1.Introduction
Process Validation is a means of ensuring that
manufacturing processes are capable of consistently
producing a finished product of the required quality. It
involves providing documentary evidence that key steps in
the manufacturing process are consistent and reproducible.
A validated manufacturing process is one that has been
proven to do what it purports or is presented to do.
The term `validation’ is intended to apply to final verification
at the production scale. Typically a minimum of three
consecutive production batches should be successfully
validated prior to the marketing of the product.
2.Scope
This guideline is intended to outline the regulatory
requirements with respect to the manufacturing process
validation studies which falls under the remit of drug
registration and to guide the applicant in preparing the
dossiers for the product licence application. These
requirements are not intended for regulating the
manufacture of active substance and other starting
materials, but intended to apply to data generated to
evaluate or validate the manufacturing process of the
finished product. For biotechnological and biological
products, more extensive data may be required.
3.Data submission requirements
• Option 1 - The data submission should include a
validation report (see Content of Validation Report) on
three consecutive successfully validated production
batches.
• Option 2 - In circumstances where submission of data
on 3 consecutive production batches is not feasible at
the time of application, the following can be submitted to
DRA to obtain marketing approval :
Documents required:
a) Development pharmaceutics report; and
b) Validation report on 1 pilot batch or validation scheme
In addition, the applicant is required to fulfill the following
standard commitment :
• To undertake that 3 consecutive full production batches
are successfully validated before the product is
marketed
• To submit the report to the Drug Regulatory Authority
(DRA) within a specified time frame- or to make the
information from these studies available for verification
post authorisation by DRA according to national
procedure.
• Option 3 - For products that have been approved by a
reference agency, the applicant is required to provide a
declaration statement to the effect that the same preapproval
dossiers pertaining to process validation that
have been submitted to the reference regulatory agency
are submitted to DRA for evaluation. Under certain
circumstances where validation documents may not
form part of the pre-approval dossiers, the DRA may
request for Validation Report or Validation Scheme. In
addition, the applicant is required to undertake that 3
consecutive full production batches are successfully
validated before the product is marketed and to submit
the report to DRA upon request.
4.Content of Development Pharmaceutics
The report on pharmaceutical development or development
pharmaceutics should address the following:
a) Rationale for selecting the dosage form
b) Choice of product components (Active substance and
excipients)
• Compatibility considerations
• Physico-chemical characteristics
c) Formulation of product
• Use of overages
• Effect of pH and other parameters
• Effect of antioxidants, solvents, chelating agents,
type/concentration of anti-microbial agents, etc
• Stability, homogeneity and batch reproducibility
considerations
d) Choice of manufacturing processes, including
sterilization procedures
e) Choice of containers and packaging materials
• Container-closure integrity
• Sorption and leaching issues
The development pharmaceutics report should establish that
the type of dosage form selected and the formulation
proposed are appropriate for the intended (medicinal)
purpose specified in the application for drug registration. It
should also identify the formulation and processing aspects
that are critical for batch homogeneity and reproducibility,
and that hence have to be monitored routinely. The
development pharmaceutics report (and the pilot batch
report, where applicable) should provide a link to the
validation scheme proposed for the manufacture of
production scale batches.
5.Content of Validation Scheme
Process validation scheme outlines the formal process
validation studies to be conducted on the production scale
batches. It should contain the following information:
a) A short description of the manufacturing process in a
schematic drawing or flow chart
b) A summary of the critical processes, control variables
and justification for their selection
c) Finished product specification (release)
d) Details analytical methods (reference to the dossier)
e) In process controls proposed with acceptance criteria
f) Additional testing intended to be carried out (eg. With
proposed acceptance criteria and analytical validation
appropriate)
g) Sampling plan – where, when and how samples are
taken
h) Details of methods for recording and evaluation of
results
i) Proposed time frames for carrying out the studies
6.Content of Validation Report
The following information should be provided in the report:
a) Summary
b) Introduction
c) Batches used for validation
d) Manufacturing equipment
e) Critical process steps and parameters
f) Acceptance criteria
g) Sampling plan
h) Tabulation of the test results
i) Batch Analysis
j) Evaluation of data, and where applicable, including
statistical process control analysis
k) Evaluation of data including comparison against
acceptance criteria
l) Discussion on deviations and out of specification results
m) Conclusion and recommendations
Where appropriate a short description of the manufacturing
process in a schematic drawing or flow chart may be
required by the DRA.
7.Notes on
retrospective
validation & concurrent
validation
A) Retrospective validation
For existing products already on the market for some time,
retrospective validation may be performed. Retrospective
validation involves the trend analysis (using control chart,
etc) of historical manufacturing and QC data (eg. Results of
assays, dissolution test, pH, SG, etc) of the product. Data
from 10-20 batches of the product produced using the same
stable manufacturing process should be analysed, to
demonstrate that the manufacturing process is under control
and `capable’. A Cpk (Process Capability) of 1.0, 1.33 and
2.0 represents a 3, 4, 6 sigma respectively. The
measurement of Cp or Cpk will be accepted as one of the
statistical methods for analysing the process control.
B) Concurrent validation
In the case of orphan drugs, when the number of production
batches per year is expected to be low, concurrent
validation is acceptable. The applicant should seek prior
consent from DRA before submitting the application to
register any drug product that uses concurrent validation
approach.
8.Change Control Procedures are required to manage, plan and document the
changes proposed in the manufacturing processes.
Adequate supporting data should be generated to show
evidence that the revised process would still ensure that the
product meets the desired quality and approved
specification.
Minor changes in SOP’s, environment, equipment etc are
unlikely to require regulatory approval if they can be shown
not to affect the quality of the finished product.
Other types of changes that would have significant impact
on the quality of the finished product would require prior
regulatory approval. Such significant changes include
changes to process (eg. mixing times, drying temperatures,
sterilization process), change of equipment that involves
different design and operating parameters. The applicant
should submit appropriate supporting data for these
changes.
9.Examples of Control variables and test attributes in the manufacture of commonly available
pharmaceutical dosage forms
The Asean GMP Operating Manual should be referred to for examples of control variables and test attributes that are applicable to the manufacture of commonly available pharmaceutical dosage forms.
10.Table of Contents of Process validation documentation
(Appendix A)
Appendix A is a form that needs to be completed by the
applicant for checking purpose.
11.Glossary (Appendix B)
Appendix B gives definitions of the terms used in the
guideline.
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