How to Calculate Cubic Feet Per Minute-Definition, Formula

Example

Definition:

Cubic Feet Per Minute (CFM) is a measurement for finding the air volume velocity and it is commonly used for measuring the air flow in heating or cooling diffuses. CFM is also used as a rating and it depends on your room size to ensure adequate ventilation.

Formula:

CFM = (fpm * area)

Where,

'fpm' denotes feet per minute. 'ft' denotes area in square feet.

Example:

Given,

Feet per Minute = 20 fpm, Area in square feet = 55 ft².

To Find,

Cubic Feet Per Minute

Solution:

Substitute the value of FPM=20 and Area=55 ft² in the formula, CFM= (fpm * area) = 20 * 55 = 1100.

Destructive Testing:

Quantity of control / retain sample dosage units to be used for destructive testing shall be governed by the tests recommended for the complaint.

e.g.:  Drug ineffective, adverse drug event, broken tablets, soft / extremely hard tablets, microbial contamination, variation in dose, organoleptic complaints (taste and smell related), etc.       

Non-destructive Testing:

Quantity of control / retain sample dosage units to be examined for non-destructive testing shall be governed by criticality of complaint.

- Critical: 100 % (All the control / retain sample dosage units)

- Major: About 50 % of control / retain sample dosage units

- Minor: About 25 % of control / retain sample dosage units

e.g.: complaint about thickness / weight of dosage form etc.

Organoleptic evaluation / Visual examination:

Bottle / bulk pack :

Bottles / bulk pack of all control / retain samples shall be opened and examined.

Blister / strip pack:

Quantity of control / retain sample dosage units to be used for Organoleptic evaluation / visual examination shall be governed by criticality of complaint. 

- Critical: 100 % (All the control / retain sample dosage units)

- Major: About 50 % of control / retain sample dosage units

- Minor: About 25 % of control / retain sample dosage units     

e.g. Product mix up, dark / faded / unreadable embossing on dosage unit, broken dosage units, Leaking / Melted / Cloudy capsules , count variation, specks on tablets, foreign matter in dosage unit / bottle, open capsules, discoloration of dosage unit, soft tablets, microbial contamination, etc.    

Control / Retain sample for packaging component examination :

Bottle(s) / strip(s) / blister(s) / carton(s) / pack insert(s) / sticker label(s) of all control / retain samples shall be examined in case of complaint related to packaging component. E.g. torn label, coding defect, less blister, empty blister / strips, seal puncture in bottle, pocket puncture etc.           

Critical Complaint

• Product mix-up (including different strengths of same product)
• Mislabeling (incorrect label, incorrect lot number/expiry, unreadable critical data)
• Missing label on bottle / smudged or unreadable coding detail on bottle label / blister/ strip
• Missing coding details on bottle label / primary pack/ blister/ strip
• Missing information on label / blister/strip/package insert
• Microbial contamination or any significant chemical, physical or other change or deterioration in the drug product
• Failure in one or more quality parameters of drug product to meet the specification established for it in the application.
• Foreign substance/matter embedded on the tablet
• Metallic/Glass Contamination
• Foreign matter inside bottle
• Presence of insect
• Missing dose in therapeutic life saving drug

Major Complaint

• Tablet Discoloration
• Intact elimination of tablets/granules (Ghost tablet/granules) / Drug ineffective
• Spot on tablet (Black/Blue/Brown/Red/Other)
• Quick disintegration of tablet in mouth
• Broken Tablets
• Tablet capping / Lamination / edge damage / chipped tablet / coating defect / half tablet / twin tablet
• Missing imprinting on tablet
• Loose hair in bottle / pack
• Breaking / crumbling of tablets in blister / strip/ bottle
• High / Low fill in sachet
• Soft Tablets
• Difficulty in swallowing the product (Suspension/ Tablet)
• Organoleptic (Bad Taste / Odor)
• Bottle with Burnt seal / Broken seal / Partial seal / Improper sealing
• Empty sealed bottle  / sachet
• Loose caps of bottles
• Shortage of units in the bottle
• Broken desiccant (canister / sachet)
• Damaged / Dented bottles
• Double printing on label / carton
• Cosmetic defect on Carton / Product Information Leaflet (PIL)
• Empty carton / Carton with Product Information Leaflet (PIL) only
• Improper sealing of sachet
• Wrong Product Information Leaflet (PIL)
• Braille error in carton
• Temperature Excursion during shipment

Minor Complaint

• 2D Data-Matrix grade on carton found outside the acceptable grade
• Shortage of unit packs in shipper
• Shortage of blister(s) / strip(s) in carton
• Missing component in carton
• Shipper/carton Damage

1.0 GAMBA WALK:

Gamba Walk means “Go” and “See” i.e. Going to the source / place to check the facts thoroughly and understand the situation to have right information to make right decision. This can be the first technique to be used for investigation triggered from deviations, incidents, complaints, OOS, etc. Using said technique below mentioned steps shall be followed.

• Observe the problem / situation first hand, personally (not to rely on the report of others).
• Talk to those at the sharp end (counselling).
• Explore the contributing visible and invisible factors
• Analyse each factor and conclude the probabilities.
• Gamba helps to gain agreement on the problem. This technique can be used in combination of other tools/ techniques.

2.0 FISHBONE DIAGRAM (CAUSE & EFFECT DIAGRAM):

This tool is aimed at first generating possible rootcauses for the problem and then narrowing focus into the most probable cause for the problem. This shall be used in case there is a need to display and explore many possible causes for a specific problem or condition. It isused form or complex rootcaus analysis. Following steps are involved in RCA using Fishbone Diagram. 

• Define the problem (write problem on far-right side of diagram under the heading “problem summary” or “Effect”).
• Categories and brainstorm the main causes (Six-M). Man (Person), Methods (Procedure), Mother Nature (Environment), Materials (Product), Machines (Equipment) and Measurement      shall be used as groups or headings as each bone. More groups can be added, as required.
• One by one, each group/ heading shall be considered to find out different alternatives that could be the probable contributory factors. Each factor shall be analysed and checked for potential relationships between multiple contributory factors.

Eliminate factors one by one after analysis that could not be the contributing factors or root cause.

Finally list the probable causes based on most contributing factors to identify the exact root cause or causes among them.

Six- M are the most significant causes or potential causes of the problem. These forms the main branches from the “backbone arrow”. Any additional cause identified shall be included as a separate category, if required.

​“Materials”: defective material, wrong material, contaminated material, Mix-up in material, Material from unapproved source, inappropriate sampling and testing, etc.

“Man”: unauthorize to operate, unskilled and untrained person, insufficient number of people, procedure not followed, etc.

“Machine (equipment)”: incorrect tool selection, poor maintenance or design, defective equipment or tool, out of calibration, inappropriate capacity, key process variable, critical control points, validation parameters etc.

“Methods (process)”: no or deficient procedure, practices are not the same as written procedures, method not validated, procedure changes etc.

“Measurement”: wrong measuring techniques used, measuring steps not followed, measuring technique not validated etc.

“Milieu / mother nature (Environment)”: improper maintenance of temperature, humidity conditions, storage conditions during transportation etc.

3.0  5–WHY ANALYSIS: It is questions based tool and can be used for each possible factor identified for a problem. Question shall be asked to the right person in right way at right time and place. Following steps shall be followed while using this tool.

• Write down the specific problem.
• Ask question that “WHY did that happened”. Write the answer below the problem.
• Minimum five ‘WHY’ shall be asked to identify root cause using this tool. By the fifth “WHY”, investigator should have identified or be close to identifying root cause. If the cause is not identified till the 5th “WHY”, repeat the question “WHY” until the primary cause is identified. The cause, when identified should preclude the recurrence of an identified non-conformance.
• This tool can be used individually or in combination with other tools e.g. Fishbone diagram

4.0 FAULT TREE ANALYSIS (FTA): This is a graphical tool that provides a systematic description of the combinations of possible occurrences in a system, which can result in an undesirable outcome. This method can combine system and human failures. FTA can be used to establish the pathway to the root cause of the failure. FTA can be used to investigate complaints or deviations to fully understand their root cause and to ensure that intended improvements will fully resolve the issue and not lead to other issues. Refer below mentioned steps for using this tool.

