Introduction:

 UV-Visible spectroscopy is a mature and well-established analytical technique used extensively in many industry sectors including Environmental Analysis, Pharmaceutical Testing, Food and Beverage Production etc.

Spectroscopy is the measurement and interpretation of electromagnetic radiation absorbed or emitted when the molecules or atoms or ions of a sample moves from one energy state to another energy state.

UV spectroscopy is type of absorption spectroscopy in which light of ultra-violet region (200-400 nm) is absorbed by the molecule which results in the excitation of the electrons from the ground state to higher energy state.

Principle:

UV-Visible Spectroscopy is based on the Lambert-Beer principle which states that the absorbance of a solution (A) is directly proportional to its path length (l) and its concentration (c) when the wavelength of the incidence light remains fixed.

Basically, spectroscopy is related to the interaction of light with matter.

As light is absorbed by matter, the result is an increase in the energy content of the atoms or molecules.

When ultraviolet radiations are absorbed, this results in the excitation of the electrons from the ground state towards a higher energy state.

Molecules containing π-electrons or non-bonding electrons (n-electrons) can absorb energy in the form of ultraviolet light to excite these electrons to higher anti-bonding molecular orbitals.

The more easily excited the electrons, the longer the wavelength of light it can absorb.

The absorption of ultraviolet light by a chemical compound will produce a distinct spectrum which aids in the identification of the compound.

If there is no absorption of the light passing through the solution, the transmittance is 100%.

Apparatus:

The UV-Visible Spectrophotometer is the analytical instrument used for the UV-Vis spectroscopic analysis. Spectrophotometers are available in different configurations however most can be categorized into either single beam, split beam or double beam types depending on the design of their optical system. Such types of instrument comprise the following components in their constructions:

1. Light Source :

• Tungsten filament lamps and Hydrogen-Deuterium lamps are most widely used and suitable light source as they cover the whole UV region.
• Tungsten filament lamps are rich in red radiations; more specifically they emit the radiations of 375 nm, while the intensity of Hydrogen-Deuterium lamps falls below 375 nm.

2. Monochromator :

• Monochromators generally is composed of prisms and slits.
• Most of the spectrophotometers are double beam spectrophotometers.
• The radiation emitted from the primary source is dispersed with the help of rotating prisms.
• The various wavelengths of the light source which are separated by the prism are then selected by the slits such the rotation of the prism results in a series of continuously increasing wavelength to pass through the slits for recording purpose.

3. Cell Compartment :

• One of the two divided beams is passed through the sample solution and second beam is passé through the reference solution.
• Both sample and reference solution are contained in the cells.
• These cells are made of either silica or quartz. Glass can’t be used for the cells as it also absorbs light in the UV region.

4. Detector :

• Generally two photocells serve the purpose of detector in UV spectroscopy.
• One of the photocell receives the beam from sample cell and second detector receives the beam from the reference.
• The intensity of the radiation from the reference cell is stronger than the beam of sample cell.

5. Signal Processing System :

• Most of the time amplifier is coupled to a pen recorder which is connected to the computer.
• Computer stores all the data generated and produces the spectrum of the desired compound.

This absorption spectroscopy uses electromagnetic radiation between 190 and 800 nm and is divided into two regions

1. UV (190–400 nm)- Deuterium lamp

2. Visible (400–900 nm) – Tungsten lamp

Because the absorption of UV or visible radiation by a molecule leads to transition among electronic energy levels of the molecule, it is also often called electronic spectroscopy.

UV-Visible Analysis is Suitable For,

  1. Analytes that can be dissolved in solvents like water, ethanol and hexane.

  2. The analyte need to absorb UV or Visible light.

  3. With UV /Vis we can do quantitative measurements a single analyte in solution(or more than one analytes om solution provided that do not interfere with each other).

Not Suitable For,

1. Analytes that have a photochemical reaction at the wavelength range of interest.

2. Partially dissolved, unclear or colloidal samples.

The UV-Visible spectrum shows the absorbance of one or more sample component in the cuvette when we scan through various wavelengths in the UV/Vis region of the electromagnetic spectrum.

System suitability is to prove that system is working perfectly before the analysis on HPLC, GC, TOC analyser or any other system. It is required to done before every sample analysis. HPLC, short for High-performance liquid chromatography is a technique used for separating the components in a mixture.

