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Even the terms of reference of an influential parliamentary enquiry into Britain's abortion laws have attracted controversy. MPs conducting the probe - which kicked off today - wanted to take some of the heat out of the debate by limiting submissions to scientific evidence rather than ethical and moral arguments, but in their submissions, most on the anti-abortion side of the debate argue that it is impossible to separate the two.

Trace Elements

Trace elements are inorganic substance found in small amounts in the tissue and required for various metabolic process; together with the vitamins (see below) they are sometimes referred to as micronutrients. The elements considered essential are chromium, copper, fluorine, iodine, iron, manganese, molybdenum, selenium, and zinc. Iron, in the form of haem, plays an essential role in oxygen transport while iodine is required by the thyroid for the formation of thyroid hormones; most of the other essential trace elements are cofactors for various enzymes. Boron, nickel, silicon, and vanadium may also be essential, and it has been suggested on the basis of animal studies that there might be a requirement for tin.

Well-defined deficiency syndromes exist for copper, iodine, iron, selenium, and zinc; although deficiency of other trace elements is possible, their deficiency syndromes are not well defined because of their ubiquity in the diet. Guidance concerning the intake of various trace elements has been published—see also Human Requirements under Vitamins, below.

Vitamins

Vitamins are organic substance required by the body in small amounts for various metabolic processes. Most are not synthesized in the body, or are synthesized in small or insufficient quantities. Vitamins are sometimes classified as fat soluble or water soluble. Substances in the vitamin A, D, E, and K groups are generally fat soluble, and biotin, folic acid, niacin, Pantothenic acid, vitamins B₁, B₂, B₆, and B₁₂, and vitamin C substances are generally water soluble.

Vitamin deficiency may result from an inadequate diet, perhaps due to increased requirements such as during pregnancy, or may be induced by disease or drugs. Vitamin may be used clinically for the prevention and treatment of specific vitamin deficiency states and details of these uses are provided under the individual drug monographs.

Large doses of vitamins (megavitamin therapy) have been proposed for a variety of disorders, but adequate evidence of their value is lacking. Excessive intakes of most water-soluble vitamins have little effect due to their rapid excretion in urine, but excessive intakes of fat-soluble vitamins accumulate in the body and are potentially dangerous.

Stability

Water-soluble vitamins are liable to degrade in solution especially if exposed to light. Addition of vitamin mixtures to infusion solutions for Parenteral nutrition should therefore be carried out as possible before infusion. Solutions should be used within 24 hours of preparation and be protected from light.

Human Requirements

Vitamin and trace elements are essential nutrients and in many countries guidance has been published concerning their intake.

In the UK various terms are used to define intake:

· Estimated average requirement (EAR) is used for the requirements of energy, proteins, vitamins, or minerals of a group of people and usually about half will need more and half less than the specified figure.

· Lower reference nutrient (LRN) is applied to proteins, vitamins, or minerals and is that amount that is enough for only a few people who have low needs.

· Reference nutrient intake (RNI) is also applied to proteins, vitamins, or minerals and is an amount that is enough, or more than enough, for about 97% of people in a group.

· A safe intake is used to indicate an intake or range of intakes where there is not enough information to estimate EAR, LRNI, or RNI, but rather it is an amounts enough for almost everyone but is not so large as to cause undesirable effects.

· Dietary reference value (DRV) is used to cover EAR, LRNI, RNI, and safe intake.

It is emphasized in the report that these intakes are not meant to be recommendation for any individual or group; they do not reflect either a recommendation that such an amount should be taken daily in the diet or as a supplement. They are intended rather as yardsticks for the assessment of dietary surveys and food supply statistics; to provide guidance on appropriate dietary composition and meal provision; or for food labeling purposes in which case it is envisaged that an ERA will be used.