• Fault Tree can either be presented “Left to Right” or “Top to Bottom”. Write the problem/ system either at the far “Left” side or on the “Top”.
• Define Top level faults next to the problem/ system i.e. define starting point for the analysis by detailing the failure for the analysis.
• Identify causes for top-level faults (what events could cause top-level faults to occur).
• Identify next level of events (each event leading to the top-level failure may also have precipitating causes). For each event found continue to identify causes to identify root cause or basic cause.
• Add probabilities to event/ causes (when possible, add actual or relative probability of occurrence of each event/ cause).

5.0 BRAINSTORMING: one of the creative problems solving method (technique) that allows the people to come-up with suggestions/ ideas that could solve the problem or help to identify the cause of the problem. This technique can be used individually or in combination with other RCA tools, as required. The steps involved in Brainstorming are mentioned below.

• A meeting with Cross Functional Team shall be called to brainstorm on problem/ situation.
• People shall ask to think and share their views/ suggest ideas to overcome the problem. Collect as many ideas as possible from all participants.
• All views/ suggestions shall be analysed to identify the cause of problem. Document the details.
• Look for those items that appear in more than one category. This shall be evaluated by investigation team reach a consensus using best collective judgement of listing “most probable causes”.

This procedure describes an assessment process to identify, evaluate and determine control strategy to control the levels of the Nitrosamine impurities in the drug product within acceptable limits.

Sources for Nitrosamine impurities include but not limited to;

• API, Excipients, Solvents, Packing materials, utilities, equipment, manufacturing process etc.

Nitrosamine assessment shall be done in three steps

Step 1: Evaluation of risk: To determine/identify the potential presence of nitrosamine impurities in drug products.

Step 2: Confirmatory Testing:  To perform confirmatory testing on the products identified to be at risk of N-nitrosamine formation or (cross-) contamination and report confirmed presence of nitrosamine

Step 3: Implementation of changes:  To notify changes required to be implemented in the process to mitigate the nitrosamine impurities, if impurities are detected, to regulatory bodies.

Risk Evaluation and Risk assessment shall be employed in two steps:

Step-1: Evaluation of Risk

Risk evaluation will be performed for the finished products by taking into consideration the chemically synthesized APIs, excipients and packaging materials from different vendors used in the finished product and the manufacturing process.

Raw Materials & Packaging material: Information on nitrosamine impurities risk assessment shall be obtained from raw and primary packaging material vendors as per Questionnaire provided at the time of qualification of raw and packing material vendors.

Packaging Process: Risk of nitrosamine impurities generation due to packing process should be evaluated. Common assessment for all primary packaging materials shall be performed.

Purified Water: Common risk assessment for generation and distribution of purified water shall be performed for evaluation of risk. 

Equipment: Risk of nitrosamine impurities generation due to equipment shall be assessed. Common risk assessment shall be performed for all the equipment contact surfaces.

Step-2: Confirmatory Testing

If any risk identified during preparation of nitrosamine assessment for any product, CAPA shall be raised to complete below actions:

Confirmatory testing should be carried out using appropriately validated and sensitive methods in accordance with the prioritization deriving from the risk evaluation. Specifications for individual nitrosamine impurities shall be calculated with maximum daily dose of API containing in finished product.

Products identified as high priority should be tested as soon as possible.

Confirmatory testing of all medicinal products identified to be at risk of presence of nitrosamines and submission of required changes in the manufacturing authorizations should be concluded at an earlier time if otherwise justified.

QA shall inform the competent authorities through Regulatory Affairs immediately if tests confirm the presence of nitrosamine impurity above the acceptable limit.

QA in coordination with respective department shall investigate the root cause and implement the changes in the manufacturing process to mitigate or reduce the nitrosamine impurities. 

Revision of API & Drug product specifications to include Nitrosamine impurities based on the outcome of confirmatory testing and root cause identification.

Outcome of the risk assessments:

• Step-1: No risk identified
• Step-1: Risk identified
• Step-2 (Confirmatory analysis outcome): No nitrosamine detected
• Step-2 (Confirmatory analysis outcome): Nitrosamine detected

Determination of Specifications limits :-

The limits shall be based on the ICH M7(R1) principles for “cohort of concern” substances. AI limit corresponding to a theoretical excess cancer risk of <1 in 100,000) considering a lifetime daily exposure should be calculated for individual N-nitrosamines in human medicinal products.

For the impurities with known acceptable limits in ng/day, the specification limits shall be derived as below:

Acceptable intake (ng/day) / Max. Daily dose (mg) = Specifications in ppm

For the impurities with unknown acceptable limit, the specification limit shall be derived by considering the acceptable intake of TTC 18 ng/day as below:

18 / Max. Daily dose (mg) = Specifications in ppm

Calculation of total limit when more than one nitrosamine is identified:

For determining limits in the case of presence of more than one nitrosamine, two approaches are considered acceptable in order not to exceed the acceptable risk level of 1:100,000 as outlined in ICH M7(R1) guideline:

• The total daily intake of all identified N-nitrosamines not to exceed the AI of the most potent N-nitrosamine identified, or
• Total risk level calculated for all identified N-nitrosamines not to exceed 1 in 100,000.

Methodology for testing:

Confirmatory test to be conducted by Government Certified lab on API and Finished product.

Testing of the API or its intermediates is recommended if the risk evaluation indicates that the API or its intermediates are a potential source of nitrosamine impurities in the FP. In such cases, the results of API or intermediate testing may be used to support root cause investigations and to justify control strategy for nitrosamine impurities.

For the purpose of confirmatory testing as part of step 2, number of batches manufactured shall be selected based on the below criteria (API as well as FP):

• 10% of annual Finished batches manufactured or API batches procured, or 3 per year, whichever is highest
• Newly produced batches of finished products
• Retained samples of batches still within expiry date
• If fewer than 3 batches are manufactured annually, then all batches shall be tested

Above approach shall be used provided the source of risk has been identified and is well understood (e.g. by spike and purge studies) such that impurity levels are expected to be consistent from batch to batch

Requirement of Analytical methodology to determine Nitrosamine impurities

Methods for determination of various nitrosamines shall be developed and validated for testing in-house.

Alternately, method specified in European Pharmacopeia Chapter 2.5.42 may be adopted after verification

Following considerations shall be taken when developing analytical methods:

• Interference caused by presence of trace amounts of nitrosamines in testing materials utilized (e.g. water, airborne sources, plastics products and rubber/elastomeric products);
• Contamination during sample preparation (avoiding cross contaminations from gloves, membranes, solvents etc.) which could lead to false positive results;
• In situ formation of nitrosamines during analysis;
• Use of accurate mass techniques is required (MS/MS or high-resolution accurate mass systems) in order to overcome interference in the identification of the specific peak of a certain nitrosamine (e.g. false positives have been observed from DMF co-eluting with NDMA).

The analytical methods need to be sufficiently sensitive in order to adequately detect and quantify trace levels of nitrosamine impurities

• Limit of quantification (LOQ) to be determined as much low as feasible with high sensitivity technique/instruments and to perform Accuracy and Precision of impurity at this level
• The LOQ should be ≤ of the acceptable limit based on the relevant acceptable intake (AI) for the respective nitrosamine impurity. Refer the relevant table. Generally, method shall be sensitive such that the LOQ of the analytical method employed should be ≤ 10% of the acceptable limit based on the AI, where feasible;
• Different analytical methods may be used for determination of multiple nitrosamines. If the same analytical method is used for multiple nitrosamines, the selectivity of the method should be demonstrated at the LOQ for each nitrosamine

Finished product where confirmatory testing indicated presence of nitrosamine impurities, Quality Assurance along with cross functional technical team shall investigate and implement the control strategy/ measures to minimize the risk of generation of or contamination with nitrosamines. For E.g.: Change in manufacturing process, change in raw material quality, Introduction of appropriate specifications or appropriate methods and measures on the premise and equipment such as cleaning procedure and environmental monitoring, etc.

Frequency of testing:

If quantitative testing is performed as a routine control, the LOQ should be ≤ of the acceptable limit based on the relevant acceptable intake (AI) for the respective nitrosamine impurity.

If quantitative testing is performed to justify skip testing, the LOQ of the analytical procedure employed should be ≤ 30% of the acceptable limit based on the AI.

If quantitative testing is performed to justify omission of specification, the LOQ of the analytical method employed should be ≤ 10% of the acceptable limit based on the AI.

Exceptions are anticipated for medicinal products used at high daily doses (AI may be below technical feasibility of the method), or in case more than one nitrosamine is anticipated or identified in a given medicinal product.

