Preliminary Hazard Analysis (PHA) Determine Equipment Re-qualification Frequency

Preliminary Hazard Analysis (PHA) Utility to Determine Equipment and Instrument Re-qualification Frequency

Preliminary Hazard Analysis (PHA) Utility to Determine Equipment and Instrument Re-qualification Frequency

An Introduction to Equipment Qualification

The pharmaceutical industry induces full of experiments and it often requires conducting batch reactions using toxic or flammable materials. In many cases, complex chemical reactions are carried out with significant energy release. Such exothermic reactions processing can cause fire, explosion or runaway reaction hazards and these are quite life threatening for personnel and facilities. Equipment qualification is a critical step in overall process validation (PV), typically referred to as Stage 2A of the PV life cycle. It is outlined in many regulation and guidelines, including the FDA’s 2011 Process Validation Guidance and Annex 15 of the EU GMP, among others.

While handling the Equipment, one is likely to face the ambiguity of how often to do a given task or activity using them. It is necessary for the equipment to be periodically re-qualified if there is a performance dip with consistent working to ensure the quality of products. Here the focus is on the re-qualification decision-making framework based on the use of the preliminary hazard analysis (PHA), a tool used in quality risk management.

Preliminary Hazard Analysis (PHA) Utility to Determine Equipment and Instrument Re-qualification Frequency

Prior to use in production or quality control testing all new equipment should require passing through all stages of qualification such as

  • Design qualification (DQ)
  • Installation qualification (IQ)
  • Operational qualification (OQ)
  • Performance qualification (PQ)

A robust equipment qualification program is appropriate based on the uses and risks of the equipment. The activities of each of these qualification steps should be well documented, to provide evidence that the equipment is fit for its intended purpose, and those records should be available for review by request.

Stages of equipment and instrument qualification

Figure 1: Stages of equipment and instrument qualification

In the figure above, if we follow the illustration we see that once the equipment has been initially qualified, the qualification program should speak to the periodic re-qualification of equipment. It is a part of implementing any changes through a defined change control process impacting the qualified state of the equipment. Based on the criticality of the equipment used in production or on the quality control testing of products the extent of the re-qualification should be done.  Documentation of the periodic review of pertinent data is indispensable to confirm that a process/method/system continues to consistently produce a result meeting predetermined acceptance criteria.


Two primary principles of quality risk management in the pharmaceutical industry are:

  • The risk evaluation of quality should be based on scientific knowledge and concern about the protection of the personnel and facilities.
  • The quality risk management process should be commensurate with the level of risk with respect to the level of effort, formality, and documentation.

ICH Q9 on Preliminary Hazard Analysis (PHA)

As continuing to the question of “When or at what frequency should the periodic review is performed?”  How should one structure the program to help the user determine when to perform the review? What guidelines to follow to create this aspect of the qualification program?

The answer to these is to perform the ICH Q9 (Quality Risk Management) – the risk management tool PHA. According to ICH Q9, the definition of PHA is that it is a tool to analyse hazardous situations and events that might cause harm, to estimate probable hazards in occurrence for a given activity, facility, product or system based on applying prior experience or knowledge of a hazard or failure to identify future hazards.

The tool consists of the following components:

  • identification of the possibilities that the risk event happens
  • qualitative evaluation of the extent of possible injury or damage to health as an outcome
  • using a combination of severity and likelihood of occurrence, relative ranking of the hazard is given
  • the detection of the possible remedial measures

Figure 2 denotes the PHA worksheet. If we can build a worksheet to organize the analysis and assist with the facilitation of the activities, the PHA tool could essentially address all the review of the parameters, as well as correlate the risk priority ranking to a periodic review frequency for the subject equipment.

It requires team expertise in the quality risk management process, how to use the PHA tool, scoring criteria, and key definitions. It generally consists of equipment owners, process owners, and quality assurance to perform the analysis possessing a strong understanding of the whole hazard analysis. The inputs of each column to the worksheet are directed and provided by a two-step triage approach using risk blocks scored against criteria as high, medium, and low rankings as in Tables 1, 2, and 3.

Figure 2: PHA worksheet example



 PHA work sheet example



Table 1: Severity Rankings

Severity Rankings

 Table 2: Probability (Occurrence) Rankings

Probability (Occurrence) Rankings

 Table 3: Detectability Rankings

Figure 3: Risk class determination

The preliminary risk class based on severity and probability (or occurrence) was first determined as in Figure 3.

Risk priority ranking

Figure 4: Risk priority ranking

Risk priority ranking

Table 4: Example of Periodic Review Frequency

Further the hazard parameters are evaluated against detect-ability, resulting in a risk priority ranking (Figure 4). It correlates to the periodic review frequency for the subject equipment (Table 4). Once the worksheet is completed with input from team members, the periodic review frequencies should be reviewed and agreed to by all. The following PHA worksheet (Figure 5) provides an example of a completed analysis activity.

Figure 5: PHA worksheet example — completed analysis activity


PHA worksheet example — completed analysis activity
PHA worksheet example — completed analysis activity

Inferences drawn about how this method of hazard analysis can be beneficial

  • The PHA tool enables to build a usable worksheet allowing all members of the team to participate in the risk analysis activity to provide subject matter expertise, voice concerns, and promote issues for further discussion.
  • Additionally, by facilitating the team meetings, time schedules were managed and those issues that were a challenge were tabled and discussed offline.
  • At the end of each completed worksheet, team members provide feedback regarding the risk analysis activity noting the efficient use of time, effective use of risk management tools, and delivery of risk priority rankings for subject equipment in correlation with the periodicity frequency.
  • Therefore, using a risk management tool such as PHA, a periodic review frequency can be identified and applied to qualified equipment. This enables a timely recheck of the equipment by means of pertinent data like manufacturing performance trend data, change history, and/or deviation history and that in turn would help in assuring consistent production results meeting the predetermined acceptance criteria.

{PDF} Tablet Evaluation – Pharmaceutics Pharmaceutical Apparatus Material PPT

PDF Tablet Evaluation - Pharmaceutics Pharmaceutical Apparatus Material.JPG

Topic: {PDF} Tablet Evaluation – Pharmaceutics Pharmaceutical Apparatus Material: Tablets are defined as solid unit dosage form of medicaments intended for oral use. They became most popular as they were easy in preparation compared to any other type of dosage forms. But the major drawback exists in its manufacturing. If any minor problem occurs during their manufacturing then the whole batch of the unit should be discarded. It is necessary to avoid any sort of errors during its manufacturing and as a result evaluation of tablets is very important before dispatching of a batch. In the present study, we discussed about the evaluation tests for tablets.

Tablet Evaluation:

Before a tablet is released out into the market it has to pass a few quality checks, which is mandatory. Evaluation of tablet includes the assessment of tablets physical, chemical and biological properties. To studies them the following test are formulated

  •    Appearance,
  • • Size and Shape,
  • • Organoleptic properties,
  • • Uniformity of thickness,
  • • Hardness,
  • • Friability,
  • • Drug Content Uniformity,
  • • Weight Variation Test,
  • • Wetting time,
  • • Water Absorption Ratio,
  • • In vitro Dispersion Time,
  • • In vitro Disintegration Test,
  • • In vitro Dissolution Studies,
  • • Two set of apparatus,



Appearance is the first most required quality for the acceptance of tablet. General elegance and its identity play a major role for the consumer acceptance. Acceptance of the appearance of batches of the tablet has been done based on the measurement of the following factors like size, color, shape, presence or absence of odor, taste etc. [26-50]. Size and shape

General appearance is the physical appearance of the tablet it has two aspects to address

First one is the patient compliance, if the tablet is appearance is legible and good, it improves the patient compliance.

The second one Is for the manufacturer, it helps him in trouble free manufacturing if there is tablet to tablet, batch to batch and lot to lto uniformity of tablet.

General appearance would include a number of aspects like, size, shape, odor, taste, texture, legibility, identifying marks.

For rapid identification of the tablet and consumer acceptance the tablet are given a specific colour, the colour of the tablet will enable the manufacturer form differentiating the tablet lot.

The uniformity of the colour is important parameter here, the tablet should be free form mottling.

The colour uniformity and gloss of the tablet is evaluated by using reflectance spectrophotometer, tristimulus colorimetric measurement, microreflectance photometer.

Size and shape

Size and shape of a tablet has been determined by its thickness. Size and shape of a tables plays an important role in its patient compliance as the size of the tablet increases it is not much easier for its administration. Micrometer is the devise which is used to determine the thickness of a tablet. It can be acceptable if the batch falls within the ±5% of standard deviation.

Organoleptic properties:

Color should be distributed uniformly without appearance of any signs of mottling. Colour of the tablet should be compared with the standard colour for comparison.

Uniformity of thickness:

To determine the uniformity of thickness random selection of tablets has to be done from each and every batch and need to measure its thickness independently. If the thickness of any single tablet varies then the batch containing that batch will not be dispatched into market


The weight variation test would be a satisfactory method for determining drug content uniformity of drug distribution. In practice this test is performed by taking 20 tablets, from a batch. 20 tablets are weighed at a time and the average weight is taken. Then the tablet is weighed individually.


Average Weight Percentage Difference
130 mg or less 10
More than 130 mg through
324 mg
More than 324 mg 5


The thickness of individual tablets is measured with a micrometer, which gives us information about the variation between tablets. Tablet thickness should be within a ±5% variation of a standard value. Any variation in thickness within a particular lot of tablets or between manufacturer’s lots should not be clear to the unaided eye for consumer acceptance of the product. In addition, thickness should be controlled to smooth the progress of packaging.

