LEAK TEST FOR AMPOULES

Ampoules are small glass containers that contain a sterile medicinal liquid intended for parentral use. Presence of capillary pores or tiny cracks can cause microbes or other dangerous contaminants to enter the ampoules or may lead to the leakage of contents to outside. This may lead to contamination of the sterile contents and also spoilage of appearance of the package.
Changes in temperature during storage can cause expansion and contraction of the ampoule and its contents, thereby accentuating interchange if an opening exists. Leaker test for ampoules is intended to detect incompletely sealed ampoules so that they can be discarded in order to maintain the sterile conditions of the medicines.Tip seals are more likely to be incompletely closed than pull seals.Open capillaries or cracks at the point of seal result in LEAKERS.

TEST PROCEDURE:

Leakers are detected by this process in a visible manner. Ampoules are placed in a vacuum chamber, completely submerged in a deeply colored dye solution of about 0.5 to 1% methylene blue.
A negative pressure is applied within the ampoule. Subsequent atmospheric pressure causes the dye to penetrate an opening thus making it visible after the ampoule has been washed.
The vacuum, about 27 inches Hg, should be sharply released after 30 minutes. Detection of leakers is prominent when ampoules are immersed in a bath of dye during autoclaving cycle as this has the advantage of accomplishing both leaker detection and sterilization in one operation.

DISADVANTAGES:

Capillaries of 15 micron or smaller diameter cannot be detected by this test.
Vials and bottles are not subjected to such a leaker test as the rubber closer is not rigid.

LEAKAGE TEST FOR INJECTABLE AND NON INJECTABLE PLASTIC CONTAINERS

Fill about 10 containers with water and fit with an appropriate closure.
Keep these containers in an inverted position at room temperature for about 24 hrs. Check for any leakage from any container.

WATER VAPOUR PERMEABILITY TEST

Take five containers and fill them with nominal volume of water. Heats seal these containers with an aluminium foil - polyehtylene laminate or other seal. Weigh the containers accurately and allow to stand for 14 days at a relative humidity of 55 - 65% and a temperature between 20 to 25@C. Reweigh the containers. The loss in weight in each container should not be more than 0.2%.

VARIOUS METHODS FOR LEAKAGE DETECTION

Above mentioned test are specific for certain types of material. Some other approaches also available to detect the leak in various types of container based upon different mechanisms. Let's see one by one:-

(1) OBSERVATION OF VISUAL DEFECTS (pinholes, capillaries):

This is done by leak test using methylene blue dye what I mentioned for ampoules.

(2) WEIGHT CHANGE:

This calculated by plotting a graph with loss or gain versus time under specifically defined condition (what I mentioned in water vapour permeability test).

(3) PRESSURE VACUUM CHANGES:

By the application of pressure and/or vacuum under defined conditions can help detect any leaks to external atmospheres like gases in the form of bubbles. Detection by visual inspection are limited to around 1 cm3 per minute with the possible detection of pinholes up to 20-25m.
Pressure decay systems are operated to a specified pressure and then monitored for pressure drop by which leaks down to 10-3 cm3/sec.
Pressure increase method can also be used in which leakage from a pack under vacuum is detected as a positive pressure change.
Flexible packs generally intend to extend (or indent) when the pack is under vacuum or pressure in sealed condition. A grossly leaking pack does not show any such movement and a slightly leaking one shows less movement. By assessing these movements the leak can be analyzed with the help of transducers or spring loaded sensors.
The sense of deflection and force changes can be detected with typical instruments like blister testers.
Both these methods are more sensitive than the older conventional vacuum with dye tests and can detect pinholes down to 10m. These tests are also non destructive and the time period is as small as 0.5 to unit second in order to minimize temperature effects.