Periodic review of Nitrosamine Assessment:

Periodic review of Nitrosamine impurities risk assessment shall be done every 2 years from date of assessment for change in the nitrosamine impurities risk factors / sources as below:

Addition/Deletion of vendors (Finished product / API / Excipients / packaging materials) for the input materials of the product.

• Change in Purified Water source, Nitrogen and Compressed Air.
• Change in manufacturing equipment.
• Change in manufacturing process

Quality Assurance shall get the updated Nitrosamine assessment/ declaration from all vendors for all the materials at every 2 years for periodic review of Nitrosamine impurities risk assessment.

Airlock – An enclosed space with interlocked doors, constructed to maintain air pressure control between adjoining rooms (generally with different air cleanliness standards). The intent of an airlock is to preclude ingress of particle matter and microorganism contamination from a lesser controlled area.

Action limit – An established relevant measure (e.g. microbial, or airborne particle limits) that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation.

Alert level – An established relevant measure (e.g. microbial, or airborne particle levels) giving early warning of potential drift from normal operating conditions and validated state, which does not necessarily give grounds for corrective action but triggers appropriate scrutiny and follow-up to address the potential problem. Alert levels are established based on routine and qualification trend data and are periodically reviewed. The alert level can be based on a number of parameters including adverse trends, individual excursions above a set limit and repeat events.

Aseptic preparation/processing – The handling of sterile product, containers and/or devices in a controlled environment in which the air supply, materials and personnel are regulated to prevent microbial, endotoxin/pyrogen and particle contamination.

 Aseptic Process Simulation (APS) – A simulation of the entire aseptic manufacturing process in order to verify the capability of the process to assure product sterility. Includes all aseptic operations associated with routine manufacturing, e.g. equipment assembly, formulation, filling, lyophilization and sealing processes as necessary.

Asepsis – A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbial contamination of the exposed sterile product.

 Bacterial retention testing – This test is performed to validate that a filter can remove bacteria from a gas or liquid. The test is usually performed using a standard organism, such as Brevundimonas diminuta at a minimum concentration of 107 Colony Forming Units/cm² .

Barrier – A physical partition that affords aseptic processing area (usually grade A) protection by separating it from the background environment. Such systems frequently use in part or totally the Barrier Technologies known as RABS or isolators.

Bioburden – The total number of microorganisms associated with a specific item such as personnel, manufacturing environments (air and surfaces), equipment, product packaging, raw materials (including water), in-process materials, or finished products.

Bio-decontamination - A process that eliminates viable bioburden via use of sporicidal chemical agents.

Biological Indicators (BI) – A population of microorganisms inoculated onto a suitable medium (e.g. solution, container or closure) and placed within a steriliser or load or room locations to determine the sterilisation or disinfection cycle efficacy of a physical or chemical process. The challenge microorganism is selected and validated based upon its resistance to the given process. Incoming lot D-value, microbiological count and purity define the quality of the BI.

Blow-Fill-Seal (BFS) – A technology in which containers are formed from a thermoplastic granulate, filled with product, and then sealed in a continuous, integrated, automatic operation. The two most common types of BFS machines are the Shuttle type (with Parison cut) and the Rotary type (Closed Parison).

Campaign manufacture – A manufacture of a series of batches of the same product in sequence in a given period of time with strict adherence to established and validated control measures.

Classified area – An area that contains a number of cleanrooms (see cleanroom definition). Cleaning – A process for removing contamination e.g. product residues or disinfectant residues.

Clean area – An area with defined particle and microbiological cleanliness standards usually containing a number of joined cleanrooms.

Cleanroom – A room designed, maintained, and controlled to prevent particle and microbial contamination of drug products. Such a room is assigned and reproducibly meets an appropriate air cleanliness level.

Cleanroom classification – A method of assessing the level of air cleanliness against a specification for a cleanroom or clean air equipment by measuring the total particle concentration.

Cleanroom qualification – A method of assessing the level of compliance of a classified cleanroom or clean air equipment with its intended use.

Closed system – A system in which the product is not exposed to the surrounding environment. For example, this can be achieved by the use of bulk product holders (such as tanks or bags) that are connected to each other by pipes or tubes as a system, and where used for sterile products, the full system is sterilised after the connections are made. Examples of these can be (but are not limited to) large scale reusable systems, such as those seen in active substance manufacturing, or disposable bag and manifold systems, such as those seen in the manufacture of biological products. Closed systems are not opened until the conclusion of an operation. The use of the term “closed systems” in this Annex does not refer to systems such as RABS or isolator systems.

Colony Forming Unit (CFU) – A microbiological term that describes a single detectable colony that originates from one or more microorganisms. Colony forming units are typically expressed as CFU per ml for liquid samples, CFU per m3 for air sample and CFU per sample for samples captured on solid medium such as settle or contact plates.

Contamination – The undesired introduction of impurities of a microbiological nature (quantity and type of microorganisms, pyrogen), or of foreign particle matter, into or onto a raw material, intermediate, active substance or drug product during production, sampling, packaging or repackaging, storage or transport with the potential to adversely impact product quality.

Contamination Control Strategy (CCS) – A planned set of controls for microorganisms, endotoxin/pyrogen and particles, derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to active substance, excipient and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.

Corrective intervention – An intervention that is performed to correct or adjust an aseptic process during its execution. These may not occur at a set frequency in the routine aseptic process. Examples include such as clearing component jams, stopping leaks, adjusting sensors, and replacing equipment components.

Critical surfaces – Surfaces that may come directly into contact with, or directly affect, a sterile product or its containers or closures. Critical surfaces are rendered sterile prior to the start of the manufacturing operation, and sterility is maintained throughout processing.

Critical zone – A location within the aseptic processing area in which product and critical surfaces are exposed to the environment. Critical intervention – An intervention (corrective or inherent) into the critical zone.

D-value – The value of a parameter of sterilisation (duration or absorbed dose) required to reduce the number of viable organisms to 10 per cent of the original number. Dead leg – Length of non-circulating pipe (where fluid may remain static) that is greater than 3 internal pipe diameters.

Decommission – When a process, equipment or cleanroom are closed and they will not be used again.

Decontamination – The overall process of removal or reduction of any contaminants (chemical, waste, residue or microorganisms) from an area, object, or person. The method of decontamination used (e.g. cleaning, disinfection, sterilisation) should be chosen and validated to achieve a level of cleanliness appropriate to the intended use of the item decontaminated. See also Bio-decontamination.

Depyrogenation – A process designed to remove or inactivate pyrogenic material (e.g. endotoxin) to a specified minimum quantity.

Disinfection – The process by which the reduction of the number of microorganisms is achieved by the irreversible action of a product on their structure or metabolism, to a level deemed to be appropriate for a defined purpose.

Endotoxin – A pyrogenic product (i.e. lipopolysaccharide) present in the Gram negative bacterial cell wall. Endotoxin can lead to reactions in patients receiving injections ranging from fever to death.

Equilibration time – Period which elapses between the attainment of the sterilisation temperature at the reference measurement point and the attainment of the sterilisation temperature at all points within the load.

Extractables - Chemical entities that migrate from the surface of the process equipment, exposed to an appropriate solvent at extreme conditions, into the product or material being processed.

First Air – Refers to filtered air that has not been interrupted prior to contacting exposed product and product contact surfaces with the potential to add contamination to the air prior to reaching the critical zone.

Filter Integrity test - A test to confirm that a filter (product, gas or HVAC filter) retain their retentive properties and have not been damaged during handling, installation or processing.

Form-Fill-Seal (FFS) –An automated filling process, typically used for terminally sterilised products, which constructs the primary container out of a continuous flat roll of packaging film while simultaneously filling the formed container with product and sealing the filled containers in a continuous process. FFS processes may utilize a single web system (where a single flat roll of film is wrapped around itself to form a cavity), or a dual web system (where two flat rolls of film are brought together to form a cavity), often with the aid of vacuum moulds or pressurised gases. The formed cavity is filled, sealed and cut into sections. Films typically consist of a polymeric material, polymeric coated foil or other suitable material.

Gowning qualification – A programme that establishes, both initially and on a periodic basis, the capability of an individual to don the complete gown.

Grade A air supply – Air which is passed through a filter qualified as capable of producing grade A total particle quality air, but where there is no requirement to perform continuous total particle monitoring or meet grade A viable monitoring limits. Specifically used for the protection of fully stoppered vials where the cap has not yet been crimped.

HEPA filter – High efficiency particulate air filter specified in accordance with a relevant international standard.