PDF Tablet Evaluation - Pharmaceutics Pharmaceutical Apparatus Material.JPG

Different shapes and sizes of tablet are available in the market they are manufactured in order to differentiate them based on their purpose of use and quantity of active ingredient, and the age group of the patient who is going to be administered with the drug.

Heart shape tablet signify that they are for the cardiac problems, small toy shape, tablet are manufactured in order to attract children etc.

The shape and size of a tablet would vary based on tooling used in the tablet manufacturing.

The prime consideration here would be the crown size, because if the concavity is very high it many lead to capping, or chipping problem.

The crown size is measured by using micrometer, and sliding caliper scale is used to measure the size of 5 to 10 tablets at a time.

We use Micrometer for tablet thickness


Pharmaceutical manufacturers in order to differentiate their product from the other manufacturers emboss a special marking g on the tablet. The marking can be an embossing, engraving or printing.

Apart from the company marking there can be imprints which include product code, product name, product potenct,

But care must be taken that the letters that are embossed on the tablet are properly printed without double impression.


The hardness of the tablet is important for drug products that have bioavailability problem or that are sensitive to altered dissolution release profiles as a function of the compressive force employed. Tablet hardness is the force necessary to break the tablet diametrically. The tablets must be hard enough to withstand mechanical stress during packaging, shipment, and handling by the consumer.

Section <1216> of the USP 24/NF19 outlines a standard tablet friability test applicable to manufactured tablets. Most compounding pharmacy would not have the apparatus specified in Section <1216>. However, there are several hand operated tablet hardness testers that might be useful. Examples of devices are the Strong Cobb, Pfizer, and Stokes hardness testers. The principle of measurement involves subjecting the tablet to an increasing load until the tablet breaks or fractures. The load is applied along the radial axis of the tablet. Oral tablets normally have a hardness of 4 to 8 or 10 kg; however, hypodermic and chewable tablets are much softer (3 kg) and some sustained release tablets are much harder (10-20 kg).

Tablet hardness and strength are the essential to see that the tablet can with the shock and stress during manufacturing packing and transportation, and while handled by the patient.

To test the hardness of the tablet Monsanto tester, Strong-cobb tester, the Pfizer tester, the Erweka tester, the Schleuniger tester are used.

Hardness is sometimes termed the tablet crushing strength. To perform this test the tablets are located between two anvils and force is applied to the anvils, and the strength required to break the tablet is noted. If the tablet is too hard, the disintegration time is long and cannot meet up the dissolution specification, if its too soft, it cannot withstand handling when dealing with processes such as coating or packaging and shipping operations. The force with which the tablet is broken is expressed in kilograms and a hardness of 4Kg is usually well thought-out to be the minimum for satisfactory tablets. Oral tablets have a hardness of 4 to 10kg ; but, hypodermic and chewable tablets  have a hardness of 3 kg  and sustained release tablets have about 10-20 kg.

Pfzier hardness tester was used for measuring the hardness of the formulated Paracetamol tablets. From each batch 3 tablets were taken at random and subjected to test. The mean of these 3 tablets were calculated.

Friability is the tested for a tablet to see weather the tablet is stable to abrasion or not, it is tested by using Roche friabilator. This is made up of a plastic drum fixed with a machine which rotated at 25 rpm for 100 revolutions. And then the twenty tablets which were weighed prior to the test are taken out of the drum and cleaned with a cloth and weighed once again, the weight variation must not be less than 0.5 to 1.0% for an conventional tablet.


Weight variation test is performed to check that the manufactured tablets have an uniform weight.

As per USP twenty tablets are weighed individually and an compendia weight is taken, the average weight is obtained by dividing the compendia weight by 20, now the average weight is compared to the individual weight of the tablet,

For a tablet to pass the test not more than 2 tablets should lie out of the specified percentage and if no tablet differs by more than two times the percentage limit.

Average weight

Maximum percentage difference allowed

WETTING TIME (Gohel et al., 2004)

A circular tissue paper of 10cm diameter were placed in a Petri dish having an internal diameter of 10 cm. 10 ml of water containing methylene blue (10% w/w) was added to the Petri dish. The tablet was carefully placed in the centre of the Petri dish and the time taken for the water to reach the upper surface of the tablets was known as wetting time.


Disintegration is the first physical change observed for a drug when it enters into the body, thus to see simulate the disintegration of the tablet in the body the disintegration test is performed.

As per USP the disintegration apparatus consist of 6 glass tubes with a 10 number mesh at the bottom, each tube is 3 inch long.

This arrangement of 6 tubes is placed in a medium simulated to the disintegration environment. Which is maintained at 37oc +/- 2oc, in 1 liter vessel.

This system is made to move up and down through a distance of 5 to 6 cm at a frequency of 28 to 32 cycles per minute.

The disintegration time of the tablet is compared with the values in the monograph.


20 tablets were weighed and powdered. A quantity of powder containing 0.15 g of Paracetamol was added to 0.1 M NaOH, diluted with 100 ml of water. It was shaken for 15 minutes and sufficient water was added to produce 200 ml. 10 ml of the filtrate was diluted to 100 ml with water. Then 10 ml of the resulting solution was added to 10 ml of 0.1 M NaOH, finally diluted to 100 ml with water. The absorbance was measured at maximum of 257 nm. Calculate the content of C5H9N02 taking 715 as the value of A (1%, 1cm) at maximum at 257 nm.


Tablet dissolution: Disintegration time determination is a useful tool for production control, but disintegration of a tablet does not imply that the drug has dissolved. A tablet can have a rapid disintegration time yet be biologically unavailable. The dissolution rate of the drug from the primary particles of the tablet is the important factor in drug absorption and for many formulations is the rate-limiting step. Therefore, a dissolution time is more indicative of the availability of a drug from a tablet than the disintegration test. Even though this is an important parameter to measure, most pharmacies do not have the equipment needed to conduct these kinds of tests.

The rate and extent of drug release form the tablet is estimated by dissolution test

Different types of apparatus are used to study the dissolution test of the tablet. As per IP apparatus I (paddle) and apparatus II(basket) are used. called basket dissolution apparatus and paddle dissolution apparatus

But as per USP dissolution apparatus used are

USP 30 classification

i. Rotating Basket (Ph.Eur./BP/JP)

ii. Paddle (Ph.Eur./BP/JP)

iii. Reciprocating Cylinder (Ph.Eur.)

iv. Flow Through Cell (Ph.Eur./BP/JP)

v. Paddle Over Disk (Ph.Eur.)

vi. Rotating Cylinder (Ph.Eur.)

vii. Reciprocating Holder

  1. DISSOLUTION KINETICS (Higuchi WI, 1962)

Method used to compare dissolution data is:

  • Model Dependent Methods (zero order, first order, Higuchi and Korsmeyer’s- Peppas).

Drug release kinetics

Drug release kinetics was studied from the datas obtained from in-vitro drug release studies which were plotted in various kinetics models: Zero order (equation 1) as Cumulative percentage of drug released against Time, First order (equation 2) as Log cumulative percentage of drug unreleased against Time, and Higuchi model (equation 3) as Cumulative percentage of drug released against Square root of time.

C = K0 t                                    (equation 1)

where       K0 indicates zero order rate constant expressed as                            concentration per time and t indicates the time in                                   hours.

A graph of concentration against time gives a straight line with a slope equal to K0 and intercept the origin of the axis.

log C = log C0 – K t/2.303                              (equation 2)

where         C0 be the initial concentration of drug,

K be the first order constant, and t is the time.

Q = K t1/2                                                                        (equation 3)

where        K indicates the constant of the system, t indicates the   time in hours.

Drug release were plotted in Korsmeyer equation (equation 4) as Log cumulative percentage of drug released against Log time, and the exponent was calculated from  the slope of the straight line.

Mt / Mα =  K tn                                                             (equation 4)

where          Mt / Mα is the fraction of solute release, t is the release time,  K is the kinetic constant

The dissolution time and rate is compared to the values mentioned in the monograph.

In vitro disintegration test

Disintegration is defined as the process of breakdown of tablet into small particles. Disintegration time of a tablet is determined by using disintegration test apparatus as per IP specifications. Place each tablet in each 6 tubes of the disintegration apparatus a then add a disc to each tube containing 6.8 pH phosphate buffer. The temperature of the buffer should maintain at 37 ± 2°C and run the apparatus raised and lowered for 30 cycles per minute. Note down the time taken for the complete disintegration of the tablet without any remitants .

1. J. S. Swarbrick, Encyclopedia of Pharmaceutical Technology, Third dition – 6 Volume Set,
Taylor & Francis, 2006.

Lachman et al., 1990


Homology Modelling of Protein Steps Tools Software Tutorial PDF PPT Papers

Homology Modelling of Protein Steps Tools Software Tutorial PDF PPT Papers

What is Homology Modelling?

Homology modelling allows users to safely use rapidly generated in silico protein models in all the contexts where today only experimental structures provide a solid basis: structure-based drug design, analysis of protein function, interactions, antigenic behavior, and rational design of proteins with increased stability or novel functions. In addition, protein modeling is the only way to obtain structural information if experimental techniques fail. Many proteins are simply too large for NMR analysis and cannot be crystallized for X-ray diffraction.

