IN PROCESS QUALITY CONTROL
The development of a drug product is a lengthy process involving drug discovery, laboratory testing, animal studies, clinical trials and regulatory registration. To further enhance the effectiveness and safety of the drug product after approval, many regulatory agencies such as the United States Food and Drug Administration (FDA) also require that the drug product be tested for its identity, strength, quality, purity and stability before it can be released for use. For this reason, pharmaceutical validation and process controls are important in spite of the problems that may been countered. Process controls include raw materials inspection, in-process controls and target so for final product. IPQC stands for in process quality control. These are checks that are carried out before the manufacturing process is completed. The function of in-process controls is monitoring and if necessary adaption of the manufacturing process in order to comply with the specifications. this may include control of equipment and environment too. In process materials should be tested for identity, strength, quality and purity as appropriate and approved or rejected by the quality control unit during the production process. Rejected in-process materials should be identified and controlled under a quarantine system designed to prevent their use in manufacturing.
INTRODUCTION
The development of a drug product is a lengthy process involving drug discovery, laboratory
testing, animal studies, clinical trials and regulatory registration. To further enhance the effectiveness and safety of the drug product after approval, many regulatory agencies such as the United States Food and Drug Administration (FDA) also require that the drug product be tested for its identity, strength, quality, purity and stability before it can be released for use. For this reason, pharmaceutical validation and process controls are important in spite of the problems that may been countered. Process controls include raw materials inspection, in-process controls and target so for final product. The purpose is to monitor the on-line and off-line performance of them manufacturing process and then validate it. Even after the manufacturing process is validated, current good manufacturing practice also requires that a well-written procedure for process controls is established to monitor it performance. The QA/QC good practice guidance outlined here reflects practicality, acceptability, cost-effectiveness, existing experience, and the potential for application on a world wide basis. A QA/QC programme contributes to the objectives of good practice guidance, namely to improve transparency, consistency, comparability, completeness, and confidence in national inventories of emissions estimates. The outcomes of the QA/QC process may result in a reassessment of inventory or source category uncertainty estimates. For example, if data quality is found to be lower than previously thought and this situation cannot be rectified in the timeframe of the current inventory, the uncertainty estimates ought to be re-evaluated.
DEFINITION OF IPQC
IPQC stands for IN PROCESS QUALITY CONTROL . These are checks that are carried out
before the manufacturing process is completed. The function of of in-process controls is
monitoring and if necessary adaption of the manufacturing process in order to comply with the specifications .this may include control of equipment and environment too. In-process materials should be tested for identity, strength, quality and purity as appropriate and approved or rejected by the quality control unit during the production process. Rejected in-process materials should be identified and controlled under a quarantine system designed to prevent their use in manufacturing .Written procedure should be established and followed that describe the inprocess controls and tests as specified:
• Tablet or capsule weight variation.
• Disintegration time.
• Content uniformity and homogenecity.
• Dissolution time and rate.
• Clarity,Completeness or pH of solutions.
PRACTICAL CONSIDERATION IN DEVELOPING QA/QC SYSTEMS
Implementing QA/QC procedures requires resources, expertise and time. In developing any
QA/QC system, it is expected that judgments will need to be made on the following: Resources allocated to QC for different source categories and the compilation process; Time allocated to conduct the checks and reviews of emissions estimates; Availability and access to information on activity data and emission factors, including data quality; Procedures to ensure confidentiality of inventory and source category information, when required; Requirements for archiving information; Frequency of QA/QC checks on different parts of the inventory;The level of QC appropriate for each source category; Whether increased effort on QC will result improved emissions estimates and reduced uncertainties; Whether sufficient expertise is available to conduct the checks and reviews. In practice, the QA/QC system is only part of the inventory development process and inventory agencies do not have unlimited resources. Quality control requirements, improved accuracy and reduced uncertainty need to be balanced against requirements for timeliness and cost effectiveness. A good practice system seeks to achieve that balance and to enable continuous improvement of inventory estimates. Within the QA/QC system, good practice provides for greater effort for key source categories and for those source categories where data and methodological changes have recently occurred, than for other source categories. It is unlikely that inventory agencies will have sufficient resources to conduct all the QA/QC procedures outlined in this review on all source categories. In addition, it is not necessary to conduct all of these procedures every year. For example, data collection processes conducted by national statistical agencies are not likely to change significantly from one year to the next. Once the inventory agency has identified what quality controls are in place, assessed the uncertainty of that data, and documented the details for future inventory reference, it is unnecessary to revisit this aspect of the QC procedure every year. However, it is good practice to check the validity of this information periodically as changes in sample size, methods of collection, or frequency of data collection may occur. The optimal frequency of such checks will
depend on national circumstances. While focusing QA/QC activities on key source categories
will lead to the most significant improvements in the overall inventory estimates, it is good
practice to plan to conduct at least the general procedures. General QC Procedures on all parts of the inventory over a period of time. Some source categories may require more frequent QA/QC than others because of their significance to the total inventory estimates, contribution to trends in emissions over time or changes in data or characteristics of the source category, including the level of uncertainty. For example, if technological advancements occur in an industrial source category, it is good practice to conduct a thorough QC check of the data sources and the compilation process to ensure that the inventory methods remain appropriate. It is recognized that resource requirements will be higher in the initial stages of implementing any QA/QC system than in later years. As capacity to conduct QA/QC procedures develops in the inventory agency and in other associated organisations, improvements in efficiency should be expected.