(4) GASEOUS DETECTION TESTS:

This test makes use of gases associated with the product or a gas which is specifically introduced for the leakage detection process. The commonly used gases are:
Helium uses mass spectrometry which enables leakage to be detected down to 10-12 Pa m3s. This test needs high vacuum that may not be ideal for the component being tested. Other halogens are also used for gas detection.
Oxygen, i.e. Mocon Ox-tran: It uses a stream of dry nitrogen whereby presence of oxygen is detected coulometrically.
Carbon dioxide, e.g. Mocon Permatran C used to detect carbon dioxide in another dry gas using infrared technique.
Moisture vapour, e.g. Mocon Permatran W or Dynamic water vapour tester measures moisture by a photoelectric sensor.
Radio isotope tracer gas, e.g. using krypton 85 where a high sensitivity is reported.

(5) BURST TESTS:

The strength of the seals can be estimated by tensile tests as seal or peel tests or the air pressure that is sufficient to create rupture.
This test is carried out by placing a hypodermic needles arrangement and pressurizing the pack against it at a specific rate until the pack bursts. Depending on the nature of the seal the rupture may arise in the body of the pack or at the seal.
An alternative to this can be done by applying steadily increasing mechanical compression on a pack placed in a jig.

(6) MICROBIAL INTEGRITY:

Different methods have been developed under normal pressure and vacuum in order to check whether highly contaminated liquid, gel or media based material will grow back or penetrate closure systems. Alternative methods of leak detection are more preferable as variable results been observed with this method.

(7) CRACK, PINHOLE, CAPILLARY DETECTION:

The old conventional dye/vacuum immersion tests were used earlier to check the seal efficiency in ampoules. These methods have been replaced by electrical conductivity and capacitance type tests.
Typical equipments include NIKKA DENSOK AMPOULE INSPECTION MACHINE.
This machine employs a high frequency and high voltage. It distinguishes between good glass (a non conductor) and areas of cracks or pinholes where current will flow between the inner and outer glass surfaces.
There are other machines that make use of capacitance and dielectric constants where a material with defects will display a higher dielectric constant.

(8) THERMAL CONDUCTIVITY:

These make use of a thermistor bridge that is balanced against air and is subsequently upset if another gas leaks into the leak.

(9) CHEMICAL TRACER TESTS:

This test follows the principle of interaction between material i.e. ammonia on one side and hydrochloric acid on the other forms a white cloud of ammonium chloride indicating leakage. Pinhole can be well detected by this method.

(10) THERMOCOUPLE GAUGES:

This technique based on the mechanism of temperature change. These are mainly used to detect a drop in temperature when a solvent type systems escape under vacuum. It is also used to detect the presence of warmer gases.

TABLET COATING PROBLEMS

BLISTERING:- It is the  detachment of film from the tablet substrate as the elasticity of surface film compromised.

Cause- generally occur due to higher temperature during various stages of coating.

CHIPPING: It is generally a edge phenomena in which at the edge of tablet the surface film chipped off.

Cause decrese in rotation speed of pan, poor coating solution.

CRATERING: It is defect in which a defect in film coating leads to craters appearing exposing the tablet surface.

Cause insufficient drying time, high volume of coating solution used

PICKING: It is defect where a surface film is pulled away from the surface when the tablet sticks together and then part due to being detached away from the core. 

Cause over wetting of tablets due to polymer solution, improper drying.

PITTING: It is a defect in which deformation occur or pitts formation occur in the surface of a tablet core without any visible disruption of the film coating.

Cause it generally occur when the temp of core of the tablets generally higher than the melting points of material used in it. 

BLOOMING: It is defect where dullness in coating colour of tablet occur after  prolonged storage at high temperatures.

Causes use of low molecular weight plasticizer, 

BLUSHING: It is defect in which whitish specks or haziness occur  in the film.

Cause occur due to the high caoting temp. Leads to percipitation of polymers on surface. 

COLOUR VARIATION: A defect which involves variation in colour of the film.
Cause poor mixing, uneven spray pattern, migration of dyes during drying etc.