Inherent interventions – An intervention that is an integral part of the aseptic process and is required for either set-up, routine operation and/or monitoring (e.g. aseptic assembly, container replenishment, environmental sampling). Inherent interventions are required by procedure or work instruction for the execution of the aseptic process.

Intrinsic sterile connection device – A device that reduces the risk of contamination during the connection process; these can be mechanical or fusion sealing. Isokinetic sampling head – A sampling head designed to disturb the air as little as possible so that the same particles go into the nozzle as would have passed the area if the nozzle had not been there (i.e. the sampling condition in which the mean velocity of the air entering the sample probe inlet is nearly the same (± 20 percent) as the mean velocity of the airflow at that location). Isolator – An enclosure capable of being subject to reproducible interior bio-decontamination, with an internal work zone meeting grade A conditions that provides uncompromised, continuous isolation of its interior from the external environment (e.g. surrounding cleanroom air and personnel). There are two major types of isolators: i. Closed isolator systems exclude external contamination of the isolator’s interior by accomplishing material transfer via aseptic connection to auxiliary equipment, rather than use of openings to the surrounding environment. Closed systems remain sealed throughout operations. ii. Open isolator systems are designed to allow for the continuous or semi-continuous ingress and/or egress of materials during operations through one or more openings. Openings are engineered (e.g. using continuous overpressure) to exclude the entry of external contaminant into the isolator.

Leachables – Chemical entities that migrate into products from the product contact surface of the process equipment or containers under normal condition of use and/or storage.

Local isolates – Suitably representative microorganisms of the site that are frequently recovered through environmental monitoring within the classified zone/areas especially grade A and B areas, personnel monitoring or positive sterility test results.

Lyophilization – A physical-chemical drying process designed to remove solvents, by way of sublimation, from both aqueous and non-aqueous systems, primarily to achieve product or material stability. Lyophilization is synonymous to the term freeze-drying.

Manual aseptic processing– An aseptic process where the operator manually compounds, fills, places and /or seals an open container with sterile product.

Operator - Any individual participating in the processing operation, including line set-up, filling, maintenance, or other personnel associated with manufacturing activities.

Overkill sterilisation – A process that is sufficient to provide at least a 12 log10 reduction of microorganisms having a minimum D-value of 1 minute.

Parison – The "tube" of polymer extruded by the BFS machine from which containers are formed.

Pass-through hatch – Synonymous with airlock (see airlock definition) but typically smaller in size.

Patient – Human or animal including participants in a clinical trial.

Post-aseptic processing terminal heat treatment– A terminal moist heat process employed after aseptic processing which has been demonstrated to provide a sterility assurance level (SAL) ≤10-6 but where the requirements of steam sterilisation (for example, F0≥8 min) are not fulfilled. This may also be beneficial in the destruction of viruses that may not be removed through filtration.

 Pyrogen – A substance that induces a febrile reaction in patients receiving injections

Rapid Transfer System/Port (RTP) – A System used for the transfer of items into RABS or isolators that minimizes the risk to the critical zone. An example would be a rapid transfer container with an alpha/beta port.

Raw material – Any ingredient intended for use in the manufacture of a sterile product, including those that may not appear in the final drug product.

 Restricted Access Barrier System (RABS) – System that provides an enclosed, but not fully sealed, environment meeting defined air quality conditions (for aseptic processing grade A), and using a rigid-wall enclosure and integrated gloves to separate its interior from the surrounding cleanroom environment. The inner surfaces of the RABS are disinfected and decontaminated with a sporicidal agent. Operators use gloves, half suits, RTPs and other integrated transfer ports to perform manipulations or convey materials to the interior of the RABS. Depending on the design, doors are rarely opened, and only under strictly pre-defined conditions.

Single Use Systems (SUS) – Systems in which product contact components are used only once to replace reusable equipment such as stainless steel transfer lines or bulk containers. SUS covered in this document are those that are used in manufacturing processes of sterile products and are typically made up of disposable components such as bags, filters, tubing, connectors, storage bottles and sensors.

Sporicidal agent – An agent that destroys bacterial and fungal spores when used in sufficient concentration for specified contact time. It is expected to kill all vegetative microorganisms.

Sterile Product – For purpose of this guidance, sterile product refers to one or more of the sterilised elements exposed to aseptic conditions and ultimately making up the sterile active substance or finished sterile product. These elements include the containers, closures, and components of the finished drug product. Or, a product that is rendered sterile by a terminal sterilisation process.

Sterilising grade filter – A filter that, when appropriately validated, will remove a defined microbial challenge from a fluid or gas producing a sterile effluent. Usually such filters have a pore size equal or less than 0.22 µm.

Terminal Sterilisation – The application of a lethal sterilising agent or conditions to a product in its final container to achieve a predetermined sterility assurance level (SAL) of 10⁻⁶ or better (e.g. the theoretical probability of there being a single viable microorganism present on or in a sterilised unit is equal to or less than 1 x 10-6 (one in a million)). Turbulent airflow – Air that is not unidirectional. Turbulent air in cleanrooms should flush the cleanroom via mixed flow dilution and ensure maintenance of acceptable air quality.

Unidirectional airflow – An airflow moving in a single direction, in a robust and uniform manner, and at sufficient speed, to reproducibly sweep particles away from the critical processing or testing area.

Unidirectional Airflow (UDAF) unit – A cabinet supplied with filtered unidirectional airflow (previously referred to as a Laminar Airflow Unit or LAF).

Worst case – A set of conditions encompassing processing limits and circumstances, including those within standard operating procedures, that pose the greatest chance of process or product failure (when compared with ideal conditions). Such conditions have the highest potential to, but do not necessarily always result in product or process failure.

Water system – A system for producing, storing and distributing water, usually compliant to a specific pharmacopeia grade (e.g. purified water and water for injection (WFI)).

Z-value – The temperature difference that leads to a 10-fold change in the D-value of the biological indicators.

What is Your Opinion!Comment 

General Requirements for Reduce Testing 

Reduce testing is applicable if all other tests in specification meet its acceptance criteria.

A full testing shall be done for each received RM/PM/FP/In process materials once (preferably) for first batch in a calendar year and same shall be tracked through Tracker/Planner

The Risk on Reduced testing shall be evaluated based on risk assessment

The Risk Assessment shall be performed by considering the following criteria but not limited to:

• Criticality of In-process test for Finish Product
• Trend of In-process
• Trend of Finished Product
• Number of OOS/ Deviation / Lab Incident / Market complaints
• Approved status of the supplier for Raw Materials/packing materials
• Quality of the In-process tests 
• Quality Score of the Suppliers
• Any Requirements from the Regulatory Agency / Customers / Business Partners.

The number of batches applicable for reduced testing and its frequency is based on the Risk assessment conclusion.

After the approval of Risk assessment any changes in documents (e.g., Specification, BMR, BPR) shall be routed through Change Management Procedure

Specific note to be included in specification with (*) / (#) mark to identify test to be performed on each Lot/Batch and other tests to be performed once in a year respectively.

 Reduced Testing Limitation/Re-assessment/Termination:

Limitation:

Reduced testing is not Applicable for RM/PM used for R&D trials Batches/Non GMP trials batches.

Reduced testing is not applicable for first 3 batches from any new Supplier.

The same reduced testing approach shall be applied for re-test materials which are stored in in-house warehouse as per manufacturer’s storage conditions.

Reduce testing is not applicable for the batches in the following cases

• Deviation associated with product/material.
• Introduction of new Vendor for the first time
• OOS, OOT associated with product/material.
• Incident associated with product/material.
• Market complaint associated with product/material.
• Recall associated with product/material.
• AHU system failure. 
• Power failure.
• Purified water system failure
• Any other exception comes out from the risk assessment.

Re-Assessment:

The requirement of the reduced testing is re-assessed if the RM/PM/FP/In process materials having the following discrepancies:

• Deviation associated with product/material.
• OOS, OOT associated with product/material.
• Incident associated with product/material.
• Market complaint associated with product/material.
• Recall associated with product/material.

Termination:

The termination of approved reduced tasting shall be performed after the approval from QA Head by proposing the termination of reduced testing.

Reduced testing procedure Shall be resumed after proper Root cause identification for the failure with an appropriate CAPA followed by performing risk assessment.

What is Your Opinion !Comment

 

 

Topic: Equipment Qualification

Question: What is the V model in Qualification?

