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PHARMA CONCEPTS

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CLEANING HOLD TIME STUDIES



APIC Cleaning Validation guideline states, “For both dedicated and multi-product facilities, the frequency with which the cleaning procedure should be performed should be validated to assess the risks related to potential degradation and microbiological contamination’’.

Eudralex Annex 15 states, “The influence of the storage time before cleaning and the time between cleaning and use taken into account to define (dirty and clean) hold times should be assessed during cleaning validation.

The World Health Organization (WHO) states, “The period and conditions for storage of unclean equipment before cleaning, and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures”.

Health Canada states, “Time-frames for the storage of unclean equipment, prior to commencement of cleaning, as well as time frames and conditions for the storage of cleaned equipment should be established”

PICS states, “The period and when appropriate, conditions of storage of equipment before cleaning and the time between cleaning and equipment reuse, should form” part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation”.

The US FDA Guide to Inspections Validation of Cleaning Process states, “Always check for the presence of an often critical element in the documentation of the cleaning processes; identifying and controlling the length of time between the end of processing and each cleaning step. This is especially important for topicals, suspensions, and bulk drug operations. In such operations, the drying of residues will directly affect the efficiency of a cleaning process”.


Dirty Equipment Hold Time (DEHT):

DEHT is defined as the time between end of use of the equipment and the start of equipment cleaning.

The purpose of validating the dirty equipment hold time is to provide evidence that the length of time equipment may sit idle prior to cleaning and the condition under which this storage occurs will not challenge the ability of the cleaning process to remove process or microbial residues.

Keeping residues on equipment surfaces prolonged time may make them harder to remove and thus challenge the ability of the cleaning process to clean the residuals. Also, permitting process residues, media, or solutions to settle in equipment or open to environment may allow to occur microbial proliferation that challenges the capability of the cleaning cycle to successfully remove microbial contamination.

Methodology for Validation:
Held dirty equipment after processing for an extended period of time (for example 24 hrs.) before cleaning and monitor chemical & microbial contaminants at specified periods (for example 0 hrs., 8 hrs., 12 hrs., 16 hrs., and 24 hrs.)

  • It would be ideal to discuss with manufacturing team to identify longest time interval that equipment would be uncleaned after usage.
  • It would be ideal to use worst case approach to select equipment / equipment train for the study.
  • Rinse & swab sampling techniques to be used for monitoring of both active and cleaning agent contents along with total microbial count from swab samples.


Clean Equipment Hold Time (DEHT):

CEHT is defined as the time between completion of the cleaning of the equipment and the equipment re-use.

The purpose of validating the clean equipment hold time is that nothing stays clean forever. There are possibilities for re-contamination of cleaned equipment through endogenous sources (growth of microorganism already present in equipment) as well as exogenous sources (such as entry of external contamination in to equipment)

If equipment is stored wet for a sufficient time, there is a reasonable probability microbes will readily grow to an unacceptable level and that make equipment unsuitable for manufacturing usage.

Methodology for Validation:
Held Clean equipment for an extended period of time (for example 7 days) before re-use and monitor chemical & microbial contaminants at specified periods (for example 1st day, 2nd day, 3rd day, 4th day, 5th day, 6th day and 7th day.)
  • It would be ideal to discuss with manufacturing team to identify longest time interval that equipment would be unused after cleaning.
  • It would be ideal to use worst case approach to select equipment / equipment train for the study.
  • Rinse & swab sampling techniques to be used for monitoring of both active and cleaning agent contents along with total microbial count from swab samples.

Refer below for other details.


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THE STORY OF NITROSAMINE IMPURITIES & VALSARTAN RECALLS

The word Nitrosamine impurities are blasted in the pharmaceutical industry from July 2018 after identifying the traces of the toxic nitrosamine genotoxic impurities like N-nitrosodimethylamine (NDMA) & nitrosodiethylamine (NDEA) in the APIs made by china manufacturer Zhejiang Huahai, Zhejiang Tianyu, and Indian manufacturer Hetero lab manufactures generic sartans, the angiotensin inhibitor blockers (ARBs), a generic valsartan distributed by Torrent Pharmaceuticals prescribed to some patients to treat high blood pressure. 



