Process Validation: An Overview
Deepak Prashar*
Department of Pharmaceutical
Sciences, Manav Bharti
University, Solan (H.P.), India
ABSTRACT:
Validation
is an act of
demonstrating a procedure, process, and activity which will consistently lead
to the expected results. In pharmaceuticals there are wide varieties of
procedures and processes which need to be validated. The validation process
consists of identifying and testing all aspects of a process that could affect
the final test or product. Prior to the testing of a process, the system must
be properly qualified. A properly designed system will provide a high degree of
assurance in order to evaluate every step, process and change before its
implementation.
In this paper, statistical issues, regulatory requirements required for process
validation options in drug development are discussed.
KEYWORDS: process validation, cGMPs, pilot
scale-up, validation options, statistical issues
INTRODUCTION:
Process
validation is establishing documented evidence which provides a high degree of
assurance, for a specific process will consistently produce a product meeting
its predetermined specifications and quality y characteristics1. A
validated process assures that the final product has a high probability of
meeting the standards for identity, strength, quality, purity and stability of
the drug product. Control procedures shall be established to monitor output and to validate performance of the
manufacturing processes which are responsible for causing variability in the
characteristics of in-process material and the final drug product. There is no separate set of
process validation guidelines since the requirements of process validation are
embodied within the purpose and scope of the present cGMP
regulations2. The main application of process validation is least product recalls and troubleshooting
assignments in manufacturing operations and more technically and economically
sound products and their manufacturing processes. Under FDAs Preapproval Inspection (PAI) program3
the scientifically sound justifications of qualification and controlled
documentation for every final product is made by the R & D department
(Table 1).
PRIORITY BASED PROCESS VALIDATION:
In
a pharmaceutical firm, limitation of resources makes it quite difficult to
validate an entire companys product line at once. Hence the order of
importance or priority with respect to validation is required. As far as the
company policy suggests, the priority is given to the most profitable product.
Still there is an accepted criterion for the validation in the companies based
on priorities. Sterile products
accompanied with their manufacturing processes are given higher priority in
comparison to Non-sterile products. Table 2 enlists the sterile and non sterile
products.
Table 1: Qualification and Control
Documentation Checklist
|
S. NO. |
cGMP SECTION |
QUALIFICATION AND CONTROLLED DOCUMENTATION |
|
1 |
General provisions |
------------------------------------------------------- |
|
2 |
Organization and personnel |
Responsibilities of the
quality control unit |
|
3 |
Buildings and facilities |
Plant and facility installation
and qualification Maintenance along with
sanitation and pest control |
|
4 |
Equipment |
Installation and
qualification of equipment and cleaning methods |
|
5 |
Control of components,
containers and closures |
Incoming component testing
procedures |
|
6 |
Production and process
controls |
Process control systems,
reprocessing control of microbial contamination |
|
7 |
Packaging and labeling
controls |
Depyrogenation, sterile packaging, filling and closing, expire
dating |
|
8 |
Holding and distribution |
Warehousing and distribution
procedures |
|
9 |
Laboratory controls |
Analytical methods, testing
for release component testing and stability testing |
|
10 |
Records and reports |
Computer systems and
information systems |
|
11 |
Return and salvaged drug
products |
Batch reprocessing |
PROCESS
VALIDATION AND PILOT SCALE-UP:
The pilot program is defined as the scale-up operations
conducted subsequent to the product and its process leaving the development
laboratory but prior to its acceptance by the full scale manufacturing unit.
For the successful pilot program product and process scale-up should proceed in
graduated order with elements of process validation at each stage of piloting
program4-5. There are a few development activities carried out prior
to the preparation of the pilot-production batch:
·
Formulation
design, selection, and optimization
·
Preparation of the
first pilot-laboratory batch
·
Conduct initial
accelerated stability testing
·
If the formulation
is deemed stable, preparation of additional pilot laboratory batches of the
drug product for expanded nonclinical or clinical use.