Ans. V- Model means Verification and Validation model. It is a widely accepted reference model for computer system validation and was introduced by International Society of Pharmaceutical Engineers (ISPE) in 1994 in the first edition of their Good Automated Manufacturing Practices guideline (GAMP)

Question: Which guideline you refer for the commissioning and qualification of process Equipments

Ans. ISPE Baseline Guide: Commissioning and Qualification-Vol 5, WHO TRS, EU Annexure-15, USFDA Part 210 and 211

Question: What is C&Q Planning Approach for new project?

Ans. The amount of planning, documentation, reporting and level of details of C&Q plan should be based on the expectations of the organization/site , size and complexity of the project and the potential impact on the quality and safety of the product

Question: What is Installation Qualification?

Ans. The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturer's recommendations.

Question: what are the tests parameters required for Installation qualification of Equipments?

Ans. The following are test parameters for IQ of the equipment but not limited to

• Verification of physical conditions like undamaged product free of physical defects (i.e. Scoring/Roughness, Dent/Pitting, Scratch, Crack, Discoloration and Rusting).
• Verification of Documents for completeness.
• Verify system P&ID as required
• Verify any system components defined in the protocol
• Verify utility connections and ensure required utilities as appropriate
• Verify instrument connections from field to PLC
• Check connection to peripheral devices (printers, data loggers, etc.)
• Check manual functionality (all switches, buttons and settings in manual mode).
• Verify that complete Parts List has been filed in maintenance Records/engineering store.
• Installation of equipment checked to current engineering drawing and Specification
• Identification of critical instruments for Calibration requirement
• Verification of material of construction
• To ensure that the machine is installed at its designated place.
• To measure the dimension wherever possible.

Question: What is material of construction for product contact surface area?

Ans. Non Reactive Like SS 316/SS316L/ Teflon, Silicon, Toughen Glass, PVC etc.

 

Question: How you verify the material of construction of the equipment?

Ans. By using 9 V battery and Molybdenum test kit, if drop of Solution turns pink after passing the 9 V current through the Molybdenum solution drop on the surface of test metal remain pink more than 30 sec, that means it is SS316 and if diminish immediately then it is SS304.

Question: How you will do System impact assessment for the equipment?

Ans. Direct impact system having the direct impact on the product quality, safety, efficacy, potency. Indirect impacts system may have impact on product quality, safety, efficacy, potency or linked with direct impact system. No impact system having no impacts on the product quality, safety, efficacy, potency

Question: How you will draft SOP for new equipments?

Ans. Referring the Equipment user/Operational manual, Maintenance manual

Question: What is User Requirement Specification?

The first document prepared for any proposed new equipment or system.  This document is written by the user to describe the user requirements for the new equipment or system. The set of owner, user and engineering requirements necessary and sufficient to create a feasible design meeting the intended purpose of the system.

Question: What is Design Qualification

Ans. The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose and comply with the requirements of URS. The design documents (drawings, specifications, etc.) are to be compared to the URS requirements and confirmed that they are in compliance. DQ will be conducted for all new equipment, facilities and critical utilities.

Question: What is Direct Impact System –

Ans. The systems which have direct impact on product quality are termed as direct impact system. These are Critical equipment is that equipment needed for processing, packaging, holding, or supporting of products and those unit operations that have the potential to impact critical process parameters and quality of the product.

Question: What is Equipment Qualification Master Plan?

Ans. A document prepared as part of project planning that describes overall philosophies, approaches, and objectives to all aspects of qualification. The document defines responsibilities and expectations for the various components of the qualification exercise.

Question: What is Factory Acceptance Test?

Ans. Documented verification that the Equipment or System meets design specification and conforms to agreed performance intent at manufacturer site before dispatch of the machine.

Question: What is Indirect Impact System?

Ans. The systems which do not have direct impact on product quality however they support or linked to a direct impact systems are termed as indirect impact systems.

 

Question: What is Operational Qualification

Ans. The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges.

Question: What is Performance Qualification

Ans.The documented verification that systems and equipment can perform effectively and reproducibly based on the approved process method and product specification and parameters, for prolonged periods.

Question: What is Re Qualification

Ans. Equipment, facilities, utilities and systems should be evaluated at an appropriate pre-defined frequency to confirm that they remain in a state of control.

Question: What is Site Acceptance Test

Ans. Documented Verification that the receipt of the item at site confirms with the standards laid down in the purchase order, DQ and URS.

Question: What are the tests parameters required for Operational qualification of Equipments?

Ans. The test parameters are

• Verification of Calibration status and review of calibration certificates of instruments identified during Installation Qualification
• Verification of Draft SOPs
• Verification of Equipment Operation
• Verification of Ranges of Parameters
• Verification of Input & Output of PLC, HMI verification, communication verification, security and access verification, backup and recovery and verification of configurable parameter and range testing and Password Verification
• Power Failure Challenge
• Verification of Safety features
• Verification of Safety Features, Alarms and Interlocks:
• Instructions for Verification of HMI Screen

Question: What are the tests parameters required for Performance qualification of Compression machine?

Ans. The Test Parameters are

• Verification of Effective Sops
• Verification of RPM of Turret, Feeder Minimum/Maximum Range
• Verification of Physical Parameters of Tablets at various speeds like Min. , Max. Hopper Level, Feeder Speed, Short punch challenges tests, Rejection Mechanism Test, Minimum and Maximum Thickness pressure

Question: What are the test parameters for Facility Qualification

Ans. The Test Parameters are

• Verification of Dimensions, Finish and Structure
• Verification of Facility against User Requirements Specification
• Verification of Facility against as Built Drawings
• Verification of Man, Material and Equipment Movement
• Measurement of Light Intensity and Noise Level.
• Location and number of Supply diffusers, Return Air Raisers, Door, Windows
• Verification of Utilities available and Drain Points

Topic: Utility Qualification (HVAC Validation)

Question:  What is the test for HVAC PQ as per ISO 14644-1, 2,3

Ans. The Test Parameters are

• Air Balancing
• Air velocity/ACPH (NLT 20 ACPH for Grade D Area)
• HEPA filter integrity (NMT 0.01 % leakage of Upstream Concentration)
• Non Viable particle count (Refer  ISO 14644-1- For Grade A, B,C,D)
• Viable Particle count (NMT 100CFU/4 Hrs Settle plate Exposure)
• Recovery Study (NMT 15 Minutes)
• Air flow Pattern (For LAF-Laminar Air Flow. For Other Grade Supply to return, High Pressure to Lower Pressure)
• Temperature/RH Monitoring
• Differential Pressure Monitoring
• Contamination Leakage Test
• Segregation Test

Topic: Utility Qualification (Compressed Air)

Question:  What are the tests required for the PQ of Compressed air as per ISO 8573

Ans. The tests are

• Dew Point
• Water Vapors
• Oil Mist
• Non Viable Particle count
• Viable Particle Count
• Carbon dioxide (CO2)
• Carbon monoxide (CO)
• Sulphur Dioxide (SO2)
• Nitrous Oxide/ Nitrogen Dioxide (NO/No2)

 

Topic: Utility Qualification (PW/WFI Qualification)

Question:  What are the Phases of PQ for Purified/WFI Water Systems?

•  Phase 1: Duration 2 to 4 Weeks: Primary objective to develop appropriate operating ranges and daily sampling and testing of chemical and microbiological parameters from all user points
• Phase 2: Duration 2 to 4 Weeks: Primary objective to demonstrate consistent operation within established ranges and established Alert and Action limits of testing parameters based on Phase – I data. Establish cleaning, regeneration and   sanitization frequency based on Phase 1 and Phase 2 data for loop, tanks, filters, and components as applicable. Daily sampling and testing of chemical and microbiological parameters from all user points
• Phase 3: Duration One Year: Primary objective is water system should continue to be monitored and evaluated on an on-going basis following a life cycle approach using online instruments or samples for laboratory based testing. To ensure that seasonal variations are evaluated. Sampling based on SOP schedule (All user point shall be covered once in week and Supply/Return Daily basis)

Question:  What is Reynolds number in Purified water distribution system?