Homology Modelling of Protein Steps Tools Software Tutorial PDF PPT Papers

Among the major approaches to three-dimensional (3D) structure prediction, homology modeling is the easiest one.
In the Homology Modelling, structure of a protein is uniquely determined by its amino acid sequence (Epstain, Goldberger, and Anfinsen, 1963). Knowing the sequence should, at least in theory, suffice to obtain the structure.
2. During evolution, the structure is more stable and changes much slower than the associated sequence, so that similar sequences adopt practically identical structures, and distantly related sequences still fold into similar structures. This relationship was first identified by Chothia and Lesk (1986) and later quantified by Sander and Schneider (1991). Thanks to the exponential growth of the Protein Data Bank (PDB), Rost (1999) could recently derive a precise limit for this rule. As long as the length of two sequences and the percentage of identical residues fall in the region marked as “safe,” the two sequences are practically guaranteed to adopt a similar structure.

Homology Modelling or Protein Modelling Example

Imagine that we want to know the structure of sequence A (150 amino acids long,). We compare sequence A to all the sequences of known structures stored in the PDB (using, for example, BLAST), and luckily find a sequence B (300 amino acids long) containing a region of 150 amino acids that match sequence A with 50% identical residues. As this match (alignment) clearly falls in the safe zone (Fig. 25.1), we can simply take the known structure of sequence B
(the template), cut out the fragment corresponding to the aligned region, mutate those amino acids that differ between sequences A and B, and finally arrive at our model for structure A. Structure A is called the target and is of course not known at the time of modeling.

Homology Modelling of Protein Steps Tools Software Tutorial PDF PPT

Homology Modelling Steps

In practice, homology modeling is a multistep process that can be summarized in seven steps:
1. Template recognition and initial alignment
2. Alignment correction
3. Backbone generation
4. Loop modeling
5. Side-chain modeling
6. Model optimization
7. Model validation

At almost all the steps choices have to be made. The modeler can never be sure to make the best ones, and thus a large part of the modeling process consists of serious thought about how to gamble between multiple seemingly similar choices. A lot of research has been spent on teaching the computer how to make these decisions, so that homology models can be built fully automatically. Currently, this allows modelers to construct models for about 25% of the amino acids in a genome, thereby supplementing the efforts of structural genomics projects.

Homology_Modelling – Protein PPT

homology modeling

Protein Homology modelling steps ppt Structures

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[PPT PDF] Pharmaceutical Water System Validation – IDENTIFICATION OF MICROORGANISMS

[PPT PDF] Pharmaceutical Water System Validation - IDENTIFICATION OF MICROORGANISMS

IDENTIFICATION OF MICROORGANISMS – Pharmaceutical Water System Validation

Identifying the isolates recovered from water monitoring methods may be important in instances where specific waterborne microorganisms may be detrimental to the products or processes in which the water is used. Microorganism information such as this may also be useful when identifying the source of microbial contamination in a product or process. Often a limited group of microorganisms is routinely recovered from a water system. After repeated recovery and characterization, an experienced microbiologist may become proficient at their identification based on only a few recognizable traits such as colonial morphology and staining characteristics. This may allow for a reduction in the number of identifications to representative colony types, or, with proper analyst qualification, may even allow testing short cuts to be taken for these microbial identifications.


Though the use of alert and action levels is most often associated with microbial data, they can be associated with any attribute. In pharmaceutical water systems, almost every quality attribute, other than microbial quality, can be very rapidly determined with near-real time results. These short-delay data can give immediate system performance feedback, serving as ongoing process control indicators. However, because some attributes may not continuously be monitored or have a long delay in data availability (like microbial monitoring data), properly established Alert and Action Levels can serve as an early warning or indication of a potentially approaching quality shift occurring between or at the next periodic monitoring. In a validated water system, process controls should yield relatively constant and more than adequate values for these monitored attributes such that their Alert and Action Levels are infrequently broached.

As process control indicators, alert and action levels are designed to allow remedial action to occur that will prevent a system from deviating completely out of control and producing water unfit for its intended use. This “intended use” minimum quality is sometimes referred to as a “specification” or “limit”. In the opening paragraphs of this chapter, rationale was presented for no microbial specifications being included within the body of the bulk water (Purified Water and Water for Injection) monographs. This does not mean that the user should not have microbial specifications for these waters. To the contrary, in most situations such specifications should be established by the user. The microbial specification should reflect the maximum microbial level at which the water is still fit for use without compromising the quality needs of the process or product where the water is used. Because water from a given system may have many uses, the most stringent of these uses should be used to establish this specification.

Where appropriate, a microbial specification could be qualitative as well as quantitative. In other words, the number of total microorganisms may be as important as the number of a specific microorganism or even the absence of a specific microorganism. Microorganisms that are known to be problematic could include opportunistic or overt pathogens, nonpathogenic indicators of potentially undetected pathogens, or microorganisms known to compromise a process or product, such as by being resistant to a preservative or able to proliferate in or degrade a product. These microorganisms comprise an often ill-defined group referred to as “objectionable microorganisms”. Because objectionable is a term relative to the water’s use, the list of microorganisms in such a group should be tailored to those species with the potential to be present and problematic. Their negative impact is most often demonstrated when they are present in high numbers, but depending on the species, an allowable level may exist, below which they may not be considered objectionable.

[PPT PDF] Pharmaceutical Water System Validation – IDENTIFICATION OF MICROORGANISMS IDENTIFICATION OF MICROORGANISMS – Pharmaceutical warer system ppt [PPT PDF] Pharmaceutical Water System Validation - IDENTIFICATION OF MICROORGANISMS

As stated above, alert and action levels for a given process control attribute are used to help maintain system control and avoid exceeding the pass/fail specification for that attribute. Alert and action levels may be both quantitative and qualitative. They may involve levels of total microbial counts or recoveries of specific microorganisms. Alert levels are events or levels that, when they occur or are exceeded, indicate that a process may have drifted from its normal operating condition. Alert level excursions constitute a warning and do not necessarily require a corrective action. However, alert level excursions usually lead to the alerting of personnel involved in water system operation as well as QA. Alert level excursions may also lead to additional monitoring with more intense scrutiny of resulting and neighboring data as well as other process indicators. Action levels are events or higher levels that, when they occur or are exceeded, indicate that a process is probably drifting from its normal operating range. Examples of kinds of action level “events” include exceeding alert levels repeatedly; or in multiple simultaneous locations, a single occurrence of exceeding a higher microbial level; or the individual or repeated recovery of specific objectionable microorganisms. Exceeding an action level should lead to immediate notification of both QA and personnel involved in water system operations so that corrective actions can immediately be taken to bring the process back into its normal operating range. Such remedial actions should also include efforts to understand and eliminate or at least reduce the incidence of a future occurrence. A root cause investigation may be necessary to devise an effective preventative action strategy. Depending on the nature of the action level excursion, it may also be necessary to evaluate its impact on the water uses during that time. Impact evaluations may include delineation of affected batches and additional or more extensive product testing. It may also involve experimental product challenges.

Alert and action levels should be derived from an evaluation of historic monitoring data called a trend analysis. Other guidelines on approaches that may be used, ranging from “inspectional”to statistical evaluation of the historical data have been published. The ultimate goal is to understand the normal variability of the data during what is considered a typical operational period. Then, trigger points or levels can be established that will signal when future data may be approaching (alert level) or exceeding (action level) the boundaries of that “normal variability”. Such alert and action levels are based on the control capability of the system as it was being maintained and controlled during that historic period of typical control.

In new water systems where there is very limited or no historic data from which to derive data trends, it is common to simply establish initial alert and action levels based on a combination of equipment design capabilities but below the process and product specifications where water is used. It is also common, especially for ambient water systems, to microbiologically “mature” over the first year of use. By the end of this period, a relatively steady state microbial population (microorganism types and levels) will have been allowed or promoted to develop as a result of the collective effects of routine system maintenance and operation, including the frequency of unit operation rebeddings, backwashings, regenerations, and sanitizations. This microbial population will typically be higher than was seen when the water system was new, so it should be expected that the data trends (and the resulting alert and action levels) will increase over this “maturation” period and eventually level off.

Pharmaceutical water System

A water system should be designed so that performance-based alert and action levels are well below water specifications. With poorly designed or maintained water systems, the system owner may find that initial new system microbial levels were acceptable for the water uses and specifications, but the mature levels are not. This is a serious situation, which if not correctable with more frequent system maintenance and sanitization, may require expensive water system renovation or even replacement. Therefore, it cannot be overemphasized that water systems should be designed for ease of microbial control, so that when monitored against alert and action levels, and maintained accordingly, the water continuously meets all applicable specifications.

An action level should not be established at a level equivalent to the specification. This leaves no room for remedial system maintenance that could avoid a specification excursion. Exceeding a specification is a far more serious event than an action level excursion. A specification excursion may trigger an extensive finished product impact investigation, substantial remedial actions within the water system that may include a complete shutdown, and possibly even product rejection.

Another scenario to be avoided is the establishment of an arbitrarily high and usually nonperformance based action level. Such unrealistic action levels deprive users of meaningful indicator values that could trigger remedial system maintenance. Unrealistically high action levels allow systems to grow well out of control before action is taken, when their intent should be to catch a system imbalance before it goes wildly out of control.