HPLC chromatographic technique is used in pharmaceutical industries for analysis. System suitability testing limits are acceptance criteria that must met before starting the analysis.

There are some System suitability parameters which can be used to check the system before starting the sample analysis are listed below.

1.    Retention time

2.    Resolution

3.    Repeatability

4.    Plate Count

5.    Tailing Factor

6.    Signal-to-noise ratio

7.    Pressure

Retention Time:

In liquid chromatography and gas chromatography, the retention time, tR, is defined as the time elapsed between the injection of the sample and the appearance of the maximum peak response of the eluted sample zone. tR may be used as a parameter for identification. Chromatographic retention times are characteristic of the compounds they represent but are not unique. Coincidence of retention times of a sample and a reference substance can be used as a partial criterion in construction of an identity profile but may not be sufficient on its own to establish identity. Absolute retention times of a given compound may vary from one chromatogram to the next.

 Resolution (Rs):

Resolution is a measure for the ratio of the distance of two adjacent peak maxima and their widths. For complex sample mixtures Rs should be determined for the critical pairs of components to characterize their separation.

Resolution is calculated by following formula,

RS = 2(tR2 − tR1) / (W1 + W2)

Where, tR2 and tR1 are retention times of two compounds, W2 and W1 are the corresponding widths at the bases of the peaks obtained by extrapolating the relatively straight sides of the peaks to the baseline.

Repeatability/Precision:

Replicate injections of a standard preparation are used to demonstrate the system performance when it gets exposed to some specified column usage, environment, and plumbing conditions. Data from five or six replicate injections are used if requirement of relative standard deviation is less than 2%.

Plate Count/ Column Efficiency:

The Column Efficiency is measured by following formula,

N = 16(tR/W)2

Where tR is the retention time of the substance, and W is the peak width at its base, obtained by extrapolating the relatively straight sides of the peak to the baseline. The value of N depends upon the substance being chromatographed as well as the operating conditions, such as the flow rate and temperature of the mobile phase or carrier gas, the quality of the packing, the uniformity of the packing within the column, and, for capillary columns, the thickness of the stationary phase film and the internal diameter and length of the column.

Tailing Factor/Symmetry Factor:

Tailing Factor is calculated by following formula,

AS = W0.05/2f

where W0.05 is the width of the peak at 5% height and f is the distance from the peak maximum to the leading edge of the peak, the distance being measured at a point 5% of the peak height from the baseline.

Signal-to-noise ratio:

This parameter is used for the lower-end calculation of the performance of the system. 

Noise: It is measured between two specific lines that bracket the baseline. 

Signal: It is measured starting from the baseline’s middle and ending to the peak’s top.

Once calculating both these factors, the ratio can be measured by dividing the signal value by the noise value. With this, generally, the noise value has to be reduced using one of the following methods:

• Signal Averaging
• Reagent and Solvent Purity
• Column Flushing and Sample Clean-Up
• Temperature Control
• Additional Pulse Damping and Mixing

The signal-to-noise ratio (S/N) is a useful system suitability parameter. The S/N is calculated as follows:

S/N = 2H/h

where H is the height of the peak measured from the peak apex to a baseline extrapolated over a distance ≥5 times the peak width at its half-height; and h is the difference between the largest and smallest noise values observed over a distance ≥5 times the width at the half-height of the peak and, if possible, situated equally around the peak of interest

System Pressure:

System suitability tests must be performed under controlled pressure limit. Monitor the pressure variation throughout the analysis.

Conclusion: The above mentioned system suitability parameters are not must. These parameters and acceptance criteria are performed during the method validation and fixed based on the method development outcome results. But system suitability should meet the acceptance criteria before starting the sample analysis.

What is PIC/S:

The Pharmaceutical Inspection Co-operation Scheme (PIC/S) is a non-binding, informal co-operative arrangement between Regulatory Authorities in the field of Good Manufacturing Practice (GMP) of medicinal products for human or veterinary use.

It is open to any Authority having a comparable GMP inspection system. PIC/S presently comprises 54 Participating Authorities coming from all over the world (Europe, Africa, America, Asia and Australasia).

PIC/S aims at harmonizing inspection procedures worldwide by developing common standards in the field of GMP and by providing training opportunities to Inspectors.

It also aims at facilitating co-operation and networking between competent authorities, regional and international organisations, thus increasing mutual confidence. This is reflected in PIC/S’ mission which is to lead the international development, implementation and maintenance of harmonized GMP standards and quality systems of inspectorates in the field of medicinal products.