Infilling- it refers to filling of intagliations(distinctive words or symbols on tablet surface)

Cause due to accumulation or settling of foam in intagliations caused due to air spraying 

ORANGE PEEL EFFECT: It is surface defect resulting in appearence of an orange peel having rough and nonglossy texture.

Cause too high spray pressure, poor tablet composition, rapid drying etc

CRACKING/SPLITTING: It is defect in which the cracks in the films occur across the crown of the tablet (cracking) or splits around the edges of the tablet (Splitting).

Causes occur when the internal stress of the film exceeds the tensile strength of fim, use of high molecular weight polymers.

Links 

http://www.pharmainfo.net/tablet-ruling-dosage-form-years/problems-tablet-manufacture-and-related-remedies/tablet-coating-problems

https://www.lfatabletpresses.com/articles/different-tablet-coating-defects-and-remedies

TABLET PROBLEMS

Problems occuring due to process

CAPPING:- It occur when the upper or lower part of the tablet separates horizontally (partially or complete) from the tablet body and comes off as a cap, during ejection of tablet from the compression machine. 

Causes- over drying of granules, lesser amount of binder, improper tooling, air entrapment.

LAMINATION:- ‘Lamination’ is the separation of a tablet into two or more distinct horizontal layers.

Causes- over speed of turret, improper setting of lower punches, over dried granules.

Problems due to excipients

CHIPPING:- ‘Chipping’ is defined as the breaking of tablet edges during the release of tablet from the press or during handling and coating operations.

Cause - punch tips worn, over drying of granules, lower amount of lubricants.

CRACKING:- When the small and fine cracks observed on the upper and lower central surface of tablets, or sometimes on the sidewalls of tablets are referred to as Cracking.

Causes- over dried granules, large size of granules, tablets expansion.

STICKING:- when the tablet material adhere to the die wall is referred as sticking.
Filming is a slow form of sticking and occur due to excessive moisture in the granules.

Cuses- excessive binder, lesser drying of granules

PICKING:- when a small amount of material from a tablet is sticking and  removed off from the tablet-surface by a punch face is called picking.
The problem is more common on the upper punch faces than on the lower ones.

Cause lesser drying of granules, lesser addition of lubricants, binder addition was high embossing letters on punch tips

MOTTLING:- it is the  unequal distribution of colour on a tablet, with light or dark spots present in an uniform surface.

Causemigration of die to the durface of granules during drying improper mixing of die coloured drug used with colourless excipients

DOUBLE IMPRESSION:- ‘Double Impression’ occur due to free rotation of punches, which have a monogram or other engraving on their face.

Cause - occur due to free rotation of punches

CORRECTIVE ACTION PREVENTIVE ACTION (CAPA)

CAPA is a fundamental management tool that should be used in every quality system.

CORRECTIVE ACTIONS

A corrective action is a term that encompasses the process of reacting to product problems, customer complaints or other nonconformities and fixing them. The process includes:
(i) Reviewing and defining the problem or nonconformity.
(ii) Finding the cause of the problem.
(iii) Developing an action plan to correct the problem and prevent a recurrence.
(iv) Implementing the plan.
(v) Evaluating the effectiveness of the correction.

PREVENTIVE ACTIONS

A preventive action is a process for detecting potential problems or nonconformance’s and eliminating them. The process includes:
(i) Identify the potential problem or nonconformance.
(ii) Find the cause of the potential problem.
(iii)Develop a plan to prevent the occurrence.
(iv) Implement the plan.
(v) Review the actions taken and the effectiveness in preventing the problem.

DIFFERENCE BETWEEN CORRECTIVE ACTION AND PREVENTIVE ACTION

The process used for corrective actions and preventive actions is very similar and the steps outlined in this document can be used for either. However, it is important to understand the differences and also be aware of the implications involved in performing and documenting each.