Because alert and action levels should be based on actual system performance, and the system performance data are generated by a given test method, it follows that those alert and action levels should be valid only for test results generated by the same test method. It is invalid to apply alert and action level criteria to test results generated by a different test method. The two test methods may not equivalently recover microorganisms from the same water samples. Similarly invalid is the use of trend data to derive alert and action levels for one water system, but applying those alert and action levels to a different water system. Alert and action levels are water system and test method specific.

Nevertheless, there are certain maximum microbial levels above which action levels should never be established. Water systems with these levels should unarguably be considered out of control. Using the microbial enumeration methodologies suggested above, generally considered maximum action levels are 100 cfu per mL for Purified Water and 10 cfu per 100 mL for Water for Injection. However, if a given water system controls microorganisms much more tightly than these levels, appropriate alert and action levels should be established from these tighter control levels so that they can truly indicate when water systems may be starting to trend out of control. These in-process microbial control parameters should be established well below the user-defined microbial specifications that delineate the water’s fitness for use.

Special consideration is needed for establishing maximum microbial action levels for Drinking Water because the water is often delivered to the facility in a condition over which the user has little control. High microbial levels in Drinking Water may be indicative of a municipal water system upset, broken water main, or inadequate disinfection, and therefore, potential contamination with objectionable microorganisms. Using the suggested microbial enumeration methodology, a reasonable maximum action level for Drinking Water is 500 cfu per mL. Considering the potential concern for objectionable microorganisms raised by such high microbial levels in the feedwater, informing the municipality of the problem so they may begin corrective actions should be an immediate first step. In-house remedial actions may or may not also be needed, but could include performing additional coliform testing on the incoming water and pretreating the water with either additional chlorination or UV light irradiation or filtration or a combination of approaches.

Source : USP

Expert Committee : (PW05) Pharmaceutical Waters 05

USP29–NF24 Page 3056

Pharmacopeial Forum : Volume No. 30(5) Page 1744

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Pharmaceutical Water System PPT – What Is Pharmaceutical Water – Principles PDF

Pharmaceutical Water System PPT - What Is Pharmaceutical Water - Principles PDF

Water is the most widely used substance, raw material or starting material in the production, processing and formulation of pharmaceutical products. It has unique chemical properties due to its polarity and hydrogen bonds. This means it is able to dissolve, absorb, adsorb or suspend many different compounds. These include contaminants that may represent hazards in themselves or that may be able to react with intended product substances, resulting in hazards to health.

Pharmaceutical Water System Ppt – What Is Pharmaceutical Water

Water is used as ingredient, and solvent in the processing, formulation, and manufacture of pharmaceutical products, active pharmaceutical ingredients (APIs) and intermediates, compendial articles, and analytical reagents. This general information chapter provides additional information about water, its quality attributes that are not included within a water monograph, processing techniques that can be used to improve water quality, and a description of minimum water quality standards that should be considered when selecting a water source.

Pharmaceutical water includes different types of water used in the manufacture of drug products.


Potable (drinkable) water
USP purified water
USP water for injection (WFI)
USP sterile water for injection
LUSP sterile water for inhalation
USP bacteriostatic water for injection
USP sterile water for irrigation

Control of the chemical purity of these waters is important and is the main purpose of the monographs in this compendium. Unlike other official articles, the bulk water monographs (Purified Water and Water for Injection) also limit how the article can be produced because of the belief that the nature and robustness of the purification process is directly related to the resulting purity. The chemical attributes listed in these monographs should be considered as a set of minimum specifications. More stringent specifications may be needed for some applications to ensure suitability for particular uses. Basic guidance on the appropriate applications of these waters is found in the monographs and is further explained in this chapter.

Control of the microbiological quality of water is important for many of its uses. All packaged forms of water that have monograph standards are required to be sterile because some of their intended uses require this attribute for health and safety reasons. USP has determined that a microbial specification for the bulk monographed waters is inappropriate and has not been included within the monographs for these waters. These waters can be used in a variety of applications, some requiring extreme microbiological control and others requiring none. The needed microbial specification for a given bulk water depends upon its use.

Pharmaceutical Water System PPT - What Is Pharmaceutical Water - Principles PDF

A single specification for this difficult-to-control attribute would unnecessarily burden some water users with irrelevant specifications and testing. However, some applications may require even more careful microbial control to avoid the proliferation of microorganisms ubiquitous to water during the purification, storage, and distribution of this substance. A microbial specification would also be inappropriate when related to the “utility” or continuous supply nature of this raw material. Microbial specifications are typically assessed by test methods that take at least 48 to 72 hours to generate results. Because pharmaceutical waters are generally produced by continuous processes and used in products and manufacturing processes soon after generation, the water is likely to have been used well before definitive test results are available.

Failure to meet a compendial specification would require investigating the impact and making a pass/fail decision on all product lots between the previous sampling’s acceptable test result and a subsequent sampling’s acceptable test result. The technical and logistical problems created by a delay in the result of such an analysis do not eliminate the user’s need for microbial specifications. Therefore, such water systems need to be operated and maintained in a controlled manner that requires that the system be validated to provide assurance of operational stability and that its microbial attributes be quantitatively monitored against established alert and action levels that would provide an early indication of system control.

Pharmaceutical Water System PPT – What Is Pharmaceutical Water – Principles PDF

Important Notes on Pharmaceutical Water Systems

  1. Control of the quality of water throughout the production, storage and distribution processes, including  microbiological and chemical quality, is a major concern. Unlike other product and process ingredients, water is usually drawn from a system on demand, and is not subject to testing and batch or lot release before use. Assurance of quality to meet the on-demand expectation is, therefore, essential. Additionally, certain microbiological tests may require periods of incubation and, therefore, the results are likely to lag behind the water use.
  2. Control of the microbiological quality of WPU is a high priority. Some types of microorganism may proliferate in water treatment components and in the storage and distribution systems. It is crucial to minimize microbial contamination by proper design of the system, periodic sanitization and by taking appropriate measures to prevent microbial proliferation.
  3. Different grades of water quality are required depending on the route of administration of the pharmaceutical products. Other sources of guidance about different grades of water can be found in pharmacopoeias and related documents.

Pharmaceutical Water System: Principles For Pharmaceutical Water Systems


  • Pharmaceutical water production, storage and distribution systems should be designed, installed, commissioned, qualified and maintained to ensure the reliable production of water of an appropriate quality. It is necessary to validate the water production process to ensure the water generated, stored and distributed is not beyond the designed capacity and meets its specifications.
  • The capacity of the system should be designed to meet the average and the peak slow demand of the current operation. If necessary, depending on planned future demands, the system should be designed to permit increases in the capacity or designed to permit modification. All systems, regardless of their size and capacity, should have appropriate recirculation and turnover to assure the system is well controlled chemically and microbiologically.
  • The use of the systems following initial validation (installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ)) and after any planned and unplanned maintenance or modification work should be approved by the quality assurance (QA) department using change control documentation.
  • Pharmaceutical Water System PPT – What Is Pharmaceutical Water – Principles PDF Doc
  • Water sources and treated water should be monitored regularly for chemical, microbiological and, as appropriate, endotoxin contamination. The performance of water purification, storage and distribution systems should also be monitored. Records of the monitoring results, trend analysis and any actions taken should be maintained.
  • Where chemical sanitization of the water systems is part of the biocontamination control programme a validated procedure should be followed to ensure that the sanitizing process has been effective and that the sanitizing agent has been effectively removed.

Pharmaceutical Water Systems: Pharmaceutical Water Storage & Distribution Systems [PDF PPT]

Pharmaceutical Water Systems Pharmaceutical Water Storage & Distribution Systems [PDF PPT]

Water storage and distribution systems

Pharmaceutical Water Systems:: Water storage and distribution systems applies to WPU systems for PW, BHPW and BWFI. The water storage and distribution should work in conjunction with the purification plant to ensure delivery of water of consistent quality to the user points, and to ensure optimum operation of the water purification equipment.

General Principles of Water storage and distribution systems of Pharmaceutical Water Systems:

  1. The storage and distribution system should be considered as a key part of the whole system and should be designed to be fully integrated with the water purification components of the system.
  2. Once water has been purified using an appropriate method it can either be used directly or, more frequently, it will be fed into a storage vessel for subsequent distribution to points of use. The the requirements for storage and distribution systems and point of use fflPOU) is provided below.
  3. The storage and distribution system should be configured to prevent microbial proliferation and recontamination of the water fflPW, BHPW, BWFI) treatment. It should be subjected to a combination of online and offline monitoring to ensure that the appropriate water specification is maintained.

2 Materials that come into contact with systems for water for pharmaceutical use in Pharmaceutical Water Systems:

Here we deal with generation equipment for PW, BHPW and BWFI and the associated storage and distribution systems.

2.2 The materials that come into contact with WPU, including pipework, valves and fittings, seals, diaphragms and instruments, should be selected to satisfy the following objectives.


The compatibility and suitability of the materials should encompass the full range of its working temperature and

potential chemicals that will come into contact with the system at rest, in operation and during sanitization.

Prevention of leaching.

All materials that come into contact with WPU should be non-leaching at the range of working and sanitization

temperatures of the system.

Corrosion resistance.

PW, BHPW and BWFI are highly corrosive. To prevent failure of the system and contamination of the water, the materials selected must be appropriate, the method of jointing must be carefully controlled and all fittings and components must be compatible with the pipework used. Appropriate sanitary specification plastics and stainless-steel materials are acceptable for WPU systems. When stainless steel is used it should be at least grade 316. In general 316L or a higher grade of stainless steel is used. The system should be passivated after initial installation or after significant modification. When accelerated passivation is undertaken the system should be thoroughly cleaned first and the passivation process should be undertaken in accordance with a clearly defined documented procedure.

