Month: April 2021
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.
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;
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
1.1 To lay down a procedure for operation of air sampler.
2.1 Microbiologist – Quality Control – To follow the SOP.
2.2 Manager – Quality Control – To ensure the compliance of SOP.
- 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
220.127.116.11 Push the liters button.
18.104.22.168 The previously selected volume appears on the screen.
22.214.171.124 To access other preset volumes press the liters button once.
126.96.36.199 The preset volumes ranges from 25 liters, 50 liters, 100 liters, 250 liters 500 liters, 750 liters and 1000 liters.
188.8.131.52 To change the volume setting, select the preset volume.
184.108.40.206 Hold the liters button down until the tester display indicates the desired sampling volume.
220.127.116.11 Start the sampling by pressing the ‘START’ / ‘DELAY’ button twice.
3.4.8 Adjusting the Timer
18.104.22.168 To change the time setting, hold the ‘START’ / ‘DELAY’ button.
22.214.171.124 The display shows previously selected value and starts to count down time.
126.96.36.199 Time can be changed in increments of 5 minutes up to 1 hr.
188.8.131.52 To start the count down press down the ‘START’ / ‘DELAY’ button again.
184.108.40.206 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.
4.1 EOC – End of cycle
4.2 IPA – Isopropyl Alcohol
4.3 QC – Quality control
4.4 SOP – Standard operating procedure
- To lay down a procedure for operation of fume hood.
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.
- 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
Annexure –I – Performance verification Record for fume hood
Annexure –I Performance verification Record for fume hood
|Make||:||Equipment ID No.||:|
|Serial No.||:||Frequency||:||Half yearly|
Anemometer ID No .:__________________ Due date :_______________
|S.No||Observed Velocity (Feet / minute )||Remarks|
Acceptance Criteria: 100 ± 15 Feet /Minute
Performance Status :
Performed by: ____________ Reviewed By : ___________
Date : ____________ Date : ____________
- To lay down a procedure for the operation and calibration of High Pump for column washing Make: Shimadzu.
2.1 Chemist / Executive – Quality Control – to follow the procedure.
2.2 Head – Quality Control for implementation and compliance.
- 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
- HPLC – High performance liquid chromatography.
- HOD – Head of Department
5. 0 REFERENCES
6. 0 ANNEXURES
- ANNEXURE – 1 – Calibration Record for Wash Pump.
ANNEXURE – 1 – Calibration Record for Wash Pump
|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|
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.
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.
1.1 To lay down a procedure for handling of Expired Raw materials
- 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
- The Executive stores shall verify all approved stocks on monthly basis for expired
- 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
- 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
- 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.
4.1 Q.A – Quality Assurance
4.2 MNC – Material Non Conformance
5.1 Procedure for reporting and monitoring of Material Non-Conformance
6.1 Annexure – 1 – “Expired Material” label..
6.2 Annexure – 2 – Expired Material Stock Register
6.3. 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.
(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.