History of PIC/S:

PIC/S was founded in 1995 as an extension to PIC (Pharmaceutical Inspection Convention) which was founded in October 1970 by EFTA (European Free Trade Association) under the title of “The Convention for the Mutual Recognition of Inspections in Respect of the Manufacture of Pharmaceutical Products”. 

The initial Members of PIC comprised the 10 Member countries of EFTA at that time, ie. Austria, Denmark, Finland, Iceland, Liechtenstein, Norway, Portugal, Sweden, Switzerland and United Kingdom. Membership of PIC was subsequently expanded to include Hungary, Ireland, Romania, Germany, Italy, Belgium, France and Australia.

It was realised in the early 1990s that because of an incompatibility between the Convention and European law, it was not possible for new countries to be admitted as Members of PIC. Australia was the last country that was able to become a Member of PIC in January 1993. Consequently, the PIC Scheme was formed on 2 November 1995. PIC and the PIC Scheme, which operate together in parallel, are jointly referred to as PIC/S.

The original goals of PIC were:

• Mutual recognition of inspections;
• Harmonization of GMP requirements;
• Uniform inspection systems;
• Training of Inspectors;
• Exchange of information;
• Mutual confidence.

Benefits :

PIC/S offers a variety of advantages to its Participating Authorities. Some of the main benefits for Medicines Regulatory Authorities resulting from PIC/S Membership are detailed below. PIC/S Membership also involves indirect benefits to industry, when their relevant Medicines Regulatory Authority becomes a Member of PIC/S.

Main benefits for Members

• Training opportunities: PIC/S provides a forum for the training of GMP Inspectors thus allowing the latter to benefit from increased training opportunities by attending PIC/S Seminars and Expert Circles and by participating in the PIC/S Joint Visits Programme. In this respect, PIC/S is unique as there is no other international training forum run jointly by Regulatory Authorities (individually, Regulatory Authorities or organisations such as WHO or the EMA provide basic training courses, mainly to new Inspectors).
• International GMP harmonization: By taking part in the meetings of the PIC/S Committee, PIC/S Participating Authorities are involved in the development and harmonisation of international GMP guides and guidelines. The PIC/S Committee also actively promotes the uniform interpretation of GMP and Quality Systems for GMP Inspectorates.
• Networking: By attending PIC/S activities, participants benefit from personal contacts with other agencies, whether they are part of PIC/S or not. This networking often simplifies contacts and the exchange of GMP related information. In addition, PIC/S is one of the few international GMP fora for networking and confidence building amongst Regulatory Inspectors where experts (GMP Inspectors, specialist GMP Inspectors and Chief Inspectors) can meet, discuss issues of mutual concern and share experiences and information. In other fora, participation is either at the level of Heads of Agencies (e.g. WHO) or at the level of experts in a particular field (ICH).
• High standards: PIC/S ensures that all Members comply with PIC/S standards at all times (assessment of new applicants and reassessment of existing Member Inspectorates). Preparing for the accession to the Scheme (or reassessment) forces improvements in the GMP inspection system and procedures. This results in increased efficiency of the GMP Inspectorate. This is particularly true for Quality System requirements, where PIC/S standards are high, and for GMP training, which is essential in PIC/S.

• Sharing of information: PIC/S allows for a more effective use of inspection resources through the voluntary sharing of GMP inspections reports. Membership is also a cost-saving measure for the inspection authorities confronted with an increase of inspections, notably in the field of Active Pharmaceutical Ingredients (APIs).
• Rapid Alert System: Through PIC/S Membership, Regulatory Authorities automatically benefit from being part of the PIC/S Rapid Alert and Recall System arising from quality defects of batches of medicinal products, which have been distributed on the market. The PIC/S Alert and Recall System is part of a wider system, which includes the Alert and Recall System of EU/EEA (European Economic area) /MRA (Mutual recognition agreements) partners.
• Facilitating the conclusion of other Agreements: Membership in PIC/S may also facilitate the conclusion of other agreements, e.g. Mutual Recognition Agreements, between Members at various levels (e.g. Australia-Canada MRA, EU-Switzerland MRA, etc.). During the recently concluded initial negotiation on ASEAN MRA on GMP Inspection, PIC/S Membership accession was accepted as one of the essential criteria for MRA (Mutual recognition agreements).