CORRECTIVE ACTIONS

A corrective action is a reaction to a problem that has already occurred. It assumes that a nonconformance or problem exists and has been reported by either internal or external sources. The actions initiated are intended to: a) fix the problem and b) modify the quality system so that the process that caused it is monitored to prevent a reoccurrence. The documentation for a corrective action provides evidence that the problem was recognized, corrected, and proper controls installed to make sure that it does not happen again.
To address the Corrective Action clause you should be identifying the root cause of non-conformances that have already taken place and implementing immediate corrective actions to contain the situation and long term corrective actions to prevent their re-occurrence.

PREVENTIVE ACTIONS

A preventive action is initiated to stop a potential problem from occurring. It assumes that adequate monitoring and controls are in place in the quality system to assure that potential problems are identified and eliminated before they happen. If something in the quality system indicates that a possible problem is or may develop, a preventive action must be implemented to avert and then eliminate the potential situation. The documentation for a preventive action provides evidence that an effective quality system has been implemented that is able to anticipate, identify and eliminate potential problems.

7 STEPS OF CAPA FOR IMPLEMENTTION

Implementing an effective corrective or preventive action capable of satisfying quality assurance and regulatory documentation requirements is accomplished in seven basic steps:

1- IDENTIFICATION- Clearly define the problem.

The initial step in the process is to clearly define the problem. It is important to accurately and completely describe the situation as it exists now. This should include the source of the information, a detailed explanation of the problem, the available evidence that a problem exists.

This should include:

(a) The source of the information.

The specific source of the information is documented. There are many possible sources: Service requests, Internal Quality Audit, Customer complaints, Internal quality audits, Staff observations, Trend data, QA inspections, Process monitoring, Risk analysis, Process performance monitoring, Management review, and Failure mode analysis. This information is important for the investigation and action plan, but also useful for effectiveness evaluation and communicating the resolution of the problem.

(b) Detailed explanation of the problem

A description of the problem is written that is concise - but complete. The description must contain enough information so that the specific problem can be easily understood.

(c) Documentation of the available evidence that a problem exists.

List the specific information, documents, or data available that demonstrates that the problem does exist. This information will be very important during the investigation into the problem. For example, the evidence for a product defect may be a high percentage of service requests or product returns. The evidence for a potential equipment problem may be steadily increasing downtime.

(d) Corrective/Preventive Action Request form

A sample form is provided “Corrective/Preventive Action Request that can be used to initiate a CAPA action and collect the initial information.

2 - Evaluation - Appraise the magnitude and impact.

The situation must be evaluated to determine both the need for action and then, the level of action required. The potential impact of the problem and the actual risks to the company and/or customers must be determined. Essentially, the reasons that this problem is a concern must be documented.

An evaluation should include:

(a) Potential Impact of the problem

Determine and document specifically why the problem is a concern and what the impact to the company and/or customers may be. Concerns may include costs, function, product quality, safety, reliability, and/or customer satisfaction.

(b) Assessment of Risk

Using the result of the impact evaluation, the seriousness of the problem is assessed. The level of risk that is associated with the problem may affect the actions that are taken. For example, a problem that presents a serious risk to the function or safety of a product may be assigned a high priority and require immediate remedial action. On the other hand, an observation that a particular machine is experiencing an increasing level of downtime each month may have a lower priority.

(c) Remedial Action that may be required

The potential impact and risk assessment may indicate a need for some immediate action to remedy the situation until a permanent solution can be implemented. In some cases the remedial action may be adequate. If so, the CAPA can then be closed, after documenting the rationale for this decision and completing appropriate follow up.

(d) Remedial Action form

A sample “Remedial Action” form is included. This form should be used to explain the steps that must be taken to avoid any further adverse effects.

3 - INVESTIGATION - Make a plan to research the problem.

A written procedure for doing an investigation into the problem is created. A written plan helps assure that the investigation is complete and nothing is missed.

