
Therefore, prospective validation should include, but not limited to the following:
Summary of the critical processing steps to be investigated,
List of equipment/facilities including measuring, monitoring/recording equipment along
with its calibration status,
Specifications for release of finished products,
List of appropriate analytical methods,
Proposed in-process controls with acceptance criteria,
Additional testing to be performed with acceptance criteria and analytical validation,
as appropriate,
Sampling plan,
Methods for recording and evaluating results,
Functions and responsibilities, and
Proposed timetable.
Criteria for Prospective Validation
Three prospective validation batches should be of same parameters,
Process parameters shall be identical for these batches,
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The first batch should be dispatched after completion of manufacturing and testing of 3
rd
batch and review of results.
If after the first batch necessity is found to change some parameters of the manufacturing
process, the following criteria should be followed: Review and repeat three batches with
revised parameters without considering the first batch to this validation.
Consider the 2
nd
, 3
rd
and 4
th
batches as prospective validation batches having identical
parameters.
If a change must be made, it should be made through the proper change control system.
The first validation batch shall be released for sale and distribution after completion of
manufacturing, testing, and review of all the three batches.
Results of all the three batches should be within acceptable limits.
A series of batches of the final product may be produced using the defined process and
specified components under routine conditions. Theoretically, the numbers of process trials
are carried out and observations made, should be sufficient to allow the normal extent of
variation and the tendency to be established to provide sufficient data for evaluation. It is
usually considered acceptable that three consecutive batches/trials validation of the process.
Batches prepared for process validation should be the same size as the intended industrial
scale batches. If it is planned that validation batches are to be sold or supplied, the conditions
under which they are manufactured should comply completely with the requirements of
GMP, including the satisfactory outcome of the validation exercise and the marketing
authorization.
Concurrent validation
Concurrent validation is like prospective validation
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. The operating company will sell the
products during the qualification runs to the public at its market price. This validation
involves in-process monitoring of critical processing steps and testing of product. This helps
to obtain and document the evidence to show that the process used for production is in a
state of control.
In exceptional cases, it may be acceptable not to complete a validation program before the
routine production begins.
The decision to carry out concurrent validation must be justified, recorded and approved by
authorized personnel.
Requirement for documentation for concurrent validation must be same as specified for
prospective validation.
Concurrent validation is carried out when……………
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A new product has been prospectively validated in a manufacturing facility,
There is any change in the manufacturing process and the impact of change in the
manufacturing process is not significant, if there is a change in the supply of important raw
materials in existing production formula.
Examples of in-process testing are:
pH values,
Hardness of tablets,
Weight variation,
Dissolution Time,
Content of uniformity,
Viscosity or density,
Uniformity of color,
Particle size distribution,
Average Unit Potency
Retrospective validation
Retrospective validation can be defined as the established documented evidence that a
system does what it supposed to do on the review and analysis of historical information
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That is, retrospective validation is obtained by the review of the history of manufacturing
and testing data to establish that the process has been within control and the product
manufactured has been within the specifications.
This type of validation is used when a product made by a process is already distributed in the
market. Retrospective validation is acceptable only for well-established processes. This type
of validation would not be appropriate where following changes have been made recently:
Composition of the product,
Operating procedure,
Operating equipment.
Validation of such processes should be based on historical data. The steps involved require
the preparation of a specific protocol and the report of the results of review of data leads to a
conclusion and/or recommendation. For this type of validation, the data become available
from
Process control chart,
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Maintenance logbooks,
Records of personnel changes,
Process capability studies,
Finished product data such as trend cards, and
Storage stability data
But the data for validation is not limited to batch processing and packaging records. For
retrospective validation the batches selected should represent all the batches manufactured
during the review period, including any batch that has failed to comply with the
specifications. The number of batches should be sufficient to demonstrate the process
consistency. To validate the process retrospectively necessary amount or type of data is to be
obtained by carrying out additional tests on retained samples. For retrospective validation,
usually ten to thirty consecutive batches are to be analyzed to produce required data. The
number of batches to be analyzed may also be reduced if justified.
Some of the essential elements for Retrospective validation are:
Minimum of 10 last consecutive batches manufactured for a defined period,
Number of lots released per year,
Batch (size/strength/manufacturer/year/period)
Master manufacturing/packaging documents,
Current specifications for active materials/finished products,
List of process deviations, corrective actions and changes to manufacturing
documents,
Data for stability testing for several batches
Revalidation (Periodic and after Change)
A written procedure should be prepared and kept to describe
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the actions to be taken, if any
change is proposed to
The starting material,
Process equipment,
Components of the product,
Environment under which the process is run, or the site,
Method of production,
Method of testing, or
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Any other change that can affect the quality of the product or reproducibility of the
process.