Ans. The Reynolds number should be more than 4000 and it indicates the relative significance of the viscous effect compared to the inertia effect and the number is proportional to the inertial force divided by the viscous force

Reynolds number can be expressed as can be expressed as

Re = (ρ u²) / (μ u / L)  = ρ u L / μ  = u L / ν (1)

Where

Re = Reynolds Number (non-dimensional)

ρ = density (kg/m³, lb_m/ft³ )

u = velocity based on the actual cross section area of the duct or pipe (m/s, ft/s)

μ = dynamic viscosity (Ns/m², lb_m/s ft)

L = characteristic length (m, ft)

ν = μ / ρ = kinematic viscosity (m²/s, ft²/s)

Question:  What is minimum value of flow velocities in Purified water distribution system?

Ans. Distribution systems should operate with nominal flow velocities of 3 feet per second or higher. (Ref. ISPE baseline pharmaceutical engineering guide, water and steam system, first edition Jan 2001, Vol. 4 pg.no.122.

Question:  What is Maximum Limit for Online Conductivity of Purified water?

Ans. It should not more than 1.3 µs/cm (Micro Siemens (µs)

Question:  What is Maximum Limit for TOC (Total organic Carbon) of Purified water?

Ans. It should not more than 500 ppb (part per billion)

Question:  What is Pore size of filter installed on the top of Purified/WFI water tank?

Ans. 0.2 micron and it is hydrophobic in nature and remain heated above 80 ⁰C

Question:  What is dead leg and what is the allowable limit?

Ans. Dead legs are sections of water piping systems that have been altered, abandoned or capped such that water cannot flow through them. This includes isolated branch lines, pipe sections with closed valves and pipes with one end capped. Dead legs experience periods of no flow which leads to stagnation and microbial proliferation. Dead leg should not significantly exceed 3 times of the branch diameter as measured from the Inner diameter pipe wall to center line of point of use valve. (Ref. WHO TRS 970, pg.no. -87)

Question:  What is the acceptance criterion for Slope in water system pipeline?

Ans. Slope measurement shall be made with a digital level or a digital protractor. The instrument used should be capable of displaying slope in degrees, percent, and In./ft (mm/m).

Unit of measurement	Ratio of  slope to length	Minimum Slope (gradient)	Minimum Slope
	NMT	mm/meter	%
GSD2*	1:100	10	1.0

*As per ASME BPE standard slope designation is defined as GSD2 for gravity drained lines

Question:  What are the tests required in IQ of Water system?

Ans: The Test are:-

Material of Construction: Materials should be used that are “not reactive, additive, or adsorptive” to the water. The component and piping material certificates should be traceable to drawings for the system (including heat marks & certificates).

Surface finish: Mechanically polish surfaces in contact with feed water to 25 micro inch Ra Max (0.64 micrometer) and to electro polish surfaces in contact with Pure steam and WFI to 20 micro inch Ra Max (0.51 micrometer).  (Ref. ISPE baseline guideline, Volume 4).

Dead Leg verification: Dead leg should not significantly exceed 3 times of the branch diameter as measured from the Inner diameter pipe wall to center line of point of use valve

Orbital Welding and Boroscopy: Internal welds are inspected by indirect visual methods (i.e. boroscopy) by facility owner or third party designee at minimum of 25 % boroscopy and minimum of 25 % radiography of total daily completed welds for automatic machine welds and 100 % of daily completed manual welds. Weld locations should be documented on the Weld map drawing should identify weld location. The heat numbers of metals jointed on either side of weld should be included. The heat numbers should be traceable to material certificates of analyses. (Heat number corresponds to the chemical composition of the material). (Ref. ISPE Commissioning and Qualification)

Line Slope:  Ratio of slope to length NMT 1:100

Hydrostatic Pressure Test: This test is performed to verify that the water or steam system is free of leaks, which can lead to contamination of the water or steam. (Ref. ISPE baseline pharmaceutical engineering guide, water and steam system, second edition 2014, pg.no.32. After Installation and before passivation, the piping systems should be pressure tested. Hydrostatic test or flushing pressure shall not be greater than the manufacturer's recommended test pressure or NMT 1.5 times of recommended pressure and then monitoring of pressure decay for four hours

Cleaning and Passivation: Cleaning and passivation procedures should include, cleaning agent used, cleaning temperature and times, passivation chemical solutions used, temperature and contact times, identification of line sections, components passivated etc

Sanitization: During validation of thermal sanitization methods, a heat distribution study should be performed to demonstrate that sanitization temperatures are achieved throughout the system; return loop shall be monitored as a worst case.

Question: Spray Valve Should be _______Rotation

Ans: Should be 360⁰. Spray Pattern shall be verified by using riboflavin dye and UV Torch light.

Question: How you define the Alert and Action Levels of Parameters

Ans: Average +2 *SD= Alert Limit

        Average +3 *SD= Action Limit

 

Topic:- Utility Qualification (Pure/Clean Steam Validation)

Question: What is the Performance Qualification Test for the pure/Clean Steam as per HTM 2010?

Ans: Non Condensable Gases: - NMT 3.5 %

         Dryness Value: ≥0.95

         Super Heat: NMT 25⁰C

         Endotoxin: NMT 0.25 EU/ml

 

Topic: Utility Qualification (Nitrogen Gas Validation)

Question: What is the Performance Qualification Test for the Nitrogen gas as per USP?

Ans: Identification: Complies to USP

        Assay of Nitrogen Gas: NLT 99.5 %

        Oxygen Contents: NMT 0.5 %

        CO2

        CO

        Water Contents

 

Topic: Sterilization (Autoclave/Tunnel/DHS)

Question: What is D Value?

Ans: D-value, or decimal reduction time, is the time it takes to reduce a microbial population by 1 logarithm, or 90% of its initial value, under specified conditions (e.g., sterilant concentration, exposure temperature, relative humidity, package configuration).

Question: What is Z Value?

Ans: The Z value is the number of degrees (temperature) or dosage units required for a one-log reduction in the D value. In other words, the Z value is the change in the sterilization condition that affects a 10-fold (one-log) reduction in the D value.

Question: What is F₀ Value and how you calculate?

Ans: F₀ value is used to determine the exposure time of material for sterilization at a particular temperature. F₀ value is the time in minute for the specified temperature that gives the same thermal lethality as at 121 °C in one minute..

F₀ =   ^(T-121/Z)

T= Temperature for sterilization

= Time Interval

Z Value= 10⁰C

Question: How you calculate F_H Value for Depyrogenation Tunnel or DHS?

Ans:

F_H =   ^(T-250/Z)

T= Temperature for sterilization

= Time Interval (in second)

Z Value= 46.4⁰C

Question: What is SAL (Sterility Assurance Level)?

Ans: Sterility assurance level is the probability that a single unit that has been subjected to sterilization nevertheless remains nonsterile. It is never possible to prove that all organisms have been destroyed, as the likelihood of survival of an individual microorganism is never zero. Typical SALs are 10⁻⁶

F₀ = D₁₂₁ (Log A-Log B)

D₁₂₁ = 1.9 (From Certificate of Biological Indicator)

Log A = Initial Population (10⁶)

Log B = Final Population After sterilization (10^-6)

12 Log Reductions= Sterility Assurance Level

Question: How many log reduction occur in Depyrogenation tunnel?

Ans. 3 log reduction

Question: What are the tests required to check the performance of Depyrogenation tunnel?

Ans. Heat Distribution

        Heat Penetration (Endotoxin Challenged Vial)

        Conveyor Belt Speed (mm/Minutes)

HEPA Filter Test for Tunnel:

Air Velocity, HEPA filter integrity, Non Viable Particle Count, Air Flow Pattern at the inlet and outlet

Topic: Cleaning Validation

Question: What is Cleaning Validation?

Ans. Documented evidence with high degree of assurance that a cleaning process will result in product meeting their predetermined quality attributes throughout its lifecycle

Question: What is NOEL – No Observed Effect Level?

Ans. The highest tested dose of a substance that has been reported to have no harmful health effects on targeted people or animals.

Question: What is PDE - Permitted Daily Exposure

Ans. Permitted Daily Exposure represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime.

Question: What is LD50 – Lethal Dose

Ans. An LD₅₀ is a standard measurement of acute toxicity that is stated in milligrams (mg) of substance per kilogram (kg) of body weight. An LD₅₀ represents the individual lethal dose required to kill 50 percent of a population of test animals (e.g., rats, pigs, monkeys).