In the USA the National Academy of Science has traditionally set recommended dietary allowances (RDA's), defined as the levels of intake of essential nutrients that, on the basis of scientific knowledge, are judged to be adequate to meet the known nutrient needs of practically all healthy persons. The allowances are amounts that are intended to be consumed as part of a normal diet. However, new dietary reference intakes (DRI's) are being developed, which will include 3 reference values in addition to the traditional RDA as follows:

· The estimated average requirement is the intake that meets the needs of half the individuals in a group

· The adequate intake is the mean intake level that appears to sustain a desired marker of health, and will be set when there is insufficient evidence to establish an RDA

· The tolerable upper intake level is the maximum intake that is not likely to adversely affect health.

Information pertaining to the requirements of specific vitamins and minerals is provided under the individual monographs.

Supplementation

An adequate dietary intake of vitamins is necessary for good health but whether vitamin supplementation in the absence of any demonstrable deficiency is beneficial or even worthwhile remains debatable.

It is generally considered that healthy persons eating a normal balanced diet should have no need for vitamin supplementation. A review of the topic pointed out that the vitamins that people chose foe self medication are often not the ones that are actually present in inadequate amounts in their diets and that the commercial preparations available often do not make it clear whether the amounts or many times greater. Supplementation should concentrate on groups of people at risk of deficiency such as neonate, who need vitamin K; pregnant and lactating women, who need calcium, folic acid, and iron; and certain groups, who need vitamin D; organs and their infants may require vitamin B₁₂ supplements. A multivitamin supplement might be considered for some groups such as the elderly and those with reduced calorie intake. However, one might have difficulty in finding a good multivitamin preparation containing all 13 vitamins bit no non-vitamins. Also with many of the multivitamin preparation the doses and ratios varied inexplicably.

A review of supplementation specifically in children concluded that, provided school children and adolescents eat a wide variety of foods, there was no need for vitamin supplementation. However, it was recommended that supplementation with vitamins A, C, and D should be given to those between the ages of 6 month and 2 years and preferably up to the age of 5 years.

A subsequent study supports the suggestion that supplementation may be of some benefit in the elderly. Supplementation can resulted in an improvement in immune response and a decreased frequency of infection in elderly subjects. It was suggested that dosage might be crucial and that excessive doses of micronutrients could impair rather than improve immune response.

Mental Function

Administration of vitamin and mineral supplement to children was reported in 1988 to increase non-verbal intelligence and the topic has science remained highly controversial. In the following two years more studies were published but these failed to substantiate the earlier possible effect and concluded that vitamin supplementation did not improve mental functioning or reasoning in children. Suggestions were made shortly after these publications that there might be a subset of children with poor nutritional status who would receive some benefit but this again was disputed.

In 1991 another study was published, this time coinciding with the lunch of the proprietary product used in the study, with the publication of a book on the subject, and with the showing on British television of a documentary concerning the study. This study purported to demonstrate that supplementation with exactly the recommended dietary allowance of vitamin improved the IQ of children, a finding that was said not to occur significantly with other quantities of vitamin supplementation. This view attracted extremely harsh criticism from physicians, nutritionists, psychologists, and epidemiologists.

Prophylaxis of Ischaemic Heart Disease

Hypercholesterolaemia is a major risk factor for the development of atherosclerosis and consequently Ischaemic heart disease. Since oxidation of lipids, particularly low-density-lipoprotein (LDL) cholesterol has been proposed as a factor in atherogenesis, the possibility of preventing atherosclerosis by the use of dietary antioxidants such as vitamin E and C and betacarotene has been investigated. Prospective epidemiological studies have revealed a reduced risk of Ischaemic heart disease in individuals taking vitamin E supplement, and those with a high carotene intake (particular smoker). In a further prospective cohort study, dietary vitamin E consumption, but not vitamin E supplementation, was associated with decreased risk of death from ischaemic heart disease. Conversely, in these studies, intake of vitamin C did not appear to be associated with a decreased risk of ischaemic heart disease. Data from some studies assessing serum or fat concentrations also provide evidence that high betacarotene concentrations are associated with decreased cardiovascular disease.