The general procedures require no additional expertise in addition to that needed to develop the estimates and compile the inventory and should be performed on estimates developed using Tier 1 or higher tier methods for source categories. A review of the final inventory report by a person not involved in the compilation is also good practice, even if the inventory were compiled using only Tier 1 methods. More extensive QC and more rigorous review processes are encouraged if higher tier methods have been used. Availability of appropriate expertise may limit the degree of independence of expert reviews in some cases. The QA/QC process is intended to ensure transparency and quality.
ELEMENTS OF QA/QC SYSTEM
The following are the major elements to be considered in the development of a QA/QC system to be implemented in tracking inventory compilation:
• An inventory agency responsible for coordinating QA/QC activities;
A QA/QC plan;
General QC procedures
Source category-specific QC procedures
QA review procedures;
Reporting, documentation, and archiving procedures.
For purposes of the QA/QC system, the QC approach includes all procedures in plus addition.
QUALITY CONTROL EQUIPMENTS
Friabilator
Friabilator is the instrument which is used to detect the friability of the tablets .Friability is the combined effects of shock and abrasions. So to resist shock and abrasions friability test is done for the tablets. In this a no. of tablets are put in the friabilator and revolves at 25rpm,dropping the tablets a distance of six inches with each revolutions .Conventional compressed tablets that lose less than 0.5 to 1.0% of their weight are generally considered as acceptable. When capping is considered on friability testing , the tablet should not be considered as for commercial use, regardless of the %age of loss seen.
Dissolution test apparatus
The dissolution test is conducted to assure that drug is properly breaks into their parts in a
respective medium. Dissolution testing can be continued through three stages .
STAGE(1-3)-Six tablets are tested and are acceptable if all the tablets are not less than
monograph tolerance limit plus 5%.if the tablet fails ,an additional six tablets are tested. The
tablets are acceptable if average of the twelve tablets are greater than or equal to tolerance limit and no unit less than tolerance limit minus 15% ,if tablet still fails the test, an additional 12 tablets are tested. The tablets are acceptable if the average of all 24 tablets is greater than or equal to tolerance limit and if not more than 2 tablets are less than tolerance limit minus
15%.Industrial pharmacists routinely test their formulations for dissolution.
Digital pH meter
Digital pH meter is used in pharmaceutical industries to assure the pH of the solutions which is needed for the preparation of the drug, pH is very important to make assure the stability of the product. Solutions stability investigation usually commence with probing experiments to confirm decay at the extremes of pH for an e.g 0.1N HCL,Water, and0.1N NaOH).These intentionally degraded samples may be used to confirm assay specificity as well as to provide estimates for maximum rates of degradation. This initial experiment should be followed by the generation of a complete pH rate profile to identify the pH of maximum stability. Aqueous buffers are used to produce solutions over a wide range of ph values with constant levels of drug, cosolvent and ionic strength. Since most solution pharmaceuticals are intended for parenterals routes of administration ,this initial ph Rte study should be conducted at a constant ionic strength that is compatible with physiologic media. Ionic strength of an isotonic 0.9% NaCl solution is 0.15.
Moisture analyzer
A moisture analyzer indicating by its name as to analyze moisture in a drug content. The formula which is used to detect moisture is as follows:
% moisture content(M.C) = ( wt. of water in sample/wt. of dry sample)*100
Drying of solids
The moisture content in a solid can be expressed on a wet-weight or dry weight basis .On a wet weight weight basis, the water content of a material is calculated as a %age of the weight of the wet solid ,whereas on the dry weight basis, the water is expressed as a %age of the weight of the dry solid. In pharmacy loss on drying is commonly referred as L.O.D, is an expression of moisture content on a wet weight basis which is calculated as follows:
Process viscometer
This instrument is capable for performing the rheologic studies of most pharmaceutical
preparations such as semi-solid preparations or formulations :pastes, ointments and creams.
Digital refractometer
Digital refractometer is used for those product which are sensitive to light refraction so it is
simply used to check the refraction spectrum of drug product.
