*Umed A. Nikam, Abhijit V. Jadhav, V. R. Salunkhe, C. S. Magdum
Rajarambapu College of Pharmacy, Kasegaon Tal:-Walva, Dist:-Sangli, M.S. India
The present article gives an introduction and general overview on process validation
of pharmaceutical manufacturing process especially tablet manufacturing process.
The principal objective of dosage form design is to achieve a predictable therapeutic
response to a drug included in a formulation which is capable of large scale
manufacture with reproducible product quality. Solid dosage forms include tablets
and capsules. Quality is always an imperative prerequisite when we consider any
product. Therefore, drugs must be manufactured to the highest quality levels.
Process Validation is one of the important steps in achieving and maintaining the
quality of final product. This article covers Introduction, type of validation
,Prospective validation Retrospective validation Concurrent validation Revalidation
,Elements of Process Validation, Product Lifecycle View ,Phases of Process
Validation , Rationale for selection of critical steps and parameters for process
validation, Documentation ,SOP, Validation Master Plan, Validation Protocol,
General notes process variations, critical factors and sample thief ,sampling plan and
acceptance criteria, the validation report, studies on the process validation by all
these parameter highlight the quality output of finished dosage form.
Process validation, Quality management, manufacturing procedure, protocol.
The concept of validation was first proposed by two Food and Dru Administration (FDA) officials, Ted Byers and Bud Loftus, in the mid 1970 s in order to improve the quality of pharmaceuticals Assurance of product quality is derived from careful attention to number of factors including selection of quality parts and materials, adequate product and process design, control of the process, and in process and end product testing1. Due to the complexity today s medical products, routine end product testing alone often is not sufficient to assure product quality for several reasons. Some end-products tests have limited sensitivity E.g.:- In some cases, where end product testing does not several all variations that may occur in the product, which may have an impact on safety and effectiveness, destructive testing is required to show that the manufacturing process is adequate.
Even the details of the equipments and their maintenance were also involved.
Validation Master Plan
An approved written plan of objectives and actions stating how and when a company will achieve
compliance with the GMP requirements regarding validation. VMP is a summary intention document stating the scope of the validation and outlining the methods to be used to establish the performance adequacy. The validation master plan should provide an overview of the entire validation
operation, its organizational structure,\ its content and planning. The main elements of its being the list/inventory of the items to, relevant to product and process controls within a firm should be included in the validation master plan. It even holds the calibration and qualification of equipments, summary and conditions of Validation Protocol.
A written plan of actions stating how process validation will be conducted, it will specify who will conduct the various tasks and define testing parameters, sampling plans, testing methods and specifications, will specify product characteristics, and equipment to be used. It must be specify the minimum number of batches to be used for validation studies, it must specify the acceptance
criteria and who will sign \ approve \ disapprove the conclusions derived from such a scientific study. The validation protocol should contain the following elements,
- Short description of the process.
- . Summary of critical processing steps to be investigated.
- . In process, finished product specification for release.
- . Sampling plans.
- . Departmental responsibility.
- . Proposed timetable.
- . Approval of protocol.
The validation working party is convened to define, investigate, progress, collate, co-ordinate and
ultimately approve the entire effort, including all of the documentation generated. The working part would usually involve the following staff members
Head of Quality Control (Manager),
Executive-QC, Head of Engineering
(Manager), Production executive,
Validation Executive, Validation
Manager, Head of Quality Assurance (Manager).
Selection of Critical Steps and Parameters for Process Validation
It is the process of collecting particles by creating bonds between them. It is most critical step in tablet manufacturing as virtually all tablet characteristics like flow, weight variation, hardness, disintegration, and dissolution etc. depend on the granulation parameters. The granulation variables that need be controlled are;
- . Mixing speed
- . Granulation time
- . Feed rate
- . Amount of binder solution and its concentration
the granulator used, because high shear-granulators like RMG, Iodize
mixer produces denser granules compared to low shear granulators like FBG, their by questioning their suitability for fast-release preparation.
This step involves drying of wet mass. Moisture content in granules is an important factor, which has bearing on tablet characteristics. Hence to control moisture content, critical process variables like inlet temperature, drying time are to be monitored and controlled, if the moisture content is less (over dried granules). It produces fines upon milling, which in turn causes weight variation, capping and
chipping. Drying time needs to be controlled, because shorter drying period results in granules having
entrapped moisture, which during compression escapes from the granules having entrapped moisture,
which during compression escapes from the granules and causes the granules to stick to punches (case hardening) where as longer drying period produces friable granules.
It involves mixing of granules with other blending materials. The purpose of blending is to get uniform distribution of drug, appoint that becomes critical for low dose products like tablet and to impart good flow and anti adhesion property to the blend. Here the critical controlling variable is the mixing time, as under blending will result in segregation of blend and increase in disintegration
time due to coating of the granules with low melting lubricants like stearates. Hence content uniformity testing of drug is to be done at periodic intervals.