However, despite these promising epidemiological data, results from randomized placebo-controlled trials have failed to find any befit for betacarotene supplements in the primary or secondary prevention of inconclusive, in the Alpha Tocopherol, Beta Carotene Cancer Prevention (ATBC) study, which monitored cardiovascular disease as a secondary end-point, vitamin E was not associated with a decreased incidence of ischaemic heart disease, and betacarotene was associated with a small increased risk. In further analyses, neither supplement appreciably altered the incidence of angina pectoris, nor showed any beneficial effects on cardiovascular deaths in the subset of men with previous myocardial infractions. In has been suggested that the lack of effects of vitamin E in this study may be due to an insufficiently high dose of Tocopherol. Similarly, neither the Betacarotene and Retinal Efficacy Trial (CARET) nor the Skin Cancer Prevention Study found on effects for betacarotene supplementation on the risk of death from cardiovascular disease. In studies specifically on cardiovascular end-points, no benefit from betacarotene supplements was seen in a large, randomized, placebo-controlled study in healthy men, and an initial study of supplementation with high-dose vitamin E in patients with evidence of ischaemic heart disease failed to show any beneficial effects on cardiovascular deaths. However, there was a reduction in non-fatal myocardial infraction and major cardiovascular events. The Heart Outcomes Prevention Evaluation (HOPE) study also showed that vitamin E treatment for 4 to 6 years had no effect on cardiovascular events in high-risk patients. Another large-scale study is underway; the Heart Protection Study is assessing the effects of a ‘cocktail’ of vitamin E, vitamin C, and betacarotene on the development of ischaemic heart disease in high risk subjects. Until results from all studies are known, it has been recommended that the emphasis should be on consuming a balanced diet including antioxidant-rich fruits, vegetables, and whole grains rather than vitamin supplements. For a discussion of the possibility that folic acid may reduce ischaemic heart disease through its homocysteine-lowering effects.

Prophylaxis of Malignant Neoplasms

There is evidence that a diet rich in fruit and vegetables is associated with a lower incidence of malignant disease, particularly of the respiratory and digestive tracts. It has been hypothesized that some of the benefits of such a diet derive from the role of antioxidant vitamins such as the carotenoids and vitamins C and E in scavenging free radicals. However, it is by no means certain that these are the only, or necessary the most important, dietary components responsible for benefit, since components such as dietary fibre may also play a role. In addition, different antioxidants may vary in their properties and efficacy, and the appropriate dosage remains largely conjectural, and perhaps as a result the evidence of benefit is often conflicting.

Several clinical trials of the use of vitamin A or betacarotene in the secondary or primary prevention of malignancy have been reported. Prolongation of disease-free intervals in patients with various malignant Neoplasms was reported in 1 study of betacarotene, and another reported remission of oral leukopenia in patients treated with betacarotene and vitamin A. Vitamin A alone was reported to reduce the incidence of primary tobacco-related Neoplasms in a study of patients treated surgically for lung cancer. However, other results have largely failed to substantiate any benefit for secondary prevention. No reduction in the incidence of new skin cancers, or in malignant transformation of cervical dysplasia, or in new colorectal adenomas was reported in 3 other studies. In a primary prevention study, a combination of betacarotene, vitamin E and selenium was associated with a reduction in stomach and esophageal cancers in a population at high risk of these cancers and with a diet low in micronutrients in China. In contrast, other primary prevention studies have failed to show any benefit, and possibly some harm, from betacarotene supplements in will-nourished populations. A study in smokers showed an increase in lung cancer and associated mortality in those receiving betacarotene (20 mg daily), but not these receiving vitamin E (50 mg daily). Similarly, an increased risk of lung cancer was noted in recipients of betacarotene (30 mg daily) with vitamin A (25 000 units daily) in another study in individual at high risk of lung cancer, and this study was stopped early as a result. A third study in healthy men found no benefit or harm for betacarotene supplements (50 mg on alternate days) in terms of incidence of malignant Neoplasms, including those of the lung.