This procedure should include:

(a) The objectives for the action
The objective is a statement of the desired outcome(s) of the corrective or preventive action.
The action will be complete when all aspects of the objective have been met and verified.

(b) An investigation strategy

A set of specific instructions for determining the contributing and root causes of the problem is written.
This procedure directs a comprehensive review of all circumstances related to the problem and must consider: equipment, materials, personnel, procedures, design, training, software, external factors.

(c) Assignment of responsibility and required resources

An important part of the investigation procedure is to assign responsibility for conducting each aspect of the investigation. Any additional resources that may be required is also identified and documented. For example, specific testing equipment or external analysis may be required.

(d) Investigation Procedure form

A sample “Investigation Procedure” form is included. This is a written plan of action for the investigation into the problem. It should include the overall objective and the instructions for conducting the investigation. The person or persons responsible for the investigation and an expected completion date should also be entered.

4 - ANALYSIS - Perform a thorough assessment.

The investigation procedure is used to conduct the investigation into the cause of the problem. The goal of this analysis is primarily to determine the root cause of the problem described, but any contributing causes are also identified.

(a) Every possible cause is identified and appropriate data collected.
A list of all possible causes is created which then form the basis for collecting relevant information, test data, etc.

(b)The necessary data and other information is collected that will be used to determine the primary cause of the problem.
The results of the data collection are documented and organized.
Data may come from a variety of sources: testing results and/or a review of records, processes, service information, design controls, operations, and any other information that may lead to a determination of the fundamental cause of the problem.The data collected is organized into a useable form.The resulting documentation should address all of the possible causes previously determined. This information is used to determine the root cause of the problem. The effectiveness of the analysis will depend on the quality and thoroughness of the information available.

(c) Everything related to the problem must be identified, but the primary goal must be to find the root cause.Use the data to complete a Root Cause Analysis. This involves finding the actual cause of the problem rather than simply dealing with the symptoms. Finding the primary cause is essential for determining appropriate corrective and/or preventive actions.

(d) Problem Analysis form

A sample “Problem Analysis” form is included. This form is optional but is intended to be used for recording information related to the analysis of the problem. The form can be used as a collection point for the information discovered during the analysis and any supporting data or documentation can be attached.

5 - ACTION PLAN - Create a list of required tasks.

Using the results from the analysis, the best method(s) for correcting the situation (or preventing a future occurrence) is determined and act ion plan developed. All of the tasks required to correct the problem and prevent a recurrence are identified and incorporated into an action plan.
The plan includes changes that must be made and assigns responsibility for the tasks. The action plan should also identify the person or persons responsible for completing each task.

(a) Actions to be completed

List all activities and tasks that must be accomplished to correct the existing problem or eliminate a potential problem, and prevent a recurrence. It is very important identify all actions necessary to address everything that contributed to or resulted from the situation.

(b) Document or Specification Changes

Needed changes to documents, processes, procedures, or other system modifications should be described. Enough detail must be included so it is clearly understood what must be done and what the outcome of the changes should be.

(c) Process, Procedure, or System changes

If any changes to processes, procedures, or systems must be made they are described. Enough detail should be included so that it is clearly understood what must be done. The expected outcome of these changes should also be explained.

(d) Employee Training

Employee training is an essential part of any change that is made and should be made part of the action plan. To be effective, all modifications and changes made must be communicated to all persons, departments, suppliers, etc. that were or will be affected.

(e) Action Plan form

A sample “Action Plan” form is included. This should provide a set of written procedures that detail all of the actions that must be done to resolve the problem and prevent it from recurring. This includes corrective and preventive activities, document changes, training, etc. The person or persons responsible and an expected completion date should also be entered on the form.

6 - IMPLEMENTATION - Execute the action plan.

The corrective / preventive action plan that has been created is now implemented. All of the required tasks listed and described in the action plan are initiated, completed, and documented.
Implementation Summary
All of the activities that have been completed as required in the “Action Plan” should be listed and summarized. This section should contain a complete record of the actions thatwere taken to correct the problem and assure that it will not recur. This includes changes, preventive measures, process controls, training, etc.