Smooth internal Finish.

Once water has been purified it is susceptible to microbiological contamination and the system is subject to the formation of biofilms when cold storage and distribution are employed. Smooth internal surfaces help to avoid roughness and crevices within the WPU system. Crevices can be the source of contamination because of possible accumulation of microorganisms and formation of biofilms. Crevices are also frequently sites where corrosion can commence. The internal material finish should have an arithmetical average surface roughness of not greater than 0.8 micrometre fflRa). When stainless steel is used, mechanical and electro-polishing techniques may be employed. Electro-polishing improves the resistance of the stainless-steel material to surface corrosion.


The selected system materials should be easily joined by welding in a controlled manner. The control of the process should include, as a minimum, qualification of the operator, documentation  of the welder set-up, work session test pieces logs of all welds and visual inspection of a defined proportion of welds, e.g. 100ft hand welds, 10ft automatic welds.


All system components should be fully documented and be supported by original or certified copies of material certificates.

Materials used for Pharmaceutical Water Systems:

Suitable materials that may be considered for sanitary elements of the system include 316L ffllow carbon) stainless steel, polypropylene, polyvinylidene-diFluoride and perFluoroalkoxy. The choice of material should take into account the intended sanitization method. Other materials such as unplasticized polyvinyl-chloride ffluPVC) may be used for treatment equipment designed for less pure water such as ion exchangers and softeners.

None of the materials that come into contact with WPU should contain chemicals that will be extracted by the water. Plastics should be non-toxic and should be compatible with all chemicals used. They should be manufactured from materials that should at least meet minimum food grade standards. Their chemical and biological characteristics should meet any relevant pharmacopoeia specifications or recommendations. Precautions should be taken to define operational limits for areas where water circulation is reduced and turbulent Flow cannot be achieved. Minimum Flow rate and change volumes should be defined.

3. System sanitization and bioburden control -Pharmaceutical Water Systems:

1 Water treatment equipment, storage and distribution systems used for BPW, BHPW and BWFI should be provided with features to control the proliferation of microbiological organisms during normal use, as well as techniques for sanitizing the system after intervention for maintenance or modification. The techniques employed should be considered during the design of the system and should take into account the interdependency between the materials and the sanitization techniques.

2 Systems that operate and are maintained at elevated temperatures ffle.g. > 65) are generally less susceptible to microbiological contamination than systems that are maintained at lower temperatures. When lower temperatures are required due to the water treatment processes employed or the temperature requirements for the water in use, special precautions should be taken to prevent the ingress and proliferation of microbiological contaminants fflsee section 6.4.3 for guidance).

4 Storage vessel requirements -Pharmaceutical Water Systems:

1 General

1 The water storage vessel used in a system serves a number of important functions. The design and size of the vessel should take into consideration the following.

2 Capacity

1 The capacity of the storage vessel should be determined on the basis of the following requirements:

It is necessary to provide a buffer capacity between the steady-state generation rate of the water-treatment equipment and the potentially variable simultaneous demand from user points.

The water-treatment equipment should be able to operate continuously for significant periods to avoid the equipment stress that occur when the equipment cycles on and off too frequently.

The capacity should be suffcient to provide short-term reserve capacity in the event of failure of the water-treatment equipment or inability to produce water due to a sanitization or regeneration cycle. When determining the size of such reserve capacity, consideration should be given to providing suffcient water to complete a process batch, work session, tank turnover by recirculation to minimize stagnation, or other logical period of demand.

3 Contamination control considerations -Pharmaceutical Water Systems:

The following should be taken into account for the efficient control of contamination:

) The headspace in the storage vessel is an area of risk where water droplets and air can come into contact at temperatures that encourage the proliferation of microbiological organisms. The use of spray-ball or distributor devices should be considered in these systems to wet the surfaces during normal operation, chemical and/or thermal sanitization.

) Nozzles within the storage vessels should be configured to avoid dead zones where microbiological contamination might be harboured.

) Vent filters are fitted to storage vessels to allow the internal level of liquid to Fluctuate. The filters should be bacteria-retentive, hydrophobic and should ideally be configured to allow in situ testing of integrity. Offline testing is also acceptable. The use of heated vent filters should be considered for continuous hot storage or systems using periodic heat sanitization to prevent condensation within the filter matrix that might lead to filter blockage and to microbial growth that could contaminate the storage vessels.

) Where pressure-relief valves and bursting discs are provided on storage vessels to protect them from under- and over-pressurization, these devices should be of a sanitary design. Bursting discs should be provided with external rupture indicators to ensure that loss of system integrity is detected.

Requirements for water distribution pipework -Pharmaceutical Water Systems:


The distribution of BPW, BHPW and BWFI should be accomplished using  a continuously circulating pipework loop. Proliferation of contaminants within the storage tank and distribution loop should be controlled. Good justification for using a non-recirculating one-way system should be provided.

2 Filtration should not usually be used in distribution loops or at take off-user points to control biocontamination. Such filters are likely to conceal system contamination.

Temperature control and heat exchangers

Where heat exchangers are employed to heat or cool WPU within a system, precautions should be taken to prevent the heating or cooling utility from contaminating the water. The more secure types of heat exchangers of the double tube plate or double plate and frame or tube and shell configuration should be considered. Where these types are not used, an alternative approach whereby the utility is maintained and monitored at a lower pressure than the WPU may be considered. The latter approach is not usually adopted in BWFI systems.

Where heat exchangers are used they should be arranged in continually circulating loops or subloops of the system to avoid unacceptable static water in systems.

When the temperature is reduced for processing purposes the reduction should occur for the minimum necessary time. The cooling cycles and their duration should be proven satisfactory during the qualification of the system.

Pharmaceutical Water Systems Pharmaceutical Water Storage & Distribution Systems [PDF PPT]

3 Circulation pumps

Circulation pumps should be of a sanitary design with appropriate seals that prevent contamination of the system. Where stand-by pumps are provided, they should be configured or managed to avoid dead zones trapped within the system.

Consideration should be given to preventing contamination in systems where parallel pump systems are used, especially if there is stagnant water when one of the pumps is not being used.

4 Biocontamination control techniques

1 Water purification systems should be sanitized using chemical or thermal sanitization procedures as appropriate fflproduction and distribution). The procedure and conditions used fflsuch as times and temperatures) should be suitable.

2 The following control techniques may be used alone or more commonly in combination:

maintenance of continuous turbulent flow circulation within water distribution systems reduces the propensity for the formation of biofilms the system design should ensure the shortest possible length of pipework;

) for ambient temperature systems, pipework should be isolated from adjacent hot pipes;

) dead legs in the pipework should be minimized through appropriate design, and as a guide should not significantly exceed three times the branch diameter as measured from the ID pipe wall to center line of the point-of-use valve where significant stagnation potential exists;

) pressure gauges should be separated from the system by membranes;

) hygienic pattern diaphragm valves should be used;

) pipework for steam-sanitized systems should be sloped and fully drainable;

) the growth of microorganisms can be inhibited by:

– ultraviolet radiation sources in pipework;

– maintaining the system heated fflgreater than 65 °C);

– sanitizing the system periodically using hot water guidance temperature > 70’°C);

– sanitizing the system periodically using superheated hot water or clean steam;

– routine chemical sanitization using ozone or other suitable chemical agents. When chemical sanitization is used, it is essential to prove that the agent has been removed prior to using the water. Ozone can be effectively removed by using ultraviolet radiation.

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Source: WHO

M Pharmacy Parmaceutics Project : APPROACHES TO COLON-SPECIFIC DRUG DELIVERY [Ceutics]

M Pharmacy Parmaceutics Project APPROACHES TO COLON-SPECIFIC DRUG DELIVERY [Ceutics]



In recent years, a large number of solid formulations targeting the lower parts of the GI tract, especially the colon, have been reported. These formulations may be broadly divided into four types, which are

  1. pH-dependent system designed to release a drug in response to change in pH,
  2. Time controlled ( or Time-dependent) system designed to release a drug after a predetermined time,
  3. Microbially-controlled system making use of the abundant enterobacteria in the colon,
  4. Enzyme-based systemsProdrug, and
  5. Pressure-dependent system making use of luminal pressure of the colon.

Among these, first three are most widespread formulation technologies being developed for pharmaceutical market.



Solid formulations for colonic delivery that are based on pH-dependent drug release mechanism are similar to conventional enteric-coated formulations but they differ in target site for delivery and therefore type of enteric polymers. In contrast to conventional enteric-coated formulations, colonic formulations are designed to deliver drugs to the distal (terminal) ileum and colon, and utilize enteric polymers that have relatively higher threshold pH for dissolution (Dew et al., 1982; Tuleu et al., 2001). Most commonly used polymers (Table 2) are derivatives of acrylic acid and cellulose. These polymers have ability to withstand an environment ranging from low pH (~1.2) to neutral pH (~7.5) for several hours. Apparently, it is highly desirable for pH-dependent colonic formulations to maintain their physical and chemical integrity during passage through the stomach and small intestine and reach the large intestine where the coat should disintegrate to release the drug locally. It should be however noted that GI fluids might pass through the coat while the dosage form transits through the small intestine. This could lead to premature drug release in the upper parts of GI tract and as a result loss of therapeutic efficacy may occur. One approach to overcome this problem is to apply

higher coating levels of enteric polymers; however, this also allows influx of GI fluids through the coat, and the thicker coats often rupture under the influence of contractile activity in the stomach. In general, the amount of coating required depends upon the solubility characteristics (solubility, dose/solubility ratio) of the drug, desired release profile and surface area of the formulation, and composition of the coating solution/dispersion.