Vitamin C

Vitamin C has also been proposed for this purpose but there is no real evidence to justify it. It certainly appears to be ineffective as adjuvant therapy in the treatment of advanced malignancy, and combination with betacarotene and vitamin E failed to show any effect in preventing colorectal adenoma. At physiological concentration vitamin C is an important antioxidant, but supplementation is unlikely to be justified in anyone eating a balanced diet.

Vitamin E substances

Vitamin E substances are also known to play an important antioxidant role in the body. Animal studies have suggested that they should inhibit tumour production, and the Chinese study mentioned above found combined antioxidant therapy including vitamin E to be benefit in the primary prevention of stomach and esophageal cancers. Other studies in western populations have generally been disappointing; vitamin E had no effect on lung cancer incidence in those at risk, and did not prevent the development of new colorectal adenomas.

However, further analysis of the lung-cancer study suggests that vitamin E may have protected against prostate cancer.

Result from the Nurses’ Health study have indicated that prolonged use of multivitamins was associated with reduced risk of developing cancer of the colon. This effect was thought to be due to the folate component and could be demonstrated after 15 years of use, but not after shorter-term ingestion. Dietary folate was also associated with a modest reduction in risk for colon cancer.

At present, therefore, the only conclusion that appears uncontroversial is that a diet involving frequent consumption of fruit and vegetable is likely to be beneficial. However, given the present difficulties in treating many malignancies once they develop interest in the topic seems likely to continue.

Aluminii Oxidum Hydricm; Aluminum Hydroxide; Wassehaltiges Aluminiumoxid.

CAS — 21645-51-2 [Al (OH) ₃].

ATC — A02AB01.

NOTE. Compound preparation of aluminum hydroxide may be represented by the following names:

• Co-magaldrox x/y (BAN)—where x and y are the strengths in milligram of magnesium hydroxide and aluminium hydroxide respectively.

Pharmacopoeias. In Chin., Eur Int, Japan, Pol, and US.

Pharmacopoeial description

Ph. Eur.: Hydrated Aluminium Oxide (Dried Aluminium Hydroxide (BP 2001) contains the equivalent of 47 to 69% Al₂O₃. It is a white amorphous powder. Practically insoluble in water; it dissolves in dilute mineral acids and in solution of alkali hydroxides. Store in airtight container at a temperature not exceeding 30º.

USP 25: Aluminium Hydroxide Gel is amorphous aluminium hydroxide in which there is a partial substitution of carbonate for hydroxide. It is a white viscous suspension from which small amounts of clear liquid may separate on standing. It has a pH of between 5.5 and 8.0. Store in airtight containers. Avoid freezing.

Dried Aluminium Hydroxide Gel is an amorphous from of aluminium hydroxide in which there is a partial substitution of carbonate for hydroxide. It contains the equivalent of not less than 76.5% of Al (OH) ₃ and may contain varying quantities of basic aluminium carbonate and bicarbonate. The labeling requirements states that 1g of dried aluminium hydroxide gel is equivalent to 765mg of Al (OH) ₃. It is a white, odorless, tasteless, amorphous powder. Insoluble in water and in alcohol; soluble in dilute mineral acids and in solution of fixed alkali hydroxide. A 4% aqueous dispersion has a pH of hot more than 10.0. Store in airtight containers.

Algeldrate (USAN, pINN) is defined as a hydrate aluminium hydroxide with general formula of Al (OH) _3, xH₂O.

Adverse Effects and Precautions

Aluminium hydroxide, like other aluminium compounds, is astringent and may cause constipation; large doses can cause intestinal obstruction.

Excessive doses, or even normal doses in patients with low-phosphate diets, may lead to phosphate depletion accompanied by increase bone desorption and hypercalciuria with the risk of osteomalacia.

Aluminium salts are not, in general, well absorbed from the gastrointestinal tract, and systemic effects are therefore rare in patients with normal renal function. However, care is necessary in patients with chronic renal impairment: osteomalcia or dynamic bone disease, encephalopathy, dementia, and microcytic anaemia have been associated with aluminium accumulation in such patients given large doses of aluminium hydroxide as a phosphate-binding agent. Similar adverse effects have also been associated with the aluminium content of dialysis fluids.