During investigation also noticed that 
  • Nitroso amine impurities are likely to be present in the batches since 2012 when a change of process was made.
  • NDMA was unexpected therefore not controlled
  • Significant levels found.
  • NDMA is a possible carcinogen for Humans.

Even though initially NDMA identified, number of following Nitroso impurities identified as part of further investigation. 



NDMA- Nitrosodimethylamine 

NDEA- Nitrosodiethylamine 

NDBA- Nitrosodibutylamine 

NMBA- Nitrosobutyl amino butyric acid 

NDIPA- Nitrosodiisopropylamine 

NIPEA- Nitrosoisopropyl ethylamine 





Origin of NDMA/NDEA: 

Regulatory firms identified that Indian Hyderabad based solvent recovery firm Lantech Pharmaceutical processing methods are left open the chances of cross-contamination of solvents that contained the impurities known as NDMA & NDEA and there is a potential to contain nitrosamine impurities through mix-up & cross-contamination for all products manufactured in their facility. 


The chemical structure of Angiotensin II receptor blockers (ARBs) contains a tetrazole group. It is apparent that tetrazole ring formations, coupled with certain manufacturing conditions in presence of DMF, produce these types of impurities in drug substance intermediates used in sartans. Other tetrazole ring formations produce APIs like Olmesartan, candesartan, irbesartan, and losartan. The impurity may also roll over to other compounds normally known as “zoles,” such as omeprazole, etc. 


Impacted Products: 
Valsartan, Losartan, Irbesartan, almost all sartans expect Telmisaratn and ranitidine …etc 

Currently identified all root causes for the presence of Nitrosamines: 

Currently identified sources of nitrosamine impurities are listed below: 

  • Use of nitrosating agents like sodium nitrite (NaNO2) in the presence of secondary (2°), tertiary (3°)  amines, or quaternary (4°)  ammonium salts within the same or different process steps (if carryover can occur).
  • Use of nitrosating agents like sodium nitrite (NaNO2), along with catalysts, solvents, and reagents, that are likely to degradation to secondary (2°) or tertiary (3°)  amines, within the same or different process steps (if carryover can occur).
  • Use of contaminated raw materials in the API manufacturing process (e.g. solvents, reagents, and catalysts).
  • Use of recovered materials (e.g. solvents, reagents, and catalysts), including recovery outsourced to third parties who are not aware of the content of the materials they are processing and routine recovery processes carried out in non-dedicated equipment.
  • Use of contaminated starting materials and intermediates supplied by vendors that use processes or raw materials that may allow nitrosamine formation.
  • Cross-contamination due to different processes run on the same line and due to operator-related errors such as inadequate phase separations.
  • Degradation of starting materials, intermediates, and drug substances, including those induced by inborn reactivity in combination with carry-over of nitrosating agents like NaNo2 could potentially occur also during finished product formulation or storage.

  • MAH observed the use of certain packaging materials (containing nitrocellulose printing primer) with lidding foil that may react with amines present in printing ink to produce nitrosamines which would then transfer to the product under certain packaging process conditions. (e.g. during vaporization & condensation of  heat-sealing blistering processes may produce nitrosamines then transfer onto the drug product)    . 

How to perform risk evaluation for Nitrosamine Impurities: 

  • MAHs along with API and finished product manufacturers are required to perform risk assessment using ICH Q9  & ICH M7 guideline in relation to toxicology assessment, control strategy and changes to the manufacturing processes for active (API) substances should be applied.
  • Nitrosamine impurity formation risk should be assessed from the development phase of the API/ Finished product manufacturing process.
  • The risk of nitrosamine formation should be assessed w.r.t  API process,  reagents, solvents, catalysts, starting materials, intermediates, impurities, and degradants. 
  • The potential risk of nitrosamine contamination (e.g. from recovered materials such as catalysts, reagents, solvents, equipment, degradation, starting materials, or intermediates) should be assessed.
  • Is there any potential of nitrosamine formation during the manufacture of the finished product and/or during storage throughout its shelf life should be assessed.
  • A representative number of samples of the relevant starting material, intermediate, API, or finished product should be tested with an appropriately validated analytical method for the evaluation of nitrosamine impurities. The number of batches/samples tested should be scientifically justified.