Indirect Benefits for Industry:

There are also indirect benefits to industry when their relevant Regulatory Authority becomes a Member of PIC/S. These benefits may include the following:

Reduced duplication of inspections;

Cost savings;

Export facilitation;

Enhanced market access.

Organisational Structure :

As the PIC Scheme is an arrangement between Regulatory Authorities, it is very flexible, dynamic and proactive. A Committee of the Participating Authorities’ representatives (PIC/S Committee) supervises the operation of the Scheme. All decisions are taken unanimously. The Committee is assisted in its task by 7 Sub-Committees (e.g. on the training of Inspectors, on GMO/GDP harmonisation, etc.), by an Executive Bureau, which steers the Organisation in between meetings, and by a small Secretariat, which mainly assists the Committee, the Sub-Committees, the Bureau and Participating Authorities in their duties.

Reference : https://picscheme.org/en/picscheme

PIC\S Guideline documents : https://picscheme.org/en/publications?tri=all#zone

1.          OBJECTIVE            

1.1       To lay down a procedure for operation of air sampler.

2.         RESPONSIBILITY                                                                                      

2.1       Microbiologist – Quality Control – To follow the SOP.

2.2       Manager – Quality Control – To ensure the compliance of SOP.

3.         PROCEDURE         

• 3.1 Take the material required for sampling to the area for air sampling.

• 3.2 Place the air sampler at specific locations as per the sampling plan.

• 3.3 Perform the air sampling as per the directions given below.

• 3.4 Volumetric Air Sampler, Make: Millipore

• 3.4.1 Pre Requisites

•  Sterilize and carry all accessories to the area to be monitored.

•  The M Air T mainly consists of M Air T apparatus, micro perforated sieves, tripod, and battery charger.

• Unlock and remove the micro perforated sieve from the tester.

• Wrap the sieve in butter paper and sterilize in autoclave.

• Take the required number of pre-sterilized agar medium cassettes  wrapped in double sleeve packing.

• Disinfect the outer surfaces of wrappings with disinfectant in use.

• Enter into the area following the area’s entry and exit procedure.

• 3.4.2 Place the air sampler at the point pre-defined approved locations mentioned in the sampling plan.

• 3.4.3 Place the cassette in the air sampler.

• 3.4.4 Switch the Tester on.

• 3.4.5 Push the ‘ON’ / ‘OFF’ Button.

• After pressing the ‘ON’ / ‘OFF’ button the previously selected air sample   volume retained in the memory appears on the display.

• 3.4.6 Press the ‘START’ / ‘DELAY’ button quickly twice

• The display flashes, tester starts and counts down the volume of air that  remains to be processed.

• At the end of the process the display indicates EOC (End of Cycle).

• 3.4.7 Adjusting the Volume to be Processed

3.4.7.1    Push the liters button.

3.4.7.2    The previously selected volume appears on the screen.

3.4.7.3    To access other preset volumes press the liters button once.

3.4.7.4    The preset volumes ranges from 25 liters, 50 liters, 100 liters, 250 liters  500 liters, 750 liters and 1000 liters.

3.4.7.5    To change the volume setting, select the preset volume.

3.4.7.6    Hold the liters button down until the tester display indicates the desired sampling volume.

3.4.7.7    Start the sampling by pressing the ‘START’ / ‘DELAY’ button twice.

3.4.8    Adjusting the Timer

3.4.8.1    To change the time setting, hold the ‘START’ / ‘DELAY’ button.

3.4.8.2    The display shows previously selected value and starts to count down  time.

3.4.8.3    Time can be changed in increments of 5 minutes up to 1 hr.

3.4.8.4    To start the count down press down the ‘START’ / ‘DELAY’ button  again.

3.4.8.5    To stop, press the ‘ON’ / ‘OFF’ button.

3.4.9    Sampling of Air

•  Unlock and remove the micro perforated sieve from the tester.

• Remove the cover from the sieve.

• Sanitize the external surface of the tester with the filtered 70% IPA.

• Position the wings of the cassette into the recessed area of tester head.

• Retain the cassette position by holding on its wings.

• Remove the lid and place it on the bench.

• Lock the micro perforated sieve into position.

• Press the ‘ON’ / ‘OFF’ button.

• Set the sampling parameters.

• Quickly press the ‘START’ / ‘DELAY’ button twice.

• Perform the air sampling.

• Perform the air sampling at workbench level.