Aluminium hydroxide used as an adjuvant in adsorbed vaccines has been associated with the formation of granulation.

Porphyria. Aluminium hydroxide is considered to be unsafe in patients with Porphyria because it has been shown to porphyrinogenic in animals.

Interactions

As outlined on, aluminium compounds used as antacids interact with many other drugs, both by alterations in gastric pH and emptying, and by direct adsorption and formation of complex that are not absorbed. Interaction can be minimized by giving the aluminium compound and any other medication 2 to 3 hours apart. The absorption of aluminium from the gastrointestinal tract may be enhanced if aluminium compound are taken concomitantly with citrates or ascorbic acid (see above).

Pharmacokinetics

Aluminium hydroxide, given by mouth, slowly reacts with the hydrochloric acid in the stomach to form soluble aluminium chloride, some of which is absorbed. The presence of food or other factor which decrease gastric emptying prolongs the availability of aluminium hydroxide to react and may increase the amount of aluminium chloride formed. About 0.1 to 0.5mg of the action is reported to be absorbed from to be absorbed from standard daily doses of an aluminium-containing antacid, leading to about a doubling of usual aluminium concentration in the plasma of patients with normal renal function.

Absorbed aluminium is eliminated is eliminated in the urine, and patients with renal failure are therefore at particular risk of accumulation (especially in bone and the CNS), and aluminium toxicity.

The aluminium compounds remaining in the gastrointestinal tract, which account for most of a dose, form insoluble, poorly absorbed aluminium salts in the intestine including hydroxide, carbonates, phosphate and fatty acid derivatives, which are excreted in the faces.

Uses and Administration

Aluminium hydroxide is used as an antacid. It is given in doses of up to about 1g by mouth. In order to reduce the constipating effects, aluminium hydroxide is often given in association with a magnesium-containing antacid, such as magnesium oxide or magnesium hydroxide.

Aluminium hydroxide binds phosphate in the gastrointestinal tract to form insoluble complexes and reduces phosphate absorption. It is thus used to treat hyperphosphataemia in patients with chronic renal failure. With this use the dose must be adjusted to the individual doses.

Aluminium hydroxide is also used as an adjuvant in adsorbed vaccines.

Poliomyelitis and dermatomyositis. Corticosteroids form the basis of the management of Polymyositis but the calliopsis that may occur in dermatomyositis does not always respond well. Aluminium hydroxide 1.68 to 2.24g daily produced clinical improvement with complete clearing of most calcified nodules after 1 year in a patient with calliopsis cutis complicating juvenile dermatomyositis. The calcified masses are made up of hydroxyapatite and amorphous calcium phosphate and reduction in phosphate absorption by aluminium hydroxide probably helped to reverse their formation. Subsequent cases have also reported benefit from aluminium hydroxide treatment in the management of calcinosis.

Cleanrooms and Clean Zones - An introduction to the Cleanrooms concept is presented by the author to demonstrate the importance clean air has on quality production. Cleanrooms are defined by the various global standards and room classifications are presented in several tables throughout this chapter. At rest and operational (static and dynamic) conditions are defined and the typical uses of Cleanrooms is presented based on air classification. A lengthy discussion regarding FS209E, British Standard 5295, International Organization of Standards 209 (ISO 209), and their corresponding particle concentrations is included in the text, with lengthy descriptions of the ISO-14644 and 14698 standards. Measuring the cleanliness of Cleanrooms requires preparation and planning for what activities will take place throughout the process. Consideration steps for how to do this are defined in this section. The requirements for carrying out operations in these Cleanrooms are discussed noting that there are no universal guidelines for calculating the proportion of viable and non-viable particles in the air. Therefore, reference to the GMP guidelines is mentioned, which follows the European Union (EU) requirements. These are listed and defined. The factors that should be used to determine the cleanliness of a Cleanrooms are listed as well, such as engineering controls and facility requirements. Various types of Cleanrooms are discussed with airflow patterns and quality illustrated and discussed. The use of clean zones within a defined work space (sometimes even Cleanrooms) is discussed from a practical and economic aspect as long as they are validated as such. Behavior within these rooms and clean zones (including safety bench) is discussed so that airflow disruption is minimized and the cleanliness of the critical area is preserved. Maintaining the effectiveness of the room and operating principles for production are stressed so that the use meets the expectations and requirements for cleanliness.