Sufficient support data should be generated to demonstrate any change control procedure
should ensure that the revised process will result in the desired quality of the product,
consistency in quality with respect to the approved specifications. Hence, any change that
may affect the quality of the product or reproducibility of the process should be recorded and
accepted. Therefore, the probable impact of the change of facilities, systems and equipment
on the product need to be evaluated, including risk analysis. Under this circumstance the
requalification and revalidation should be done.
Revalidation gives the evidence that changes a process and/or the process-environment that
are introduced and do not adversely affect the process characteristics and the quality of the
product. Similar documents would be required as for the initial validation of the process.
Facilities, systems, equipments and the processes, including cleaning, should be occasionally
evaluated to confirm that these remain valid. Where no significant changes have been made
to the validated status, a review with the evidence that the facilities, systems, equipment and
processes meet the prescribed requirements conform the requirements for revalidation.
Therefore, revalidation becomes necessary in certain situations. Some of the changes that
require validation are:
If the change in physical properties of raw materials such as density, viscosity, particle size
distribution and moisture, etc. may affect the process or product.
If the source of active raw materials (manufacturer) is changed.
If there is any change in packaging materials such as primary container or closure system.
If the process such as mixing time, drying temperature, and batch size changes.
When there is any change in the equipment such as addition of automatic detection system.
In case any change of equipment involves the replacement of equipment on a like for like
basis would normally require revalidation; that is, new equipment to be used must be
qualified.
If there is any change in the plant/facility.
Any decision not to perform revalidation studies must be fully justified and recorded.
Government Regulation
During late 1970s the importance on validation was felt to be started. Since 1963 cGMP
regulations were introduced for finished products. The FD&C Act was amended and
approved in 1962 with Section 501(a)(2)(B) as an amendment. Earlier to this both CGMP
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and process validation were not imposed/ required by law. A significant regulatory burden
before the FDA was adulteration of drug samples after collection and analysis. In fact, this
restricted the inspection of pharmaceutical manufacturing. There were injuries and deaths
due to cross contamination problem. There after the law was amended (Kefauver-Harris
Amendment). Thus, FDA got a powerful regulatory tool to protect a drug product from
adulteration in an unacceptable manufacturing process. Initial GMP regulations were
primarily based on the manufacturing guidelines formulated by Pharmaceutical
Manufacturers Association and became effective in 1963. The FDA expected a preventative
approach rather than a reactive approach to quality control. For implementation of process
validation, Section (d)(3) became important also. It gives the authority to withhold approval
of a new drug application, if the methods used in, and facilities and control systems used for
the manufacture, processing, and packing of such drugs are not adequate to preserve the
identity, strength, quality, and purity. Another requirement of this amendment was that the
FDA must inspect every drug manufacturing plant at least once every two years.
The FDA can establish acts to be prohibited and can also penalize the manufacturers of
adulterated drug and device which are in the market
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. An adulterated product can be
defined as one whose quality characteristics cannot be satisfactorily assured due to
nonconformity with current Good Manufacturing Practices (cGMPs)
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. This definition of
“adulterated product” is straightforward, but preventing actions for its occurrence can be
complex. In fact, a Validation Program ensures that the systems, policies, and procedures are
there to prevent the manufacturing of adulterated products. It’s in the cGMPs for Drugs
(21CFR 210 & 211), Biologics (21CFR 600) and Devices (21CFR 800) where the need for
validation is specified.
For drug products, Parts 210 and 211 of the cGMPs refer loosely to maintaining “appropriate
validation data.” However, the practice of validation is implied more strongly in § 211.68
(a): “Automatic, mechanical, or electronic equipment or other types of equipment, including
computers, or related systems that will perform a function satisfactorily, may be used in the
manufacture, processing, packing, and holding of a drug product.” The burden of proof lies
with the manufacturer to show equipment will “perform a function satisfactorily,” and that
proof should take the form of in-process testing or alternately, Process Validation. To clarify
the validation requirements implicit in this regulation, the Agency issued a Federal Register
Notice proposing changes to Parts 210 and 211. One change would offer this definition:
“Validation protocol means a written plan describing the process to be validated, including
production equipment, and how validation will be conducted….”. Another proposed section
states: “The manufacturer’s determination of equipment suitability shall include testing to
verify that the equipment is capable of operating satisfactorily within the operating limits
required by the process.” In both cases, a well-crafted VMP will show the Agency the
preapproved intent to comply with the expectations of cGMP regulations.
For Biologics, Part 600 addresses unique considerations associated with biological products
and blood components. Biological-derived drug products must adhere to Parts 210 & 211.
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