• When the display indicates EOC, unlock the sieve, remove it and put the  lid back on the cassette.

• To remove the cassette from the tester head, lift the cassette while firmly holding the edge.

• Label the location number, block and date on plate.

• Bring the cassettes to the microbiology lab and incubate.

• 3.4.10 Precautions to avoid false positive/negative results

• Do not use oxidizing agents such as hydrogen peroxide or per acetic acid.

• Avoid spraying liquids into the tester.

• Do not autoclave or flame the entire tester.

• The stainless steel micro perforated sieve should be autoclaved without its cover.

• Do not open the tester head.

• Do not perform any activity over the sampler while it is sampling.

4.     ABBREVIATIONS

4.1       EOC     –           End of cycle

4.2       IPA      –           Isopropyl Alcohol

4.3       QC       –           Quality control

4.4       SOP     –           Standard operating procedure

5.     REFERENCES          

Nil

6.          ANNEXURES

Nil

1.0       OBJECTIVE

1. To lay down a procedure for operation of fume hood.

2.0       RESPONSIBILITY

2.1      Chemist / Executive – Quality Control – to follow the procedure.

2.2      Supervisor / Manager – Quality Control to ensure adherence to the procedure.

2.3      Head – Quality Control for implementation and compliance.

3.0 PROCEDURE

3.1      OPERATION

• Ensure that the equipment is clean and free from dust.

• Switch on the mains to the fume hood.

• Switch on the light by switching on the red coloured switch provided on the front side of the fume hood.

• Ensure the exhaust by switching on the green button provided at the right side of the fume hood.
• Ensure the constant operation of exhaust.

• Avoid rapid movements at hood face when the door is open.

• Utilize the regulators provided at the left side of hood for water, airflow and LPG.provided inside the hood. 

• Press the black button to monitor the airflow provided on the top right side of hood.

• After completion of work ensure the cleanliness of hood and close the door by pulling it down.
• Switch off the light and then mains.

• PERFORMANCE VERIFICATION

•  AVERAGE  VELOCITY

• Check the velocity of fume hood using Anemometer at 3 different positions ( Left corner , middle and Right corner ) and record in Annexure -1

•  Acceptance criteria: 100 + 15 Feet / minute.

•  Frequency:  Half yearly

4.0 ABBREVIATIONS

Not Applicable

5.0 REFERENCES

 Not Applicable

6.0   ANNEXURES

Annexure –I – Performance verification Record for fume hood

Annexure –I Performance verification Record for fume hood

Make	:		Equipment ID No.	:
Model	:		Performed on	:
Serial No.	:		Frequency	:	Half yearly

     Average Velocity:

     Anemometer ID No .:__________________      Due date :_______________

S.No	Observed Velocity (Feet / minute )	Remarks
Average

Acceptance Criteria:   100 ± 15  Feet /Minute       

Performance Status                        :

Performed by: ____________                                                           Reviewed By : ___________

Date              : ____________                                                           Date               : ____________

1.0       OBJECTIVE

1.       To lay down a procedure for the operation and calibration of High Pump for column washing Make:  Shimadzu.

2.0 RESPONSIBILITY

2.1       Chemist / Executive – Quality Control – to follow the procedure.

2.2        Head – Quality Control for implementation and compliance.

3.0 PROCEDURE

• 3.1 OPERATION

• Ensure that the working area is clean and check the calibration status of the instrument.  
• Switch on the power to the instrument, wait for initialization.

• Keep the solvent line tube in appropriate solvents.

•  Open the drain valve 2 turns anti clock wise direction.

•  Click on ‘purge’ then pump starts flow.

• Close the drain valve after completion of purge.

• Connect  the column to the column inlet tube

• Set the appropriate flow  rate by pressing function ‘Key’

• Enter the appropriate flow rate and then press ‘Enter’.

• Displays the new set volume of flow rate.

• Press the pump key to start the pumping of set flow rate.

• After completion of washing of the column again click on pump to stop the flow.

• Enter the column washing details as per Annexure – 1 of  SOP QC073.

• Switch off the instrument after usage.

• 3.2  CALIBRATION

• 3.2.1 FLOW ACCURACY TEST

• Fix the C18, 75 x 4.6 mm column to the system.

• Keep degassed methanol (HPLC grade) in solvent line and prime thoroughly, and stabilize for about 30 min. with a flow rate of 1 ml/min.