Cleaning and Decontamination - The importance for critical, intensive cleaning of a manufacturing environment to provide for the best quality possible is essential. This section describes the purpose of cleaning, the standards which require the cleaning and decontamination process, and the cleaning process itself. In addition, engineering and facility controls are described for minimizing the transfer of contamination into the clean areas. Cleaning responsibility within a company is best done by the production workers to assure that there is a buy-in of the quality of work produced from their division, but others may be contracted to perform this function if, as the text states, they are trained and committed. The author attempts to classify critical cleaning based on the critical manufacturing functions performed in an area with more intensive cleaning occurring closer to more critical functions. Three levels of cleaning are proposed by the author: gross cleaning, intermediate cleaning, and precision cleaning, and these are described. A cleaning program development plan is recommended and questions to be answered are presented. Maintaining control of the cleaning process is vital and this incorporates not only a visual inspection, but a procedure that is validated to clean what can't be seen. This procedure will describe the techniques, methods, equipment, and solutions that are all part of a validated cleaning process. Various disinfectants have varying effects on contaminants. The author emphasizes that it is important to sample and identify the contaminants so that the proper solutions can be chosen to adequately eliminate the problem. More than anything else a company should have a program designed for cleaning and use it. This program can be designed after a thorough risk analysis of each component of a contamination control procedure.

Deep sea fishes and animals

The test consists of applying gas pressure (Nitrogen gas) to the upstream side of a wetted filter to determine the minimum pressure required to force bubble of gas through membrane filter. The test ensures the size of pores in the filter and also detects any leak in the filtration system.

PROCEDURE

1. Sterilize the filter assembly with 0.22 micron membrane disc and Prefilter.

2. A sterile tube is aseptically connected to the effluent end of the filter holder.

3. The end of the sterile tube is aseptically connected to a glass tube that is passed through a rubber bung to close a 10 liters capacity flask.

4. One end of a suitable sterile silicone tube is connected to the inlet of the filer holder and he other end connected to the outlet of a pressure vessel.

5. Connected nitrogen gas source through a filter and pressure gauge to the inlet of the pressure vessel.

6. Pass 12 liters of hot distilled water (temperature approximately 60 to 70 ºC) through the membrane by pressurizing vessel with nitrogen at a pressure less than 1.0 kg/cm².

7. As the water is forced through the filter, remove air out of the filter by slightly opening bleed value. Close the bleed value as soon as continuous flow of water starts. Collect water in two 1 liters flask.

8. After all the hot water is filtered, slowly release the pressure of the vessel.

9. Charge about 4 liters of freshly collected and cooled to room temperature distilled water to the pressure vessel and filter by pressurizing the vessel by nitrogen gas. Pressure should be less than 1.00 kg/cm².

10. Ensure that the glass tube, which is connected to the outlet tube of the filter holder, is sufficiency dipped in the water.

11. When all the water has passed through, slowly build up the nitrogen pressure in the vessel up to 0.2 kg/cm ² below the rated pressure for each membrane. I.E. 2.55 kg/cm ²for Pall TM 66 membrane up to 3.3 kg/cm ² for Durapore GVWP membrane and up to 306 kg/cm ² for Sartorius 11107 membrane.

12. No bubble should be observed at the above pressure in the liters flask.

13. If bubbles are noticed, the membrane must be discarded and repeat the procedure with a new sterilized membrane.

14. If only pressure drop is noticed, tighten the system.

15. If membrane passes integrity test, slowly release the pressure.

16. Filter the product through filter disc at operating pressure less than 1.4 kg/cm².

17. After filtration I complete, wash the membrane disc by filtering 4 liters of room temperature cooled distilled water at a pressure of less than 1.0 kg/cm².