(a) Documentation

All documents or other specifications that have been modified are listed. Typically the documentation would be attached to a final printed report of this CAPA action. This will facilitate verification of the changes for the follow up.

7 - FOLLOW UP - Verify and assess the effectiveness.

One of the most fundamental steps in the CAPA process is completing an evaluation of the actions that were taken.
This evaluation must not only verify the successful completion of the identified tasks, but also assess the appropriateness and effectiveness of the actions taken.

(a) Key questions

Have all of the objectives been met? (Did the actions correct or prevent the problem with assurances that the same situation will not happen again?)
Have all recommended changes been completed and verified?
Has training and appropriate communications been implemented to assure that all relevant employees understand the situation and the changes that have been made?
Has an investigation demonstrated that that the actions taken have not had any additional adverse effect on the product or service?

(b) Verification results

Make sure that appropriate information has been recorded that provides proof that all actions have been completed successfully.

(c) Validation results

A validation of the action is done. This must document that:
(i) The root cause of the problem has been solved,
(ii) Any resulting secondary situations have been corrected,
(iii) Proper controls have been established to prevent a future occurrence.
(iv) The actions taken had no other adverse effects.
(v) Adequate monitoring of the situation is in place.

COMPLETION

When the Follow Up has been finished, the CAPA is complete. It should be dated, and signed by appropriate, authorized personnel.

WHY PETRI DISHES INVERTED DURING INCUBATION

Petri dishes having media are incubated in inverted position after inoculation. This has different advantages those improve the result accuracy.

Petri dishes were first used by German physician Julius Petri in 1887. He covered one culture plate to another plate to prevent the contamination. Before him the culture plates were covered with the glass bell jars.

There are following advantages during incubation when we incubate the plates in inverted position.

1. When the plates are incubated in normal position, water evaporation from media occurs. These vapors condense on the lid of the Petri dish and drops fall on the colonies developed on the media surface. This causes colony mix-up with each other and spread throughout the plate surface. This creates problem in counting and proper determination of microbial count.

2. The evaporation of water from media can cause media dryness that can affect the microbial growth but when the plates are incubated in inverted position, the rate of evaporation decreases that results in proper microbial growth. Therefore, Petri dishes with media can also be stored for a longer period in inverted position.

3. The lid of Petri dishes may contain any contamination that spreads on the media and grows with the sample microbes. This may create an error in microbial count determination.

4. It is easy to handle the inverted Petri dishes because the lid of the Petri dish may open during handling when incubated in normal position and it may cause contamination from air. We label the Petri dishes at the bottom part because lid may exchange with other Petri dishes creating confusion and inverted position makes it easy to read the labeling of Petriplates.

PHARMACEUTICAL WATER

INTRODUCTION

Water is the one of the major commodities used by the pharmaceutical industry. It is widely used as a raw material, ingredient, and solvent in the processing, formulation, and manufacture of pharmaceutical products, active pharmaceutical ingredients (APIs) and intermediates, and analytical reagents. It may present as an excipient, or used for reconstitution of products, during synthesis, during production of finished product, or as a cleaning agent for rinsing vessels, equipment and primary packing materials etc. There are many different grades of water used for pharmaceutical purposes. Several are described in USP monographs that specify uses, acceptable methods of preparation, and quality attributes. These waters can be divided into two general types: bulk waters, which are typically produced on site where they are used; and packaged waters, which are produced, packaged, and sterilized to preserve microbial quality throughout their packaged shelf life. There are several specialized types of packaged waters, differing in their designated applications, packaging limitations, and other quality attributes. Different grades of water quality are required depending on the different pharmaceutical uses.
There are also other types of water for which there are no monographs. These are all bulk waters, with names given for descriptive purposes only. Many of these waters are used in specific analytical methods. These nonmonographed waters may not necessarily adhere strictly to the stated or implied modes of preparation or attributes.