• Take a 10 ml class ‘A’ calibrated dry volumetric flask.

• When the flow and pressure are stable, insert the outlet tubing into the volumetric flask and immediately start a calibrated stopwatch.

• Stop the stopwatch button when the meniscus reaches the 10 ml mark on the flask.

• Record the elapsed time in seconds.

• Calculate the flow rate using the following equation:   

10 ml * 60

                                        Calculated flow rate =       ————————-

                                                                            Measured Time in seconds

• Record the calculated flow rate in Annexure – 1

•  Similarly test the flow rate accuracy with flow rates of 0.5 and  2.0 ml/min and record the calculated flow rates in Annexure –1.

•  Acceptance criteria: ± 0.02 ml/min of set flow rate.

•  Calibration Schedule: Once three month and after any major maintenance job

4.0        ABBREVIATIONS

• HPLC         –            High performance liquid chromatography.
• HOD           –            Head of Department

5. 0      REFERENCES

Nil

6. 0      ANNEXURES            

• ANNEXURE –  1      –  Calibration Record for Wash Pump.

ANNEXURE –  1 – Calibration Record for Wash Pump

Instrument No.		Make
Calibration date		Next due date
Model		Page no	1of  1

STOP WATCH ID:______________    CALIBRATION DUE DATE OF STOP WATCH:____________

VOLUMETRIC FLASK NO:___________________

1.           FLOW ACCURACY CALIBRATION RECORD

Set flow rate	Observed elapsed Time(sec) to collect 10 ml	Flow Rate         Result    (10*60 /Time in (sec)	Difference of Flow   Rate in ml
0.5   ml/min
1.0  ml/min
2.0 ml/min

Acceptance Criteria : + 0.02 ml/min of set flow rate

Results :                                Passes/Fails

Performed By  :________                                                               Verified By   : _______

Date               :________                                                           Date          : ________

What are nitrosamines?

Nitrosamines, or more correctly N-nitrosoamines, refer to any molecule containing the nitroso functional group. These molecules are of concern because nitrosamine impurities are probable human carcinogens (a substance capable of causing cancer in living tissue). Although they are also present in some foods and drinking water supplies, their presence in medicines is even so considered unacceptable.

Background

Nitrosamines are chemical compounds classified as probable human carcinogens on the basis of animal studies. 

EU regulators first became aware of nitrosamines in medicines in July 2018 when nitrosamine impurities, including N-nitrosodimethylamine (NDMA), were detected in blood pressure medicines known as ‘valsartans’.

There is a very low risk that nitrosamine impurities at the levels found in medicines could cause cancer in humans.

What is Valsartan :

Valsartan is an Angiotensin II Receptor Blocker (ARB) and belongs to a family of analogue compounds commonly referred to as the sartans.

Further nitrosamine impurities were subsequently detected in other medicines belonging to the sartan family, including: N-nitrosodiethylamine (NDEA), N -nitrosodiisopropylamine (NDIPA), N -nitrosoethylisopropylamine (NEIPA) and N -nitroso-N-methyl-4-aminobutyric acid (NMBA).

More recently, nitrosamine impurities have been reported in pioglitazone and ranitidine containing products.

Why are they Present :

The formation of nitrosamines is generally only possible when secondary or tertiary amines react with nitrous acid. Nitrous acid itself is unstable but can be formed in situ from nitrites (NO2) under acid conditions.

In the case of the sartan compounds, most contain a tetrazole ring and formation of this tetrazole ring employs the use of sodium nitrite. Coincidently the solvents employed either were amines, or contained traces of amines, and this likely afforded the observed NDMA and NDEA. The origins of NDMA content in batches of ranitidine currently remains unclear.

However, during on-going investigations it was also concluded that the possibility for nitrosamine impurity content was broader than simply the concurrent presence of nitrites and amines in the synthesis of the active pharmaceutical ingredient (API).

Evidence suggests that sources of nitrites or amines as unintentional contaminants of starting materials, reagents and solvents – such as dimethylamine in the common solvent dimethyl formamide (DMF) – may also provide circumstances in which nitrosamines may form. The carryover of nitrites or amines from subsequent steps may also afford opportunities for formation.

Contamination from External factors :

Notably, contamination from external sources has been identified as a source of nitrosamine content. In particular, contamination from the use of recycled materials and solvents that already contain levels of nitrosamines. A cited example of this involves the use of recycled DMF, which is quenched with sodium nitrite to destroy residual azide as part of the recovery process. Furthermore, the recycling of materials and solvents is often outsourced to third parties who may not implement adequate controls in view of the content of the materials they are processing.