18. Confirm the complete filtration by operating bleed valve. Release the pressure.

19. After completion of the filtration, recheck the integrity of the membrane used as per the same procedure used for checking integrity prior to filtration.

20. In the event of a failure, repeat the integrity test to be sure the result are accurate.

If the filter fails, this second integrity test, the batch must be reprocessed, through another sterilized and integrity tested membrane.

By and large the major pieces of equipment into the sterile area such as large trolleys, ampoule filling sealing machine etc. by the very nature of the size will be moved into the sterile area either through the equipment entry door or through the change room.

Prior to moving such equipment into the sterile area, the production supervisor concerned and engineering department will ensure that it is in proper working condition. Additionally, it will be necessary to confirm that it is clean.

Just prior to the entry, the external portion of the machine will be sanitized with Sterile70% Isopropyl Alcohol and Sterile 2% Bacillocid solution (disinfectant). Initially, such a sanitized machine will be moved to the second cubical change room and retained there overnight under the UV lamp. On the following day, the machines external portion will once again be sanitized with Sterile 70% IPA and Sterile 2% Bacillocid and then moved into the sterile area.

Should it be necessary, after the entry of the equipment, Fumigation may be carried out in the sterile room to ensure there has been no abnormal increase in Microbial Count due to the major piece of equipment.

Swab test should be taken of the equipment to confirm the proper disinfection.

Area under consideration: Class 100 to Class 10,000 under the same air handling units and air-conditioning plant and component preparation area (Class 10,000). Temperature Monitoring: Limit: Not to exceed 23ºC.

1. One calibrated thermometer permanently fixed on the body of 12’ LAF unit, which can be seen from the view panel in corridor.

2. The supervisor of sterile area must read and record the temperature of sterile room at any time between 11.30 hours – 14.00 hours on all filling days.

3. The chart is can annual record for the temperature in the one room.

The instrument is not calibrated semi-annually

Positive Pressure Monitoring: Daily Record

1. Filing room and change room pressure indicating manometers are mounted on a board outside the filling room in the adjoining passage.

2. the supervisor must read and record the pressure of the rooms in the ‘Daily Pressure Record’ chart at the time of recording temperature during the working hours.

3. Simultaneously, the pressure reading of each manometer mound on the LAF mentioned below should be similarly recorded.

A. Filling Room

2 manometers mounted on one ft LAF (horizontal)

1 manometer mounted on one down-flow Gradual laminar used for ampoule filling

1 manometer mounted on one4 ft. Gradual down-flow laminar used for aseptic filtration

1 manometer mounted on the down-flow laminar above small right angle conveyor

1 manometer mounted on the down-flow laminar large turntable

Pressure Differential Across Terminal HEPA Filter Monitoring

The manometers indicating pressure differential across the terminal HEPA filter in the filling room and change rooms are mounted on a board outside the filling room in the adjoining passage. The pressure differential reading are recorded monthly

B. Component Preparation Area

One monometer on the vertical down-flow Gradual laminar on the vial/ampoule washing machine.

One monometer on the vertical down-flow laminar on the final rubber stopper washing machine.

One monometer on vertical down-flow laminar above the table used for component wrapping.

One manometer on vertical down-flow laminar flow hood above the vial sealing machine.

4. The filling room pressure must be grater than the adjacent 3^rd change room pressure by 1.25 mm of water gauge (i.e.0.05 inches of water gauge).Similarly the 3^rd change room pressure must be greater than the 2^nd change room pressure by 1.25 mm water gauge. The 2^nd change room pressure must be grater than 1^st change room pressure by 1.25 mm water gauge and the 1^st change room pressure must be grater than the outside passage by 1.25 mm water gauge.

Relative Humidity Monitoring

Sterile filling room is daily monitored for relative humidity. Dial type ‘Barrio’ brand instrument for measuring humidity is kept near the temperature indicator in the filling room. Humidity is recorded on all filling days in the prepared format. Limit not more than 55%. The instrument is calibrated semi-annually.