Widely used polymers are methacrylic resins (Eudragits), which are available in water soluble and water-insoluble forms. Eudragit L and S are copolymers of methacrylic acid and methyl methacrylate. To overcome the problem of premature drug release, a copolymer of methacrylic acid, methyl methacrylate and ethyl acrylate (Eudragit® FS), which dissolves at a slower rate and at a higher threshold pH (7–7.5), has been developed recently. A series of in vitro dissolution studies with this polymer have highlighted clear benefits over the Eudragit® S polymer for colonic targeting (Rudolph et al., 2001).


Khan et al., (1999) prepared lactose-based placebo tablets and coated using various combinations of two methacrylic acid polymers, Eudragit® L100-55 and Eudragit® S100 by spraying from aqueous systems. The Eudragit® L100-55 and Eudragit® S100 combinations studied were 1:0, 4:1, 3:2, 1:1, 2:3, 1:4, 1:5 and 0:1. The coated tablets were tested in vitro for their suitability for pH dependent colon targeted oral drug delivery. The same coating formulations were then applied on tablets containing mesalazine as a model drug and evaluated for in vitro dissolution rates under various conditions. The disintegration data obtained for the placebo tablets demonstrate that disintegration rate of the studied tablets is depends on the polymer combinations used to coat the tablets, pH of the disintegration media and the coating level of the tablets. Dissolution studies performed on the mesalazine tablets further confirmed that the release profiles of the drug could be manipulated by changing the Eudragit® L100-55 and Eudragit® S100 ratios within the pH range of 5.5 to 7.0 in which the individual polymers are soluble respectively, and a coating formulation consisting of a combination of the two copolymers can overcome the issue of high GI pH variability among individuals. The results also demonstrated that a combination of Eudragit® L100-55 and Eudragit® S100

could be successfully used from aqueous system to coat tablets for colon targeted drug delivery and the formulation can be adjusted to deliver drug at any other desirable site of the intestinal region of the GIT on the basis of pH variability.

Colon targeted drug delivery systems based on methacrylic resins has described for insulin (Touitou and Rubinstein., 1986), prednisolone (Thomos., 1985), quinolones (Van Saene et al., 1986), salsalazine (Riley et al., 1987), cyclosporine (Kim et al., 2001), beclomethasone dipropionate (Levine et al., 1987) and naproxane (Hardy et al., 1987). pH-sensitive delivery systems are commercially available for mesalazine (5-aminosalicylic acid) (Asacol® and Salofalk®) and budesonide (Budenofalk® and Entocort®) for the treatment of ulcerative colitis and Crohn’s disease, respectively.


Table 2. Threshold pH of commonly used polymers    



Threshold pH
Eudragit® L100

Eudragit® S100

Eudragit® L 30D

Eudragit® FS 30D

Eudragit® L100-55
















PVAP = Polyvinyl acetate phthalate; HPMCP = Hydroxypropylmethylcellulose phthalate; CAP= Cellulose acetate phthalate



Time-controlled systems are useful for synchronous delivery of a drug either at pre-selected times such that patient receives the drug when needed or at a pre-selected site of the GI tract. These systems are therefore particularly useful in the therapy of diseases, which depend on circadian rhythms. Time-controlled formulations for colonic delivery are also delayed-release formulations in which the delay in delivery of the drug is time-based. In these systems, it has been suggested that colonic targeting can be achieved by incorporating a lag time into the formulation equivalent to the mouth to colon transit time (Chourasia and Jain, 2003). Ideally, formulations are designed such that the site of delivery (i.e. colon) is not affected by the individual differences in the gastric emptying time, pH of the stomach and small intestine or presence of anaerobic bacteria in the colon. A nominal lag time of 5 h is usually considered sufficient, since small intestinal transit has been considered relatively constant at 3 to 4 h. In principle, time-controlled systems rely on this consistent small intestinal transit time. The drug release from these systems therefore occurs after a predetermined lag phase, which is precisely programmed by selecting a suitable combination of controlled-release mechanisms.

Available technologies based on the time controlled systems are

  1. Codes system – comprises a series of polymers that are combined to protect the drug core until the formulation arrives in the colon.
  2. Colon-Targeted Delivery System – uses lag time to achieve colon delivery. The system is comprised of three parts: an outer enteric coat, an inner semipermeable polymer membrane, and a central core comprising swelling excipients and an active component.
  3. Oros-CT – is a technology developed by Alza Corporation and consists of an enteric coating, a semipermeable membrane, a layer to delay drug release, and a core consisting of two compartments.
  4. Time Clock – delivery device developed by Pozzi and colleagues is a pulsed delivery system based on a coated solid dosage form.

The first formulation introduced based on this principle was Pulsincap® (MacNeil et al., 1990). It is similar in appearance to hard gelatin capsule; the main body is made water insoluble (exposing the body to formaldehyde vapour which may be produced by the addition of trioxymethylene tablets or potassium permanganate to formalin or any other method). The contents are contained within a body by a hydrogel plug, which is covered by a water-soluble cap. The whole unit is coated with an enteric polymer to avoid the problem of variable gastric emptying. When the capsule enters the small intestine the enteric coating dissolves and the hydrogels plug starts to swell, the amount of hydrogel is such adjusted that it pops out only after the stipulated period of time to release the contents. The viability of such a system in human volunteers has been confirmed on the basis of evaluation studies (Binns et al., 1994).

In a study by Gazzaniga et al., (1995) a novel oral time based drug release system was developed, containing core coated with three polymeric layers. The outer layer dissolves at pH > 5, then the intermediate swellable layer, made of an enteric material. The system provides the expected delayed release pattern, as also indicated by the preliminary in vivo studies on rats. Several other drug delivery systems have developed that rely upon the relatively constant transit time of small intestine (Gupta et al., 2001; Fukui et al., 2000).

Another formulation approach to achieve time-dependent delivery to the colon is osmotically controlled system (Figure 2). Theeuwes et al., (1990) described a delayed-release osmotic delivery device that can be used for localized treatment of colonic diseases or for achieving systemic absorption of drugs that are otherwise unattainable. The delivery system, commonly referred as push-pull OROS system, comprises as many 5 push-pull units encapsulated within a hard gelatin capsule. Each push-pull unit is a bilayered laminated structure containing an osmotic push layer and a drug layer, both surrounded by a semipermeable layer (approx. 0.076 mm thickness). In principle, the semipermeable membrane is permeable to the inward entry of water or aqueous GI fluids and is impermeable to the outward exit of the drug. An orifice is drilled through thesemipermeable membrane next to the drug layer. The outside surface of the semipermeable membrane is then coated by Eudragit® S-100 (approx. 0.076 mm thickness) to delay the drug release from the device during its transit through the stomach. Upon arrival in the small intestine, the coating dissolves at pH >7. As a result, water enters the unit causing the osmotic push compartment to swell, forcing the drug out of the orifice into the colon. The drug release kinetics is precisely controlled by the rate of influx of water through the semipermeable membrane. For treating the ulcerative colitis, each push pull unit is designed with a 3-4 h post gatric delay to prevent drug delivery in the small intestine.

Figure 2: Cross section of the OROS-CT colon targeted drug delivery system





These systems are based on the exploitation of the specific enzymatic activity of the microflora (enterobacteria) present in the colon. The colonic bacteria are predominately anaerobic in nature and secrete enzymes (azoreductases, β-glucuronidase, β-xylosidase, dextranases, esterases, nitroreductase, etc.) that are capable of metabolizing substrates such as carbohydrates and proteins that escape the digestion in the upper GI tract.

Polysaccharides offer an alternative substrate for the bacterial enzymes present in the colon. A number of naturally occurring polysaccharides are stable in the upper intestine yet susceptible to hydrolytic degradation in the lower intestine (Sinha et al., 2003; Vandamme et al., 2002). Most polysaccharides can be chemically modified to optimize specific properties, such as the ability to form impermeable films (Hovgaard et al., 1996). Table 3 lists a number of polysaccharide-based oral delivery systems for targeted release in the lower intestine (David R. Friend, 2005). Some of these systems have been tested in humans.

Pectin is a non-starch linear polysaccharide composed mainly of α-(1→4)-linked D-galacturonic acid groups with some 1→2 linked L-rhamnose groups. Pectin, like many other polysaccharides, is stable in the stomach and small intestine but susceptible to enzymatic degradation in the large intestine (Rubinstein et al., 1993). Calcium (Rubinstein and Glixokabir, 1995) and zinc salts (Cooke, 1967) of pectin are preferred for lower intestinal delivery since they have lower water solubility and hence better dissolution delaying properties than sodium pectinate or pectic acid. To further delay release of drugs, compression coating around a core containing drug has also been studied (Rubinstein and Radai., 1995). Improved targeted delivery to the lower intestine using pectin and other naturally occurring polysaccharides is accomplished by coating tablet or multiparticulate formulations with traditional enteric polymers. This formulation approach was tested in a human study with normal volunteers using gamma scintigraphy.

The formulations were composed of enteric-coated calcium pectinate matrix tablets prepared with and without guar gum as a binder. The tablets were found to reach the colon in most cases intact and there they disintegrated.