So during Risk Assessment of Nitrosamine impurities in Finished products we have to considered the below factors for sources of contamination (But not limited to).

a) API may contain Nitrosamine impurities- which may be carried forward to Finished product.

b) Excipients may contain Nitrosamine impurities- which may be carried forward to Finished product.

c) The incompatibility/ reactivity of the raw materials (APIs and Excipients) used in finished product formulation may lead to formation of Nitrosamine impurities.

d) Purified Water may be contaminated by nitrosamine impurities.

e) Manufacturing process may lead to formation of Nitrosamine Impurities due to the use of sodium nitrite, other nitrites, recycled reagents or solvents.

f) Equipment surface may add nitrosamine impurities during processing of the product and same shall be carried forward to finished product

g) Primary packing materials in which drug products are packed

h) The air supplied to the processing cubicle may carry nitrosamine impurity contamination to the product

i) The compressed air supplied to the processing equipments may carry nitrosamine impurity contamination to the product

These broader concerns have prompted the European Medicines Agency (EMA) to request that Marketing Authorisation Holders (MAHs) of all Finished Pharmaceutical Products (FPPs) conduct risk assessment to determine the risk of nitrosamine presence during the manufacturing of Human medicines.

1.         OBJECTIVE             

             1.1      To lay down a procedure for handling of Expired Raw materials       

2.         RESPONSIBILITY   

• Technical Assistant / Executive – Stores responsible to identify and segregate the  expired material

• QA – Executive shall be responsible to verify and labeling of the on-line rejected/expired material, to verify the non-conformance(s) if any and communicate to the Purchase Department for necessary action if required and to monitor the destruction activity

• Executive-Safety shall responsible to perform the destruction activity

• In-Charge-Stores shall responsible to ensure the compliance as per SOP

3.         PROCEDURE                       

•      The Executive stores shall verify all approved stocks on monthly basis for expired

             materials.

•      Materials which are non-moving in nature got expired over a period of time in the stores

             shall be identified and transferred to the expired area.

•      Strike out the existing approved label with a cross mark and affix the “EXPIRED

             MATERIAL” label in red colour (Anexxure-1).

•     All expired materials shall be segregated by MRR / Lot Number wise and stored separately in

            rejected material storage area.

•      The quantities shall be checked and enter material details in the Expired Materials Stock

             Register (Annexure-2).

•  Expired materials details shall be informed to Planning department for disposal instructions

•  On receiving the disposal instructions from planning department In-Charge stores shall initiate MNC as per SOP .

• QA personnel shall be forwarded the ‘Issue Details Report’ after approval of the initiated MNC by In-Charge QA and/or Head QA to the Stores Department for disposal of the material

      Destruction Procedure:

• After getting the ‘Issue Details Report’ from QA, Stores personnel shall be initiated destruction process of the material as per Annexure – 3. 

• The duly filled destruction format (Annexure – 3) and a copy of ‘Issue Details Report’ shall be forwarded to safety department along with expired raw material for destruction.

• After getting approval from Head-Q.A. remove the expired raw material from expired material room.

• Safety personnel shall destroy the material by dissolving in a bucket of water and finally discard the same into Effluent Treatment Plant. The same process shall be repeated for the entire rejected/expired quantity

• The Stores In-Charge and Quality Assurance personnel shall supervise the entire destruction process.

• Entries shall be made in the expired materials stock register after disposal.

.

4.         ABBREVIATIONS   

4.1       Q.A      –  Quality Assurance

4.2       MNC    –  Material Non Conformance

5.         REFERENCES          

5.1 Procedure for reporting and monitoring of Material Non-Conformance

6.         ANNEXURES            

6.1       Annexure – 1     – “Expired Material” label..

6.2       Annexure – 2     –   Expired Material Stock Register

6.3.       Annexure—3     –    Destruction Record.

Annexure—3      

DESTRUCTION RECORD

We have received approval from purchase for destruction of ___________________________________

as per the enclosed list vide document numbers from ____________ to ___________ date.  We

seek your clearance to destroy the same.