TYPES OF WATER USED:-

Water is the most common aqueous vehicle used in pharmaceuticals. There are several types of water are used in the preparation of drug product, such as;

NON-POTABLE WATER

Non-potable water is water that is not of drinking water quality, but which may still be used for many other purposes, depending on its quality. Non-potable water is generally all raw water that is untreated, such as that from lakes, rivers, ground water, springs and ground wells.

Purposes:-
•  cleaning of outer surface of the factory
•  used in garden
•  washing vehicles etc

POTABLE WATER

Portable water is not suitable for general pharmaceutical use because of the considerable amount of dissolved solids present. These dissolved solids consist chiefly of the chlorides, sulphates and bicarbonates of Na, K, Ca and Mg. A 100 ml portion of official water contains not more than 100 mg of residue (0.1%) after evaporation to dryness on a steam bath.

Purposes:-
•  To use as drinking water
•  Washing and the extraction of crude drugs
•  Preparation of products for external use

PURIFIED WATER

Purified water is used in the preparation of all medication containing water except ampoules, injections, some official external preparations such as liniments. Purified Water must meet the requirements for ionic and organic chemical purity and must be protected from microbial contamination. The minimal quality of source or feed water for the production of Purified Water is Drinking Water.

Purposes:-

•  For the Production of non-parenteral  preparation/formulation
•  For the Cleaning of certain equipment used in non-parenteral product preparation
•  For Cleaning of non-parenteral product-contact components
•  For All types of tests & assay
•  For the Preparation of some bulk chemicals
•  For the preparation of media in microbiology laboratories

Preparation technique:-

•  Deionization
•  Distillation
•  Ion exchange

WATER FOR INJECTION(WFI)

Water for Injection is a solvent used in the production of parenteral and other preparations where product endotoxin content must be controlled, and in other pharmaceutical applications Water For Injection (WFI) is sterile, non pyrogenic, distilled water for the preparation of products for parenteral use. It contains no added substance and meets all the requirements of the tests for purified water. It must meet the requirements of the pyrogen test. The finished water must meet all of the chemical requirements for Purified Water as well as an additional bacterial endotoxin specification. Since endotoxins are produced by the kinds of microorganisms that are prone to inhabit water, the equipment and procedures used by the system to purify, store, and distribute Water for Injection must be designed to minimize or prevent microbial contamination as well as remove incoming endotoxins from the starting water. Water for Injection systems must be validated to reliably and consistently produce and distribute this quality of water.

Purposes:-

(i) For the production of parenteral products/formulation
(ii) For cleaning of parenteral product-contact components.

Preparation technique:-
• Distillation
• Reverse osmosis
• Membrane process

Storage condition

It can be stored for periods up to a month in special tanks containing ultraviolet lamps. When this freshly prepared water is stored and sterilized in hermitically sealed containers, it will remain in good condition indefinitely.
If autoclave is not available, freshly distilled water may be sterilized by boiling the water for at least 60 minutes in a flask stoppered with a plug of purified non absorbent cotton covered with gauze, tin-foil or stout non absorbent paper; or the neck of the flask may be covered with cellophane and tightly fastened with cord.

STERILE WATER FOR INJECTION

It’s specifications are provided in USP monograph for water for injection, sterilized and packaged in suitable single-dose containers, preferably of type I glass, of not larger than 1000 ml size. It meets the requirements of the sterility test and pyrogen test and other tests under purified water.

Purposes:-

• Used for extemporaneous preparation compounding.
• Used as a sterile diluents for parenteral products.

Preparation technique:-

• By distillation of water for injection (WFI)

BACTERIOSTATIC WFI

This is sterile Water for Injection containing bacteriostatic (antimicrobial) agents. It may be packed in single-dose containers of not larger than 5 ml size and in multiple-dose containers of not larger than 30 ml size, the label of which indicates the name and the proportion of added agent.