Leak test apparatus
A leak test apparatus is used for checking the crimping of the valve which must be available to prevent defective containers due to leakage. For metal containers, this is accomplished by
measuring the “crimp” dimensions and ensuring that they meet specifications. Final testing of the efficiency of the valve closure is accomplished by passing the filled containers through the water bath. Periodic checks are made of the temperature of the water bath, these results are recorded.
IPQC TESTS FOR VARIOUS DOSAGE FORMS:
Tablets:
a) Drug contents determination.
b) Moisture contents of granules.
c) Assay of active ingredients.
d) Weight variation of uncoated tablets.
e) Hardness test.
f) Disintegration test.
Drug Content Determination
A physically sound tablet may not produce the desired effects. To evaluate a tablet potential for efficiacy, the amount of drug per tablet needs to be monitored from tablet to tablet and batch to batch, and a measure of the tablets ability to release the drug needs to be ascertained.
Moisture Content of granules
Granules should possess sufficient strength to withstand normal handling and mixing processes without breaking down and producing large amounts of fine powder. On the other hand, some size reduction during compaction into tablets is desirable to expose the areas of clean surface necessary for optimum bonding to take place so moisture content is the very important factor for producing god pharmaceutical product.
Assay of active ingredient
In a tablet an active ingredient is present which is called active pharmaceutical ingredient
(A.P.I).So to prepare the tablet assay has to be done to produce good finished product.
Hardness test
The monitoring of tablet hardness is especially important for drug products that possess real or potential bioavailability problems that are sensitive to altered dissolution release profiles as a function of the compressive force employed .One of the earliest testers to evaluate tablet
hardness was the Monsanto hardness tester to evaluate tablet hardness tester.
Disintegration test
A generally accepted maximum is that drug to be readily available to the body, it must be in
solution. For most tablets, the first important step towards solution is break down of the tablet
into smaller particles or granules, a process known as disintegration .The U.S.P device to test
disintegration uses 6 glass tubes that are 3 inches long, open at the top, and held against a 10
mesh screen at the bottom end of the basket rack assembly. To test for disintegration time, one tablet is placed in each tube , and the basket rack is positioned in a 1-L beaker of water, simulated gastric fluid and at 37°-+2°c ,such that tablet remains 2.5cm below the surface of the liquid on their upward movement and descend not closer than 2.5cm from the bottom of the beaker. A standard motor driven device is used to move the basket assembly containing the tablets up and down through distance of 5 to 6cm at a frequency of 28 to 32 cycles per minute.
I.P.Q.C TEST FOR SYRUPS AND SUSPENSION
a) Drug contents determination.
b) Assay of active ingredients.
c) pH.
d) Weight per ml.
e) particle size
Drug content determination
Determination of drug content in suspension and syrups are important because their
concentration has to be sufficient itself that it produce the pharmacological action. A suspension is much prescribed to pediatrics so their concentration has to be sufficient not to less not to large.
Assay of active ingredient
Active ingredient means pure drug present in the product .An assay of active ingredient must be done because it is the only which is responsible for pharmacological action and in syrups and suspension a small and fine particles are included in syrups and suspension.
pH of the product
pH affects the stability of the product so before filling and after filling of suspension and syrups pH has to be checked out for consistency of the product.
Particle size
In suspension and syrups a solute particles is dispersed in a suitable solvent so particle size
becomes the important factor for the suitability of the product and all the particles has to be of same size and shape for proper dispersing in the solvent.
I.P.Q.C TEST FOR SEMI- SOLIDS
a) Drug contents determination.
b) Assay of active ingredients.
c) Uniformity and homogeneity test.
d) Viscosity and specific gravity test.
e) Filling test.
Drug content determination
As all have discussed earlier drug content becomes important factor for active pharmaceutical
product. Drug content has to be of very suitable ratio that it can give the pharmacological action.
Homogenecity test
The semi-solid preparations require further treatment are transferred or pumped to the proper
homogenizer, the selection of which is governed by the degree and rate of shear stress required.
Viscosity and Specific gravity test
Once the desired semi-solid preparation have been chosen, a consistency that provides the
desired stability and has appropriate flow characterstics must be attained. For emulsion it is
routinely observed that the building up of viscosity in a freshly prepared emulsion requires some time. The is recommended, therefore that newly formulation emulsion be allowed to rest undisturbed for 24 to 48 hours before it is determined whether its rheologic properties
correspond to those that are required. The viscosity of emulsions responds to changes in
composition in accordance with the following generalizations.
• There is a linear relationship between emulsion viscosity and viscosity of continous phase.
• The greater the volume of the internal phase, the greater is the apparent viscosity.
• To control emulsion viscosity, three interacting effects must be balanced by the formulator.