Another approach used to limit drug dissolution in the upper intestine involves mixed films. Mixed films are composed of polysaccharides coformulated with water-insoluble polymers such as ethylcellulose or chitosan (partially deacetylated chitin) and gel forming polymers such as hydroxypropylmethylcellulose (HPMC). These mixed films were used to prepare coatings for tablets to deliver drugs into the colon. In vitro dissolution testing of the coated tablets using a pectinolytic enzyme preparation showed that drug release was accelerated by action of this enzyme preparation compared with dissolution medium free of the enzyme (MacLeod et al., 1999).

Another polysaccharide examined for its ability to delay release of drugs in the GI tract is guar gum (GG). GG is a galactomannan material composed of linear chains of (1→4)-β-D-mannopyranosyl units with α-D-galactopyrannosyl units linked by (1→6). The colon contains enzymes (galactomannanases) capable of degrading GG (Gibson et al., 1990) to short chain fatty acids. Both matrix tablets and compression coated tablets have been administered in humans.

Tablets composed primarily of GG and the drug dexamethasone were dosed orally in humans and their transit and disintegration followed using gamma scintigraphy (Kenyon et al, 1997). Some drug was released from the tablets prior to colonic arrival but the majority of drug was released in the large intestine and release was generally correlated with tablet disintegration. A similar study resulted in the same results although no drug was used in the formulations (Krishnaiah et al., 1998). The results generated in these two studies suggested that a compression coating approach could improve targeted release (Krishnaiah et al., 1999).

The use of GG as a compression coating to delay release of a drug (rather than a gamma emitting substance) has been studied recently. Following in vitro studies (Krishnaiah et al., 2002a) a GG-based colon targeted oral delivery system for the drug 5-fluorouracil was tested in a group of 12 healthy volunteers (Krishnaiah et al., 2003a). The results from this study are consistent with delivery of 5-fluorouracil to the large intestine:

tmax increased from 0.6±0.01 h (immediate release tablets) to 7.6±0.1 h. There was no drug detected in the plasma until approximately 5 h had elapsed. In most instances, assuming normal transit patterns, the tablets are located in the colon at this time. Similar data have been obtained with several other drugs (mebendazole, metronidazole, celecoxib, and tinidazole) (Krishnaiah et al, 2003b, 2002b 2002c, 2002d).

Xanthan gum is a high molecular weight extracellular polysaccharide, produced on commercial scale by the viscous fermentation of gram negative bacterium Xanthomonas campesteris . The molecule consists of a backbone identical to that of cellulose, with side chains attached to alternate glucose residues. It is a hydrophilic polymer, which until recently had been limited for use in thickening, suspending and emulsifying water based systems. It appears to be gaining appreciation for fabrication of matrices, as it not only retards drug release, but also provides time- independent release kinetics with added advantages of biocompatibility and inertness. Release of soluble drugs was mainly through diffusion, whereas sparingly soluble or insoluble drugs were released via erosion. It is also recommended for use in both acidic and alkaline systems.

Polysaccharide-based formulations represent a relatively simple formulation approach that can be scaled-up and prepared in a reproducible and inexpensive manner. If there are no chemical modifications to the polysaccharide (i.e., they meet compendial monographs such as USP/NF), most can be used in products without additional safety testing.


Table 3: Polysaccharide-based materials used to deliver drugs to the lower Intestine

Polysaccharide Dosage forms



Calcium salt




Mixed films

of pectin


Matrices, compression

coated tablets, Compression coating


Film coating for tablets

and beads


Rubinstein et al., 1993; 1995


Ashford et al., 1994


Wakerly et al., 1996; MacLeod et al., 1999



Chitosan derivatives

Coated capsules and




Tozaki et al., 1997

Aiedeh et al., 1999

Guar gum

Guar gum


Guar gum –



Matrix tablets,

compression coated


Coatings or matrix



Krishnaiah et al., 1998a; 1999; 2002a; 2003a

Rubinstein et al., 1995; Gliko-Kabir et al., 2000

Chondroitin sulfate





Matrix tablets



Rubinstein et al., 1992a,


Calcium salt


Swellable beads


Shun et al., 1992


Mixed films


Tablet and bead coatings


Vervoort et al., 1996



cross-linked dextran




Brbndsted et al, 1995; Chiu et al.,1999




A successful prodrug-based delivery system is one in which the promoiety (i.e, inactive portion of the prodrug) minimizes absorption until the active is released (usually by enzymatic action) near the target site. Thus, the promoiety is used to increase the hydrophilicity of the parent drug, increase molecular size, or both, thus minimizing absorption of the drug prior to reaching the target site (Sinha and Kumria., 2001).

This principle has been exploited commercially to deliver 5-aminosalicylic acid to the colon by way of a prodrug carrier. The prodrug sulphasalazine consists of two separate moieties, sulphapyridine and 5-aminosalicylic acid, linked by an azo-bond. The prodrug passes through the upper gut intact, but, once in the colon, the azo-bond is cleaved by the host bacteria, liberating the carrier molecule sulphapyridine and the pharmacologically active agent 5-aminosalicylic acid (Travis et al., 1994). This concept has led to the development of novel azo-bond-based polymers (azo-polymers) for the purpose of obtaining universal carrier systems. However, issues with regard to the safety and toxicity of these synthetic polymers have yet to be addressed.

Cyclodextrins (CyDs) have been proposed as inert carriers for targeting in the GIT. Since CyDs are poorly absorbed from the GIT due to their size and hydrophilicity and degraded in the large intestine, it is possible to use them as carriers for delivery of drugs in the lower intestine. α, β, and γ-CyD-drug conjugates of prednisolone were prepared and tested as potential colon-specific prodrugs (Yano et al, 2001a, 2001b; 2002).

It has been proved through a study in healthy human volunteers that β-CyDs are meagerly digested in small intestine but are completely degraded by the microflora of the colon. The anti-inflammatory effect and systemic side effect of the prednisolone succinate/alpha-cyclodextrin ester conjugate after oral administration were studied using IBD model rats. The systemic side effect of the conjugate was much lower than that of prednisolone alone when administered orally. The lower side effect of the conjugate was attributable to passage of the conjugate through the stomach and small intestine without significant degradation or absorption, followed by the degradation of the conjugate site-specifically in the large intestine (Yano et al., 2002).

A related approach based on polysaccharides involves the use of dextrans. Like CyDs, they are relatively stable in the upper intestine but subject to enzymatic hydrolysis in the lower intestine by dextranases produced by gut microflora. A simple approach to linking a drug to dextran involves attaching carboxyl acid groups on the drug to hydroxyl groups on the polymer. In the absence of a carboxylic acid group on the drug, a spacer molecule such as succinic or glutaric acid can be used (Harboe et al., 1988).



Another approach to controlling the site (and potentially the rate) of drug release in the GIT is using the pressure. Due to the reabsorption of water from the large intestine, the viscosity of the luminal contents increases (Digenis and Sandefer., 1991). As a result, intestinal pressures increase due to peristalsis in the distal intestine providing a potential means to trigger release of a drug from a formulation susceptible to pressure changes. Such a formulation approach, called pressure- controlled colon delivery capsule (PCDC) system has been examined in both animals and humans (Takada et al., 1995).

Formulations susceptible to changes in pressure are prepared from capsule-shaped suppositories coated with ethylcellulose. The materials used in preparation of the suppositories are polyethylene glycols (PEGs). They are selected so that they melt at body temperature. The system behaves as a balloon once the PEG liquefies. In the upper intestine, there is sufficient fluidity to maintain the integrity of balloon and no drug release occurs. In the large intestine however, pressures induced by peristalsis directly affect the EC balloon leading to rupture and subsequent drug release.







Pharmaceutics M Pharmacy Project Title – Example Summary Aim – B pharm Projects

Pharmaceutics M Pharmacy Project Title – Example Summary Aim – B pharm Projects


Pharmaceutics M Pharmacy Project Title – Example Summary Aim – B pharm Projects





Aim                             :           1) To carry bioavailability study of Ornidazole from coated tablets by using pharmaceutical excipients and compare with marketed product.

2) To carry colonic residence time  evaluation by X-ray study of Ornidazole from coated tablets.

Drugs used                 :           Ornidazole 400 mg.

Subjects                      :           Eight healthy human male volunteers

Study design              :           Crossover design

Institution                   :

Principal Investigator:

Study Procedure:

Eight human healthy male subjects in the age group of 25-30 will be enrolled in the study after physical examination by a physician and standard laboratory tests.

Inclusion Criteria:

  1. Non-allergic to drug
  2. Healthy as per the physical examination and laboratory tests
  • Non-participation in any study/blood donation during preceding three months
  1. Written informed consent

Study design: Simple randomized crossover design

The subject will be treated with single oral dose of Ornidazole after overnight fasting.  In the crossover study, subjects will be given coated tablets of Ornidazole.  Blood samples will be collected at 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 30 hours.

The subject will be treated with single oral dose of placebo tablets after overnight fasting.  In the crossover study, subjects will be given placebo tablets of Ornidazole.  X-Rays will be taken at 2, 5, 8,12 and 24 hours.

Pharmaceutics M Pharmacy Project Title – Example Summary Aim – B pharm Projects PDF

Pharmaceutics M Pharmacy Project Title – Example Summary Aim – B pharm Projects Pharmaceutics M Pharmacy Project Title – Example Summary Aim – B pharm Projects

Treatments: Eight male volunteers shall be distributed in to two groups. A 2×2 cross over design shall be used in the study. Each volunteer in the two groups will receive the floating matrix tablets and commercial dosage form as                           .