The Chemistry, Manufacturing and Control (CMC)
Coordination Committee at the specific manufacturing plant site5
carries out the process validation assignment. The following technical
operations are required to be carried out by the CMC committee:
Formulation
development (usually a laboratory function)
Process
development (usually a pilot plant function)
Pharmaceutical manufacturing
(including packaging operations)
Engineering (including
automation and computer system responsibilities)
Quality assurance
Analytical methods
development and/or Quality Control
API Operations
(representation from internal operations or contract manufacturer)
Regulatory Affairs
(technical operations representative)
IT (information
technology) operations
STATISTICAL PROCESS CONTROL AND PROCESS VALIDATION:
Statistical
process control comprises of various mathematical tools (histogram, scatter
diagram run chart and control chart) to monitor a manufacturing process and to
keep it within in-process and final product specification limits. Process validation represents the procedural environment in which those
tools are used. As a whole it appears as two sides of the same coin. Process characterization represents
the methods used to determine the critical unit operations or processing steps
and their process variables, which usually affect the quality and consistency
of the product outcomes. Process ranging represents studies that are used to
identify critical process or test parameters and their respective control
limits which normally affect the quality and consistency of the product
outcomes of their attributes. The following process characterization techniques
may be used to designate critical unit operations in a given manufacturing
process:
Table 2: Lists of sterile and non sterile products
based on priority
|
S. NO. |
Sterile
products |
Non-sterile
products |
|
1 |
Large-volume
parenterals (LVPs) |
Low-dose/high-potency
tablets and capsules/transdermal delivery systems (TDDs) |
|
2 |
Small-volume
parenterals (SVPs) |
Drugs
with stability problems |
|
3 |
Ophthalmics and other sterile products |
Oral
liquids, topicals |
|
4 |
Medical
devices |
Diagnostic
aids |
CONSTRAINT ANALYSIS:
Constraint analysis limits restrict the operational
range of each process variable or specification limit of each product
attribute. Boundary limits of any technology and restrictions as to what
constitutes acceptable output from unit operations or process steps should in
most situations constrain the number of process variables and product
attributes that require analysis.
The FDA in their proposed amendments to the cGMPs 6 have designated that the following unit
operations are considered critical and
therefore their processing variables must be controlled and not disregarded:
Cleaning
Weighing/measuring
Mixing/blending
Compression/encapsulation
Filling/packaging/labeling
FRACTIONAL FACTORIAL DESIGN:
This technique was developed as a nonparametric test
for process evaluation by Box and Hunter7 and further reviewed by
Hendrix 8. The fractional factorial is designed to reduce the number
of qualification trials to a more reasonable number. It also holds the number
of randomly assigned processing variables. Ten trials are considered as an
upper limit in a practical testing program which is reasonable in terms of
resource and time commitments.
OPTIMIZATION TECHNIQUES:
Optimization techniques are used to find either the
best possible quantitative formula for a product or the best possible set of
experimental conditions needed to run the process till completion. Chapmans
proven acceptable range (PAR) principle9 suggests that optimization
techniques may be employed in the laboratory stage of product to develop the
most stable, least sensitive formula and robust process. Optimization
techniques consist of the following essential operations:
Selection of a
suitable experimental design
Selection of
variables (independent Xs and dependent Ys) to be tested
Performance of a
set of statistically designed experiments (e.g., 23 or 32 factorials)
Measurement of responses
(dependent variables)
Development of a
predictor, polynomial equation based on statistical and regression analysis of
the generated experimental data
Development of a
set of optimized requirements for the formula based on mathematical and
graphical analysis of the data generated
Schwartz10 describes the steps involved in
the parametric optimization procedure for pharmaceutical systems. Parametric statistical methods are
employed for optimization of full factorial designs, half factorial designs,
simplex designs, and Lagrangian multiple regression
analysis11. Parametric methods are best suited for formula
optimization in the early stages of product development.
PROCESS VALIDATION OPTIONS:
As per the guidelines of FDA
there are possibly four options for process validation. The proper sequential
processing is required to prepare the product of acceptable and standard
quality.
PROSPECTIVE PROCESS VALIDATION:
In prospective process
validation, protocol (experimental
plan) is executed before the process is commercially used. The objective
of prospective validation is to demonstrate that the process will work in
accordance with a validation master plan (Table 3) prepared for pilot-product
trials. Prospective validation
is usually performed in the situations where:
1. Historical data are not
available or sufficient and in-process and end-product testing data are not
adequate
2. New equipment or
components are used
3. A new product is
reformulated from an existing product or there are significant modifications or
changes in the manufacturing process
4. The manufacturing process
is transferred from development laboratory to full-scale production
RETROSPECTIVE
VALIDATION:
The retrospective validation option is chosen for
established products whose manufacturing processes are considered stable. When
the basis of validation is economic and resource limited, prospective
validation programs cannot be justified. Retrospective validation provides documented
evidence based on review and analysis of historical information which is useful
when there is a stable process with a large historical database. The
statistical methods that may be employed to analyze numerical output data from
the manufacturing process are listed as follows:
1
Basic statistics (mean, standard deviation, and tolerance limits) 11
2.
Analysis of variance (ANOVA and related techniques)11
3.
Regression analysis 10
4.
Cumulative sum analysis (CUSUM) 12
5.
Cumulative difference analysis 12
6.