The viscosity of o/w and w/o emulsions can be increased by the reducing the particle size of the dispersed phase.
Emulsion stability is improved by a reduction in particle in particle size.
Flocculation or clumping which tends to structure the internal phase ,can be stabilizing effect, it increases the viscosity.
I.P.Q.C TEST FOR INJECTABLES
a) Drug contents determination.
b) Clarity test.
c) pH.
d) Pyrogen test.
e) Stability test.
f) Leakage test.
g) Check up of particulate matters.
Pyrogen test
The presence of pyrogenic substance in parentrals is determined by a qualitative biologic test
based on the fever response of the rabbits. Rabbits are used as test animal because they show a physiologic response to pyrogens similar to that of human beings. If a pyrogenic substance is injected into the vein of a rabbit, an elevation of temperature occurs in a period of three hours.
Sterility test
All products labeled “sterile” must pass through sterility test, having been subjected to an
effective process of sterilization. The traditional concept of sterilization is the absolute condition of total elimination of all the microorganisms. With a terminal methods of sterilization of a parenteral product, particularly steam under pressure, a probability of no more than one sterile unit in a million is readily achievable. The term aseptic indicates a controlled process in which the level of microbial contamination is reduced to the degree that microorganisms can be excluded from a product during processing. It describes apparently sterile state.
Leaking test
Ampules are intended to provide hermetically sealed container for a single dose of a product,
thereby completely barring any interchange between the contents of the sealed ampule and its
environment. Should capillary pores or tiny cracks be present, microorganisms or other
dangerous contaminants may enter the ampule or the contents may leak to the outside and spoil the appearance of the package. Changes in temperature during storage cause expansion and contraction of the ampule and contents, thereby accentuating interchange if an opening exists.
Leakers usually detected by producing a negative pressure with an incompletely sealed ampule, usually in a vaccum chamber, while the ampule is entirely submerged in a deeply coloured dye solution ,usually 0.5 to 0.1% methylene blue. Subsuequent atmospheric pressure then causes dye to penetrate an opening, being visible after the ampule has been washed externally to clear it of dye. The vaccum (27 inches Hg or more) should be sharply released after30 min. Only a tiny drop of dye may penetrate a small opening. Vials and bottles are not subjected to such a leaker test because the rubber closure is not rigid; however, bottles are often sealed while a vacuum is being pulled so that the bottle remains evacuated during its shelf life.
Clarity test
Clarity is the relative term, the meaning of which is markedly affected by the subjective
evaluation of the observer. Unquestionly a clean solution having a high polish conveys to the
observer that the product is of exceptional quality and purity .It is practically impossible,
however, to prepare a lot of a sterile product so that every unit of that lot is perfectly free from visible particulate matter, that is , from particles that are 30 to 40 micrometer and larger in size.
Consequently it is the responsibility of the quality control department to detect and discard
individual containers of a product that the ultimate user would consider to be unclean.
This clarity test is performed in industry by visual inspection machine by the light baffles against reflection into the eyes, and views against a black and white background, with the contents set in motion with a swirling action.
Stability
To enhance the assurance of successful manufacturing operations, all process steps must be
carefully reduced to writing after being shown to be effective. These process steps are often
called standard operating procedures(SOPs).No extemporaneous changes are permitted to be
made in these procedures; any change must go through the same approval steps as the original written SOP. Further external records must be kept to give assurance at the end of the production process that all steps have been performed as prescribed. Such in-process control is essential to assuring the quality of the product, since these assurances are even more significant than those from product release testing.
CONCLUSION
Monitoring chemical processes for the formation of an API is the first step to ensuring quality in pharmaceutical manufacturing. Having reliable and reproducible methods will enable the
production plant to guarantee the consistency of drugs batch after batch. Furthermore, it may
simplify the characterization of such processes and their chemical profile. Through the years,
vast publications and general information have been presented to pharmaceutical industry
specialists about the validation of analytical methods. Federal and international regulatory groups have published various guidelines to shed light on analytical method validation. No such emphasis has been given, or guidelines described, however, the validation of in- process control methods. This article intends to establish a starting point for discussions about the validation of in- process methods. So in this, in- process methods quality control and validation are dealed with several of criteria that are discussed in this review.
REFERENCES
1. Chow S. Pharmaceutical Validation and Process Controls in Drug Development. Drug
Inf J 1997;31: 1195-201.
2. Committee on Specifications for Pharmaceutical Preparations. Good Manufacturing Practices
for Pharmaceutical Products.WHO Technical Report Seriesno.82.geneva: World Health Organization, 1992, pp 14-79.
3. Celik, M.(1922) overview of compaction data analysis techniques. Drug Dev.Ind. Pharm,
18:767-810.