The study consists of two treatments (Ornidazole coated, commercial).     Ornidazole 400 mg will be given by oral route in the form of coated tablets and blood samples will be collected at 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 30 hours.

A drug free interval of at least two weeks will be kept between the two treatments.  A standard breakfast will be served 2 hours after drug administration followed by standard lunch after 4 hours.


Ornidazole is an anti infective / antibacterial and antiprotozaol drug available as 400mg, 500 mg and 1000 mg tablets for oral administration. Its chemical name is 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole.

The half-life of the drug is approximately 7.4 hours in plasma. Ornidazole is metabolised in liver through biotranformation reactions while excretion is mainly by  Urine.


Hypersensitivity to ornidazole or to other nitroimidazole derivatives

Adverse Reactions:

Somnolence, headache, nausea, vomiting, dizziness, tremor, rigidity, poor coordination, seizures, tiredness, vertigo, temporary loss of consciousness and signs of sensory or mixed peripheral neuropathy, taste disturbances, abnormal LFTs, skin reaction.


Physical properties:

Solubility                    :           It is slightly soluble in water, and soluble in chloroform.

Pka                             :           2.4 ± 0.1

Category                    :           It is a anti-infective and anti-protozoal agent



Bioavailability            :           >90 % by oral route

Absorption                 :           Absorbed from entire GIT.

Protein Binding         :           <15 %

Half life                      :           14.67 + 1.0 hrs

Dosage                       :          400 to 1000 mg daily.





The study entitled “Bioavailability study and colonic residence time evaluation by x-ray of Ornidazole from coated tablets in healthy human volunteers” has been approved / not approved for conducting in the healthy human volunteers.







To reach the colon and to be able to specifically deliver and absorb the drug there, the dosage forms must be formulated taking into account the obstacles of the gastrointestinal tract. The various strategies developed to achieve this goal have used the specific characteristics of this organ, i.e. transit time, pH, microflora, enzymes, disease and the colonic environment. Nevertheless, these parameters can vary from one individual to the next and also according to the pathological condition and diet.


Physiological Factors

Gastrointestinal transit

Gastrointestinal transit time is important for nearly all orally targeting delivery systems. The drug delivery systems first enter in to stomach and small intestine via mouth and then reach colon. In fasted state, the motility proceeds through four phases occurring in stomach and small intestine that span over a period of 2-3 h. Phase I is a quiescent period of 40-60 min, Phase II consists of intermittent contractions for a period of 40-60 min. Phase III is a period of intense contractions sweeping material out of the stomach and down the small intestine followed by Phase IV with contractions dissipating. The feeding state affects the normal pattern by irregular contractile activity.  

It has been well documented that gastric emptying varies with different types of dosage forms. Examples of gastric residence times of single-unit tablets are given in Table 1 (Abrahamsson, 1993). It has been generally accepted that liquid emptying follows a monoexponential process and digestible solids empty in a linear fashion with time.


Small intestinal transit

Normally, transit times through the small intestine generally found to be 3-4 h. Liquids, small solids (beads, small tablets), and larger capsule-sized units moved essentially at the same rates and the transit is unaffected by food status (Davis, 1986). In a more recent study concerning dosing in relation to the timing of food intake, found that although SIT is relatively independent of food and dosage form, it was actually shortened significantly if the dose is given 30 min before food intake. This can have adverse impact on the in vivo performance of the dosage forms.


Colonic Transit

In the stomach and small intestine, food residue and endogenous secretions are exposed to an essentially sterile environment through which their transit can be measured by hours. On entering the large intestine, dosage forms encounter a rich bacterial flora and transit through the large intestine can be as long as several days. It was reported that overall mean transit time is 36 h with a range of 1 to 72 h and that the transit of liquids and small solids is equal (Phillips., 1993). Thus, absorption from colon may be incomplete and erratic depending on the dose and physicochemical properties of a particular drug. In general, absorption of an insoluble drug with high dose or a drug with limited permeability is unfavorable in this region because of the limited volume of fluid available for dissolution and the significantly reduced surface area.


Table 1. Gastrointestinal transit times for felodipine CR hydrophilic matrix

section Gastric emptying (h) Small intestine transit (h) Colon arrival (h)
Fasting Fed Fasting Fed Fasting Fed
Mean 0.6 3.2 4.7 5.1 5.3 8.3
Range 0.1-1.1 1.9-4.8 3.9-5.9 2.2-7.7 4.0-7.0 6.0-11.0
P <0.001 >0.05 >0.01




pH in the Colon

The pH gradient in the GIT is not in an increased order and is subjected to both inter- and intra-subject variations. In stomach the pH is 1.5 – 2.0 and 2 – 6 in fasted and fed conditions, respectively. The acidic pH is responsible for the degradation of various pH sensitive drugs and enteric coating may prevent it. In small intestine, the pH increases slightly from 6.6 – 7.5. On entry into the colon, the pH dropped to 6.4 in right colon. The pH of mid colon was found to be 6.6 and in the left colon, 7.0 (Evans et al., 1988).

Colonic pH has been shown reduced in disease state. The mean pH in a group of 7 patients with untreated ulcerative colitis was 4.7 whereas in 5 patients receiving treatment it was 5.5 (Raimundo et al., 1992).

Colonic microflora

The human colon is a dynamic and ecologically diverse environment, containing over 400 distinct species of bacteria with a population of 1011 to 1012 CFU/mL (Cummings et al., 1991), with Bacteroides, Bifidobacterium, Eubacterium, Lactobacillus, etc greatly outnumbering other species. For example, it was reported that Bacteroides, Bifidobacterium and Eubacterium could constitute as much as over 60% of the total cultivable flora (Salyers, 1984). These bacteria produce a wide spectrum of enzymes that, being reductive and hydrolytic in nature, are actively involved in many processes in the colon, such as carbohydrate and protein fermentation, bile acid and steroid transformation, metabolism of xenobiotic substances, as well as the activation and destruction of potential mutagenic metabolites. Nitroreductase, azoreductase, N-oxide and sulfoxide reductase are the most extensively investigated reductive enzymes, while glucosidase and glucuronidase are the most extensively studied hydrolytic enzymes. The primary source of nutrition for these anaerobic bacteria is carbohydrates such as non-starch polysaccharides (i.e., dietary fibers) from the intestinal chime. It is well established that non-starch polysaccharides are fermented during transit through the colon and the breakdown in the stomach and small intestine is negligible. Enzymes responsible for the degradation of polysaccharides include α-L-arabinofuranosidase, β-D-fucosidase,  β-D-

galactosidase, β-Dglucosidase, β-xylosidase, with the last three enzymes being the most active (Englyst et al., 1987). Additionally, the composition of colonic bacteria and corresponding enzymes can be influenced by many factors, including age, diet, diseases, medication such as antibiotics, and geographic regions (Mueller et al., 2006). A unique feature of colon microflora is that the growth and activity of certain specific species, most notably bifidobacteria and lactobacilli, can be selectively stimulated by nondigestible oligosaccharides which are known as prebiotics. Similar bacteriological data were observed in the rats fed with indigestible oligosaccharides where the caecal bifidobacteria population was higher than in the controls (Campbell et al., 1997).

Volume of the ascending colon

Up to 1,500 g of liquids and undigested materials (dietary fibers, resistant starch, partially degraded polysaccharides proteins, mucins, exfoliated epithelial cells, etc.) enters colon per day, which act as the substrates for microflora fermentation. Water together with the products of the fermentation and other nutrients was efficiently absorbed in the colon, condensing the contents into feces through the transit in the colon for eventual defecation. Therefore, it is very likely that the ascending colon contains the largest quantity of liquid. It would be expected that the low water–high gas environment of the transverse colon limits dissolution of materials.  The moisture content of caecal contents is believed to be about 86% (Cummings and Macfarlane, 1991). The volume of the ascending colon was measured in healthy subjects using a single photon emission computed tomography (SPECT) by acquiring the imaging of the ascending colon filled with 99Tcm-labelled Amberlite pellets, and was found to be 170±40 ml (Badley., 1993). If the moisture content in the ascending colon is approximately comparable to that of caecal contents, the quantity of fluid in the ascending colon should be 146±34 ml.

[DOC Pdf PPT] Physiology

Pharmaceutics notes B Pharmacy M pharmacy Study Material

Disease and the Colonic Environment

General intestinal diseases such as inflammatory bowel disease, Crohn’s disease, constipation and diarrhea may affect the release and absorption of colon specific drug delivery systems. All the specific approaches so far mentioned rely on the concept that enzymes produced by colonic microflora provide the trigger for specific delivery of fermentable coatings, anti-inflammatory azobond drugs, and other prodrugs to the cecum. Carrette and co-workers (1995) demonstrated that in patients with active Crohn’s disease, the metabolic activity of digestive flora (assessed on the activity of fecal glycosidases) was decreased. Azoreductase activity in feces of 14 patients with active Crohn’s disease was 20% of that of healthy subjects and similarly, beta-D-glucosidase and beta-D-glucuronidase activities in fecal homogenates incubated under anaerobic conditions were also decreased in patients. These data probably reflect large-bowel hypermotility and the associated diarrhea, leading to lower bacterial mass in the colon and might contribute to the therapeutic failure of targeting mechanisms in active ileocolic and colic Crohn’s disease.