Purposes:-

• Used as a diluents in the preparation of parenteral products

Preparation technique:-

• By using sterile water for injection

STERILE WATER FOR INHALATION

Sterile water for Inhalation is Water for Injection that is packaged and rendered sterile and is intended for use in inhalators and in the preparation of inhalation solutions. It carries a less stringent specification for bacterial endotoxins than Sterile Water for Injection, and therefore, is not suitable for parenteral applications.

STERILE WATER FOR IRRIGATION

Sterile water for irrigations is Water for Injection packaged and sterilized in single-dose containers of larger than 1 L in size that allows rapid delivery of its contents. It need not meet the requirement under small volume injection.

Purposes:-

• To bath and moisten body tissue.
• Performing urologic procedure for surgeon.

Preparation technique:-

• From water for injection

Example:-

• Surgical irrigation solution (Splash solution)
• Urologic irrigation solution
• Glycine solution
• Sorbitol solution

WATER FOR HAEMODIALYSIS

Water for hemodialysis is used for hemodialysis applications. It may be packaged and stored in unreactive containers that preclude bacterial entry. The term “unreactive containers” implies that the container, especially its water contact surfaces, are not changed in any way by the water, such as by leaching of container-related compounds into the water or by any chemical reaction or corrosion caused by the water. The water contains no added antimicrobials and is not intended for injection.

Purposes:-

• For the dilution of hemodialysis concentrate solution.

Preparation technique:-

• From safe drinking water.

PURE STEAM
 
Pure steam is also sometimes referred to as “clean steam”.

Purposes:

• To remove any co-deposited impurity residues.
• For air humidification in controlled manufacturing environments.
• Used in steam sterilization of equipment and porous loads.
• For cleaning the places where condensate directly comes in contact with official articles, product contact containers, and surfaces.

WATER MISCIBLE SOLVENTS

Although water miscible solvents are used in parenterals, principally to enhance drug solubility, it is important to mention that they also serve as stabilizers for those drugs that degrade by hydrolysis. A water miscible solvent must be selected with grade care for it must not be irritating, toxic, or sensitizing, and it must not exert an adverse effect on the ingredients of the formulation.

• Solvents that are miscible with water are:

         dioxolanes
         dimethylacetamide
         butylene glycol
         polyethylene glycol 400 and 600
         propylene glycol
         glycerin and
         ethyl alcohol

• Water immiscible solvents include:
        Fixed oil
        ethyl oleate
        Isopropyl myristate, and
        Benzyl benzoate.

WHY 70% IPA USED IN PHARMA

70% isopropyl alcohol is most commonly used disinfectant in pharmaceutical industries. The important thing is that only 70% solution of isopropyl alcohol acts as a disinfectant killing all surface microorganisms. It is used to disinfect hands and equipment surface in pharma.

70 % isopropyl alcohol solution kills microorganisms by dissolving plasma membrane of the cell wall. Plasma membrane of gram negative bacteria consist of thin layer of peptidoglycon that easily destroyed by the alcohol. Therefore, 70 percent iso propyl alcohol is known as pharmaceutical alcohol.

Water is also required to denature the proteins of cell membrane and acts as a catalyst in the reaction. Contact time of the alcohol with the organism also play an important role. A 70% solution of alcohol takes more time in evaporation from the surface, increasing the contact time. Therefore, 70% isopropyl alcohol fulfills the both requirements.

100% isopropyl alcohol coagulates the protein instantly creating a protein layer that protects the remaining protein from further coagulation. Due to this organism is not killed but remains in dormant stage. While 70% isopropyl alcohol solution penetrates in the cell wall at slower rate and coagulates the all protein of the cell wall and microorganism dies.

Thus 70% IPA solution in water is more effective then 100% absolute alcohol and have more disinfectant capacity.