The major variables affecting the compression process are machine speed and compression force.
Variation in the machine speed leads to varied die fill volume hence varied tablet weight. Compression force needs to be controlled as it affects the tablet hardness, thickness, and
disintegration time and dissolution rate. Another controlling aspect is the machine vibration as excess vibration lead to segregation of blend in the hopper and altering the uniform distribution of the drug in the tablets.
This process involves packing in polyethylene lined aluminum foil and PVC blister pack. Temperature of rollers (sealing and forming) and speed of machine are critical
variables. Adequate forming roller temperature is essential to get proper blister formation. Adequate sealing roller temperature is essential to get proper sealing. Less temperature will leaf to leakage and higher temperature will result in burning or spoilage of aluminum foil and PVC. Leak test and
physical evaluation are carried out to establish the above variables during
blister packing operation.
In spite of the method we select for tableting we have some parameters which are to be considered during the process. These parameters were measured or estimated for process validation of the method. The parameters are: Process validation is generally done with three consecutive
batches. All the critical parameters were evaluated for fixing the optimum process parameters. Every processing step is validated for all the three batches and the results obtained must be present within the acceptance criteria, such that the product can be forwarded for the commercial production. All the problems that arise during validation are overcome and the product will be kept ready for the commercial batch production.
A significant improvement in sampling can be achieved with the use of sample thief, sometimes
known as a grain thief of historical reasons. This device consists of 2 tubes one fitting tightly inside the other and with along holes cut through the tubes in corresponding positions. One end of the outer tube fitted to a point to facilitate is insertion in to a bulk powder the sampling procedure consists of rotating the inner tube to close the holes, inserting the device into the powder, rotating the inner tube
to open the holes, allowing the powder to enter the device, rotating the inner tube once more to close the wholes and finally removing the thief from the bulk powder wholes and finally removing the thief from the bulk powder The thief sampling is better method than merely scoping off it is still an inferior technique the top of a bulk powder Even through most thieves have relatively sharp ends; the very act of plunging the thief through the bulk powder must perturb the sample to some degree.
A compression force of the thief as propagates ahead it is pressed into the bulk thus potentially of the bulk changing the strata and alteringthe wall of powder at the outer walls of the thief. Furthermore, because large particles will flow more easily than will small particles, an opened thief is liable to be filled preferentially with the coarse fraction of the particle distribution
Working procedure by sample Thief
The sleeve rotates so that the interior compartment is isolated from the bulk powder, while in the
closed position, the thief is plunged into the central mass of the powder. Once the thief is at the desired position, the unit is rotated so that the interior compartment is now exposed to bulk powder. Powder flows into the thief compartment of its own accord. Once the interior compartment of the thief is filled, the sleeve of the thief is rotated so that the interior compartment is again isolated from the bulk powder. The thief is then withdrawn from the powder, and the sample is analyzed.
Sampling Plan and Acceptance Criteria
It is the responsibility of the manufacturer to ensure that the sampling plan and acceptance criteria
defined are adequate to ascertain that the manufacturing process is well- controlled and robust to produce drug product consistently meeting specifications. The following sampling plan and acceptance criteria provide a guide for the process validation of a typical solid oral dosage manufacturing process with medium risk indication. Other sampling plans may be acceptable if
they are statistically sound and justified. The extent of sampling, tests and acceptance must take into
consideration, the level of risk, e.g. the equipment type and capacity, to patient health of the drug product and should be considered on a case-by- case basis. The finished product specifications have to be adequately justified and the analytical methods have to be validated as per the
ASEAN Guidelines for Validation of Analytical Procedures.
The validation report
A written report should be available after completion of the validation. If found acceptable, it should be approved and authorized (signed and dated) the report should include at least the following,
1. Title and objective of study
2.Reference to protocol
3. Details of material
5. Programs and cycles used 6.Details of procedures and test methods
6. Result (compared with acceptance criteria), and 8.Recommendations on the limit and criteria to be applied on future basis.
Process validation is an integral part of among all validation like equipment validation, cleaning
validation, vender validation etc. Validation is art step of assure to identity, strength, purity, safty, and
efficacy of pharmaceutical product. Applicable and critical parameter for validation process of solid dosage form must be consider to fulfills the requirement of quality assurance of final product.
1. Rockville M D. Guideline on General Principles of Process Validation. U.S. Food and Drug Administration., U.S. FDA: 2010.
2. Rockville M D. Guideline on General Principles of Process Validation. U.S. Food and Drug Administration., U.S. FDA: 1987.
4. Chaitanya Kumar G, Rout RP, Ram take S, Bhattachaiya S. Process Validation. The Indian pharmacist, 2005, 14-19.
5. Lambert J. Validation Guidelines for Pharmaceutical Dosage Forms. Health Canada/
Health Products and Food Branch Inspectorate, 2004, 7-15.
6. Satyabrata jena, Arjun G, Anil kumar ravipati N V, Satish kumar D,Vinod K R, David