Question: How you will develop Cleaning validation program

Ans. Cleaning validation program shall be organized by

• Identification of Equipment Train
• Identification of Worst Case Product
• Calculation of Limit
• Defining Sampling and Cleaning Procedure
• Analytical Method Development and Validation
• Acceptance criteria
• Documentation (Preparation, Execution of Cleaning Validation Protocol and Compilation of Report)
• Establishment of Hold Times period for Clean / Dirty equipment
• Cleaning Verification
• Cleaning Re- Validation
• On Going Monitoring

Question: How you identify the worst case product (Product A) for cleaning validation program

Ans. The Factor that consider for identification of worst case molecule are

• Type./Category of API
• API Solubility in cleaning Agent (i.e. Purified Water)
• PDE value (mg/ kg)
• LD50 (mg/ kg)
• Smallest Recommended Daily Dose (SRDD) (mg).
• Total Quantity of Insoluble, very slightly soluble & slightly soluble Excipient
• Colors/Flavours
• Equipment Train

Question: What are the criteria to calculate the MACO/ARL

Ans. There are four methods to calculate the criteria

• Dose Based Criteria
• Toxicity Based Criteria (LD50)
• HBEL (ADE/PDE)
• 10 ppm Criteria

Minimum Value out of four criteria shall be selected as acceptance criteria

Question: What is the minimum recovery factory recommended for swab and rinse Sample

Ans. NLT 70 % for Swab and NLT 50 % for rinse Sample acceptable

Question: What is the Swab Sampling Area

Ans. It can be 5 X5 cm (25 cm²) to 10 X 10 cm (100 cm²). It based on internal company policy

Question: What are the guideline for the Cleaning Validation

Ans. PDA TR29, EMA-EU, PIC/s- PI-006, APIC, USFDA-2011, WHO TRS 1033 Anx-2, ISPE Guide for cleaning validation

 

 

 

 

 

 

 

 

Question: How you calculate the Maximum Allowable Carry Over (MACO)

Ans.

1.0 Dose Criteria

SF

X

SRDD X

M.B.S

X

SA

=

MACO/ARLSWAB

LRDD

SSA

Where

ARLSWAB

=

Acceptable Residual Limit (mg/swab)

SF

=

0.001 of a dose of product A (Contaminating product) expressed as milligrams of active per single unit dose.

LRDD

=

Largest recommended daily dose (In mg) of product B (Subsequently manufactured product) taken per day.

SRDD

=

Smallest recommended daily dose (in mg) of Product A.

M.B.S

=

Minimum Batch Size (In mg) of product B (Subsequently manufactured product)

SSA

=

Shared surface area (cm2).

SA

=

Surface area swabbed (25 cm2).

2.0 HBEL Criteria (ADE/PDE)

 

MACO =	ADE (mg/day)	X	Min. Batch Size (mg)	X	SA	=	mg/swab
			LRDD (mg/Day)		SSA

3.0 Toxicity Based Criteria (LD50)

MACO=	NOEL	X	M.B.S	X	SA	=	ARLSWAB
	SF	X	LRDD	X	SSA

 

Where:	ARLSWAB	=	Acceptable Residual Limit (mg/swab)
	NOEL	=	No Observed Effect Level	NOEL = LD50 x (BW/E)
	LD50	=	Lethal Dose 50 in g/kg animal for active ingredient in product A.
	E	=	Empirical Constant (2000)
	BW	=	Weight of an average adult (70 Kg)
	SF	=	Safety Factor (1000)
	M.B.S	=	Minimum Batch Size (In mg) of product B (Subsequently manufactured product)
	LRDD	=	Largest recommended daily dose (In mg) of product B (Subsequently manufactured product) taken per day.
	SSA	=	Shared surface area (cm2).
	SA	=	Surface area swabbed (25 cm2).

 

 

4.0 10 Parts per Million Criteria (10ppm)

	R	X		M.B.S	X		SA		=	ARLSWAB
				SSA
Where:			ARLSWAB			=		Acceptable Residual Limit (mg/swab)
			R			=		10 mg of product A per kilogram of product B (10 PPM).
			M.B.S			=		Minimum Batch Size (In Kg) of product B (Subsequently manufactured product)
			SSA			=		Shared surface area ( cm2)
			SA			=		Surface area swabbed (25 cm2).

 

Topic: Process Validation

Question: What is Process Validation

Ans. Process Validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product

Question: What is Quality by Design (QbD)

Ans. A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.

Question: What is Design Space

Ans. The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality

Question: What is Quality Target Product Profile (QTPP)

Ans. A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.

Question: What is Capability of a Process

Ans. Ability of a process to produce a product that will fulfil the requirements of that product. The concept of process capability can also be defined in statistical terms

Question: What is Target Value/ Set Point

Ans. A value of the process parameter during operation, around which the control system regulates the value.

Question: What is Scale up Batch

Ans. The batch having higher batch size.

Question: What is Exhibit Batch / Submission Batch

Ans. A batch that is manufactured with the final recipe intended for commercial batches, under CGMP conditions, to generate physical and chemical data for registration support, evaluate stability etc.

Question: What is Engineering Batch

Ans. Batch(s) of the size that will be manufactured during routine marketing of the product and data of such batch size is not available prior to approval. Such batch (s) may be manufactured to evaluate characterization and optimization of the critical process parameter and conditions

Question: What is Commercial Batch

Ans. The validated batch size to be manufactured for commercial supply

Question: What is Proven Acceptable Range (PAR)

Ans. A characterized range of a process parameter for which operation within this range, while keeping other parameters constant, will result in producing a material meeting relevant quality criteria

Question: What is Normal Operating Range (NOR)

Ans. A defined range, within the Proven Acceptable Range, specified in the manufacturing instructions as the target and range at which a process parameter is controlled, while producing unit operation material or final product meeting release criteria and Critical Quality Attributes.

Question: What is Commercial Manufacturing Process

Ans. The manufacturing process resulting in commercial product (i.e., drug that is marketed, distributed, and sold or intended to be sold). For the purposes of this policy, the term commercial manufacturing process does not include clinical trial or treatment IND material.

Question: What is Concurrent Release

Ans. Releasing for distribution a lot of finished product, manufactured following a qualification protocol, that meets the lot release criteria established in the protocol, but before the entire study protocol has been executed.

Question: What is Continued Process Verification

Ans. Assuring that during routine production the process remains in a state of control.

Question: What is Process Design

Ans. Defining the commercial manufacturing process based on knowledge gained through development and scale-up activities.

Question: What is Process Qualification

Ans. Confirming that the manufacturing process as designed is capable of reproducible commercial manufacturing.

Question: What is Process Validation

Ans. The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products.

Question: What is Quality

Ans. The degree to which a set of inherent properties of a product, system, or process fulfils requirements.

 

 

Question: What is State of Control

Ans. A condition in which the set of controls consistently provides assurance of continued process performance and product quality.

Question: What is Control Strategy

Ans. A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.

Question: What is Critical Material Attributes (CMA)

Ans. A material attribute whose variability has an impact on a critical quality attribute of a product and therefore needs to be monitored or controlled to ensure the process produces the desired quality of product.

Question: What is Critical Process Parameter (CPP)

Ans. A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.

Question: What is Critical Quality Attribute (CQA)

Ans.  A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.

Question: What is Process Performance Qualification (Validation) Protocol

Ans.  A written protocol shall be prepared, reviewed and approved prior to initiation of Process performance qualification, which specifies the manufacturing operations, critical process controls, sampling, testing, acceptance criteria and sampling location of equipment used at various stages of the process.

Question: What is Process Performance Qualification (Validation) Report

Ans. A Process Performance Qualification report shall be prepared after completion of performance qualification which includes the results, summary and conclusion of the Process Performance Qualification (validation) exercise.

Question: What is Scale Dependent Parameter

Ans. These are the parameters which are impacted due to increase in batch size, scale and equipment. For example: blending time, lubrication time, compression force etc.

Question: What is Scale Independent Parameter

Ans. These are the parameters which do not have any impact due to increase / decrease in batch size, scale and equipment. For example: PSD

Question: What is Stratified Sampling

Ans. It is the process of collecting a representative sample by selecting units deliberately from various identified locations within a lot or batch, or from various phases or periods of a process to obtain a sample dosage units that specifically targets locations throughout the compression / filling operation that have a higher risk of producing failing results in the finished product uniformity of content

Question: What is Blend Uniformity

Ans. It is defined as the degree of uniformity in the amount of drug substance in the powder blend.

Question: What is Weight Correct

Ans. It is a mathematical correction to eliminate the effect of potentially variable tablet weight on measurement of mix adequacy. For example, a tablet with strength of 19.4 mg and weight of 98 mg then we have to calculate content of active in that particular table i.e. 19.4 ÷ 98 = 0.198 mg/mg. if theoretical weight of tablet is 100 mg and it contains 20 mg as active ingredient per tablet then weight corrected result would be 0.198 ÷ 0.20 × 100 = 99 % of target blend assay.