Thanks

(Warehouse – In charge)                                                                      (Quality Assurance)

Approved by : _________________

                         (Head RA & QA)

Destruction of Rejected goods

Date of destruction                              :

Destroyed by                                       :

Mode of destruction                            :

Remarks (if any)                                  :

Destruction supervised by                   : ______________________  __________________________

                                                              (Warehouse – In charge)               (Quality Assurance)

Encl. : Details of products /  materials, Batch No. & quantitiy.

_____________________________________________________________________________________

1. OBJECTIVE                                     

     1.1    To lay down a procedure for Operation of steam Boiler  6–Ton.

2.         RESPONSIBILITY   

• Assistant    Engineering – To Follow the SOP

• Executive   Engineering – To comply the SOP

3.         PROCEDURE                                               

   3.1       PRECAUTIONS

  3.1.1    Do not by pass any safety interlock.

3.1.2    Check the mobrey air break switch for low-level indication giving blow down at every 8 hours of operation.

 3.2       PRE START UP

 3.2.1    Check the water level in boiler.

 3.2.2    Check the water level in day tank.

3.2.3    Check the water hardness and PH once in a shift, the hardness should be below10 ppm and pH should be 8.5 to 9.5

 3.2.4    Check the fuel oil level in day tank

 3.2.5    Switch on the feed water pump.                                                         

3.2.6    Ensure proper temperature of Furnace Oil in Oil pre heater.

3.2.7    Open the fuel circulation valves

3.2.8    Start the fuel pump for oil re circulation

3.2.9 Close the boiler stop valves.

3.3       SET UP           

3.3.1    Steam pressure switch setting  -10.2 kg/cm²  (High), – 9.0 kg/cm² (Low).                                                     

3.3.2    Modular pressure switch setting  – Main scale at 8.5 kg/cm².

 3.3.3    Safety valve on oil pre heating header – 3.0 kg/cm².

  3.3.4    Fuel oil pressure at low flame – 13 to 14 kg/cm² & High flame – 19 to 20 kg/cm².

   3.3.5    Fuel oil backpressure at low flame  – 13. to 14 kg/cm² & high flame – 19 to 20 kg/cm².

   3.3.6   Fuel oil pre heating header pressure switch  – 3.0 kg/cm².

   3.3.7    Fuel oil temperature   Min  – 90⁰C.

                                                  Max   – 124⁰C.

  3.3.8    Stack temperature    Max – 300⁰C.

3.3.9 Pressure Reduction Valve Setting on fuel & Oil pre heating line – 3.0 kg/cm²

3.3.10  Feed water hardness – below 10 PPM.

   3.4       OPERATION

    3.4.1    Switch ON the fuel pump

    3.4.2    Check the oil  temperature and pressure

    3.4.3    Check the water level in Boiler

    3.4.4    open the Air vent Valve

    3.4.5    Switch ON the AUTO  button on MMI

    3.4.6    Check the flame Condition

   3.4.7    Close air vent valve after shell pressure has reached to 1 kg/cm²

3.4.8    Put  the modulator & firing control switch in ON position after shell pressure has reached to 3 kg/cm²

3.4.9    Check the modulating system working or not.

3.4.10  Check the smoke condition.

3.4.11  Open the stop valve after shell pressure has reached to 5.o Kg/cm².

3.4.12  Give the blow down according to salts concentration in Boiler.

3.4.13  Blow down the water from mobrey in regular intervals                      

3.4.14  Check the flame condition through view glass

3.4.15 Check the steam leakage and rectify if any.

3.4.16 Check and record the operating parameters in daily log sheet every one hour.

3.5       SHUT DOWN

      3.5.1      Put the modulating switch in ‘OFF’ position.

      3.5.2      Put the firing control switch ‘OFF’ position.  .

      3.5.3      Switch in ‘OFF’  the ‘AUTO’ button on MMI.

      3.5.4      Switch ‘OFF’ the blower.

3.5.5  Close the steam valve of oil heating header.

       3.5.6    Switch off the fuel pump.

       3.5.7    Close the fuel pump valves.

       3.5.8    Close the main steam valve.

3.5.9 Open the Air vent valve.

3.5.10`   Switch off the boiler panel

       3.5.11    Check all valves and switches once again.

      3.5.12     De-Pressurize the boiler.

4.         ABBREVIATIONS

4.1         PPM     Parts per million

4.2         MMI    Man Machine interface

5.         REFERENCES

Nil

6.         ANNEXURES

  6.1       Annexure – 1   –           Daily log sheet of steam boiler