Control charting (averages and range) 13-14
Table 3: Sequential Pattern of Validation Master Plan
|
WORK CATEGORIES |
PROCESSES INVOLVED |
|
Objective |
Proving
or demonstrating that the process works |
|
Type
of validation |
Prospective,
concurrent, retrospective, revalidation |
|
Type
of process |
Chemical,
pharmaceutical, automation, cleaning |
|
Definition
of process |
Flow diagram,
equipment/components, in-process, finished product |
|
Definition
of process output |
Potency,
yield, physical parameters |
|
Definition
of test methods |
Method, instrumentation,
calibration, traceability, precision, accuracy |
|
Analysis
of process |
Critical modules and
variables defined by process capability design and testing program |
|
Control
limits of critical variables |
Defined
by process capability design and testing program |
|
Preparation
of validation protocol |
Facilities, equipment,
process, number of validation trials, sampling frequency, size, type, tests
to perform, methods used, criteria for success |
|
Organizing
for validation |
Responsibility
and authority |
|
Planning
validation trials |
Timetable and PERT charting,
material availability and disposal |
|
Validation
trials |
Supervision,
administration, documentation |
|
Validation
finding |
Data
summary, analysis and conclusions |
|
Final
report and recommendations |
Process validated, further
trials, more process design and testing |
CONCURRENT
VALIDATION:
In-process
monitoring of critical processing steps and end-product testing of current
production can provide documented evidence to show that the manufacturing
process is in a state of control. Such validation documentation can be provided
from the test parameter and data sources disclosed in the section on
retrospective validation. Not all of the in-process tests enumerated above are
required to demonstrate that the process is in a state of control. Selections
of test parameters should be made on the basis of the critical processing variables to be evaluated.
REVALIDATION:
The
FDA process validation guidelines1 refer to a quality assurance
system in place that requires revalidation whenever there are changes in
packaging, formulation, equipment or processes which could impact on product
effectiveness or product characteristics and whenever there are changes in
product characteristics. Conditions requiring revalidation study and
documentation are listed as follows:
1.
Change in a critical component
(usually refers to raw materials)
2.
Change or replacement in a critical piece
of modular (capital) equipment
3.
Change in a facility and/or plant (usually location or site)
4.
Significant (usually order of magnitude) increase or decrease in batch size
5.
Sequential batches that fail to meet product and process specifications
CONCLUSION:
Validation
process corresponds to the management of an institution. Each and every stage of the process has to be
validated so that the end products come upto the expectation of the user. Process validation provides a certain
assurance of uniformity and integrity of the drug products. The method of
validation must prove to be in accordance with good manufacturing practice. It can be utilized for proper and smooth
running of pilot-plant. The statistically available results can be easily
studied and would be helpful in monitoring manufacturing process to keep in-process and
final product specification limits. Moreover, the options available for
validation if properly adopted could provide with best drugs and dosages forms.
REFERENCES:
1.
Guidelines on General Principles of Process
Validation,
Division of Manufacturing and Product Quality, CDER, FDA, Rockville, Maryland.
1987.
2.
Current Good Manufacturing Practices in Manufacture, Processing, Packing
and Holding of Human and Veterinary Drugs, Federal Register 43(190); 1978: 45085-45086,.
3.
Commentary, Pre-approval Inspections/Investigations, FDA. J
Parent Sci Tech 45; 1991:5663.
4.
Berry IR and Nash RA. Pharmaceutical
Process Validation. Marcel Dekker, New York. 1993.
5.
Nash RA. Making the Paper Match the Work, Pharmaceutical Formulation & Quality 2000.
6.
CGMP: Amendment of Certain Requirements, FDA Federal Register,
May 3, 1996.
7.
Box GE and Hunter JS. Statistics
for Experimenters. John Wiley, New York. 1978.
8.
Hendrix CD. What every technologist should know about experimental
design. CHEMTECH 1979.
9.
Chapman KG. The PAR approach to process validation. Pharm Tech
8(12); 1984: 22-36.
10. Schwartz JB. Optimization
techniques in product formulation. J Soc Cosmet
Chem
32; 1981: 287301.
11. Bolton S. Pharmaceutical Statistics: Practical and Clinical Applications.
Marcel Dekker, New York. 1997.
12. Butler JJ. Statistical quality
control. Chem Eng 1983.
13. Deming SN. Quality by Design. CHEMTECH 1988.
14. Contino AV. Improved plant
performance with statistical process control. Chem Eng
94; 1987: 125137.
Received on 15.10.2011
Accepted
on 28.10.2011
©
A&V Publication all right reserved
Research Journal of Pharmaceutical
Dosage Forms and Technology.
3(6): Nov.- Dec., 2011, 247-250