Question: What is Uniformity of Dosage Units

Ans.  It is defined as the degree of uniformity in the amount of drug substance among dosage units.

Question: What is Variant Component Analysis (VCA)

Ans.  A way to assess the amount of variation in a dependent variable that is associated with one or more random-effects variables.

Question: Role of Project Manager in Validator

Ans. A Project Manager is a person that is assigned the overall responsibility for initiating (creating), planning, designing, executing, monitoring, controlling (Task Assessment) and closing of a project in process validation

Question: Describe the three stages of Process Validation.

Ans. The Process Validation involves a series of activities taking place over the lifecycle of the product and process. These activities are described in three stages

• Process Design Stage (Stage 1): Involves designing the manufacturing process suitable for routine commercial manufacture, based on knowledge gained through development & scale up activities, so as to deliver product that meets the Pre-defined critical quality attributes.
• Process Qualification Stage (Stage 2): Involves completion of prerequisite qualification checks for facility, equipment, utilities and personnel, followed by performance qualification of the process to confirm whether it is capable of reproducibly yielding quality product at commercial scale.
• Continued Process Verification Stage (Stage 3): This is documented evidence for assurance which shows that the product is within specified limit of predetermined quality aspects and the process is within control during commercial manufacturing to continuously produce quality product.

It involves generating on-going assurance that the process remains in a state of control during routine commercial manufacture.

 

 

 

 

 

Topic: Computer System Validation (CSV)

Question:  What are the Software Categories as per GAMPS 5 Guide

Ans. The categories are

Cat 1 : Standard Layered Software like operating system

Cat 3 : Firmware software-non customizable (QC Instruments)

Cat 4: Software: customizable (SCADA/BMS SAP/ Trackwise)

Cat 5: In-house developed customizable:- For specific Company/ Excel sheets used for Calculation using VBA

Question:  What are the Hardware Categories as per GAMPS 5 Guide

Ans. The categories are

Cat 1 : Standard Hardware components Preassembled

Cat 2 : Customized Hardware components assembled at site

Question:  What is audit trail?

Ans. An audit trail is a process that captures Meta data details such as additions, deletions, or alterations of information in electronic record without obscuring or over-writing the original record. An audit trail facilitates the reconstruction of the history of such events relating to the record regardless of its media, including the “who, what, when and why” of the action.

• System Audit Trails:  System audit trails provide a trail of user access management related to creation, modification and deactivation/deletion along with changes in user privileges. System audit trails may also provide the details of system configuration. It also provides login- logout details of available users, logs related to back up activities, deletion of data and data import/export activities.
• Data Audit Trails: Data audit trails provide a trail of data generation, modification, deletion and record of system electronic data (including meta data) accessed and modified either by individuals or system (in built logic) during system operation. Data audit trail also include evidences of electronic signature if applicable in system.

Question:  What is your role in Manufacturing?

Ans. Providing the support to the validation team for the qualification of SCADA software, Handling and resolve all the query break downing of SCADA s system. Perform the Audit Trails Review

Question:  How you handle the Critical alarms arrived during the process.

Ans. The alarm shall be acknowledged and immediate action shall be taken based on criticality of the alarm. In case the noticed alarm is critical, Concerned Operator shall inform. Production shall acknowledge the critical alarm (whether quality impacting or quality non-impacting) and identify the reason of alarm in consultation with Quality Assurance personnel shall evaluate the requirement of impact assessment. In case alarm found to be quality impacting, an investigation shall be performed to identify the root cause of alarm and then decision to raise the event log (deviation) shall be taken based on the impact assessment. This impact assessment section shall mention the impact on product quality. The event shall be logged and investigation shall be performed as per guideline for event reporting and investigation.

Question:  What is the Procedure for User management (Activation/Deactivation/New user etc.)

Ans. On Receiving the Approved request with justification for the Activation or deactivation of user account, login through the administration role and Activation or deactivation of user account.

Question:  What are the minimum parameters verify in Batch audit Trails of manufacturing equipments

Ans. The parameters are

• Product Name or  Recipe Name
• Batch Number
• Batch start Date and Time
• User ID, User login and log out time.
• Process interruption (If any)
• CPP Parameter with in specified limit
• Any Alarm Critical/Non Critical
• Data audit trail (Satisfactory/not Satisfactory)
• Batch end date and time

Question:  What are the minimum parameters verify in System audit Trails of manufacturing equipments

Ans. The parameters are

• Audit Trail of User Access Management
• Privileges Right Matrix of All Users:
• Data Deletion from the Software:
• Date / Time Security:
• Drive Security (Access of C and D Drive is restricted to operators/User)
• Backups
• Verification of data base or flat file randomly review to discover of omitted/orphan data like data generated with file name like ABC, XYZ etc, aborted data  or duplicate data generated for same batch number etc. If it is available or not justified than handle through QMS document.
• Verification of superseded or obsolete recipe is not access to operator/supervisor or No obsolete /generic recipe available in the software.
• Audit trail function is enabled (Yes / No)

 

In the spirit of transparency and our unwavering dedication to maintaining the highest standards of quality, we feel it is essential to share insights into recent observations made during a recent facility inspection. This observation underscores our commitment to addressing compliance issues head-on, fostering a culture of continuous improvement.

The observation centres around the necessity to establish and follow robust written procedures designed to prevent microbiological contamination of drug products purporting to be sterile. Specifically, concerns were raised regarding the validation of aseptic and sterilization processes, as outlined in 21 CFR 211.113 (b).

One of the critical areas identified was the absence of smoke studies conducted under dynamic conditions in classified areas. Our procedures lacked a crucial requirement for these studies, prompting questions about the adequacy of unidirectional air during dynamic activities, such as loading bung into machine hopper in Restricted Access Barrier Systems of filling and bunging machine (RABS). The mobile Laminar Air Flow (LAF) was notably absent from assessments during these dynamic conditions, where operators transfer bung from the mobile LAF into the filling machine hopper (RABS).

Acknowledging the need for immediate action, we have revised our procedures to explicitly include instructions for conducting smoke studies under dynamic conditions. Taking a proactive stance, we have conducted comprehensive smoke studies for the bung loading process, covering both the mobile LAF and " filling machine LAF."

Stay tuned for updates as we diligently work to enhance our procedures and reinforce our commitment to excellence.

Refer Air Flow Pattren/Smoke Study Protocol in Utility Qualifications Protocol Section Designed to address the such non compliance. 

The company shell prepared a Periodic safety update report (PSUR) for each device and where relevant for each category or group of devices summarize. The result and conclusion of the analysis of the post marketing surveillance data gathered as a result of post marketing surveillance plan together with rational and description of any preventive and corrective action taken.

The PSUR shall be maintained throughout the lifetime of the devices

PSUR requirements apply only class IIA class IIB and class III devices that are CE marked

The PSUR shell set out the conclusion of the benefit risk determination and the main finding of the Post Market Clinical Followup and the volume of sale of the device and estimate evaluation of the size and other characteristics of the populations using the device and where practicable, the usage frequency of the device.

Criteria for the company as a manufacturer of the Medical devices Case given below as applicable type

Case-I: - Manufacture of the class IIB and class III devices shell update the PSUR at least annually. That PSUR shall expect in the case of custom-made devices be a part of technical documentation as specified in an Annexure-II and Annexure-III of the regulation EU 2017/745

Case-II: - Manufacture of class IIA devices shall update the PSUR when necessary and at least every 2 years. That PSUR shell expect in the case of custom-made devices be part of technical documentation specified in an Annexure II and Annexure III of regulation EU 2017/745

Case-III: - For custom made devices the PSUR shell be a part of documentation referred to in the section 2 of the Annexure XIII of regulation EU 2017/745

Case-IV:- For class III devices or implantable devices manufactured shelf submit PSUR by mean of the electronics system refer to the article 92 to the notified body involving in the confirmatory assessment in accordance with the article 52 The notified body shall review the report and its evaluation to that electronics system with the detail of any action taken such as PSUR and the evaluation by the notified body Shall be made available to the competent authority through that electronic system

For devices other than those referred to the paragraph 2, Manufactured sha;; make a PSUR available to the notified body involving in the confirmatory assessment and upon the request to competent authorities

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