Limits for nitrosamine Impurities: 



For reference, consuming up to 0.096 micrograms or 0.32 parts per million (ppm) of NDMA per day is considered reasonably safe for human ingestion based on lifetime exposure. (which means, if a person consumes 0.32ppm / 0.096mg of NDMA for the entire life of 70 years) 




The regulatory requirement from the industry: 

  • All authorized human medicinal products containing chemically synthesized APIs are to be studied, including over-the-counter (OTC) and generics products. However, in view of a large number of authorized products, MAHs should use a risk-based approach and prioritize their evaluations and confirmatory testing.
  • MAHs should prioritize products in order to establish the sequence in which their products are to be evaluated. For the purposes, MAHs may consider factors such as the maximum daily dose is taken, duration of treatment, therapeutic indication, and the number of patients treated. For example, medicinal products with a higher daily dose, and those for chronic use may take priority.
  • In order to undertake the analysis of the identified medicinal products at risk, MAHs can also use tools such as Failure Mode Effects Analysis (FMEA) and Failure Mode, Effects, and Criticality Analysis (FMECA) as stated in the ICH Q9 quality guideline on quality risk management.
  • If MAHs identify that changes are necessary in their production process and/or product formulation, they should communicate with competent authorities in order to assess the type of variation required and to submit one as needed in a timely manner.
  • This risk evaluation must be concluded within six months after the regulatory statement was published.
  • The risk evaluation’s documentation must not be submitted, though it is to be made available upon request.
  • If a risk of potential contamination has been detected, the marketing authorization holder should go for conformity testing via validated and appropriately sensitive analytical methods.
  • If nitrosamine is found, the competent authorities are to be informed immediately, irrespective of the amount detected.
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ANALYTICAL METHOD AND ITS SUITABILITY


Analytical method or procedure: 

The analytical procedure refers to the procedure or steps necessary to perform each analytical test. 

This may include but is not limited to: the method & instrument parameters, the sample/ reference standard & the reagents preparations, use of the apparatus, dilutions required, generation of the calibration curve, use of the formulae for the calculation, etc. 


In-house developed Analytical Method: 

The analytical method that was not listed in any of the pharmacopeias like USP, EP, IP, and JP and developed as per the internal requirements. 

All the in-house developed analytical methods should be validated and transferred to the laboratories where commercial batch analysis shall be performed. 


Compendial or Pharmacopoeial Analytical Method: 
The analytical method that was listed in any of the pharmacopeias like USP, EP, IP, and JP…etc. 

All the compendial or pharmacopoeial methods considered to be validated and only verification to be performed to demonstrate that the procedure is suitable for the intended purpose. 

If a method is listed in pharmacopeias like USP, EP, IP, and JP…etc, but you want to use the same method with modification or completely different methods then you should show method equivalency between your method & the method listed in monographs. 


Analytical method Validation: 
Analytical method validation is the process of demonstrating that the analytical procedure is suitable for its intended purpose. 

The following characteristics shall be considered for the demonstration of method suitability for its intended purpose. 

Method Validation Parameter
Purpose
Procedure

Specificity

Interference Study. To verify whether the interested peak is spectrally pure or not?

i.e. peak response is due to a single component only and no co-elutions exist.

Specificity of the method shall be demonstrated by analyzing the sample spiked with all known impurities at specification level and showing that no interference of impurities at the retention time of main peaks.

Precision

To verify the degree of repeatability of the analytical method under normal conditions. Usually expressed as a standard deviation. Minimum of six determinations at 100% of the test or target concentration

Repeatability

Repeatability is the results of the method operating over a short time interval under the same conditions

Reproducibility

Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology).

Intermediate Precision

Intermediate precision is the result from within lab variations due to random events such as different days, analysts, equipment, etc. If reproducibility is performed then intermediate precision not required.

Accuracy

To verify the exactness of the analytical method or closeness of the accepted reference value and actual value found from the experiment.

Collecting data from a minimum of nine determinations over a minimum of three concentration levels covering the specified range (for example, three concentrations, and three replicates each).
 The data should be reported as the percent recovery of the known, added amount, or as the difference between the mean and true value with confidence intervals.

Limit of Detection

The lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value.

S/N ratio is determined by comparing  signals from the analyte of known low concentrations samples with blank samples and determining the minimum concentration at which the analyte can be consistently detected. 

S/N ratio between 3:1 or 2:1 is considered as acceptable for estimating the detection limit. The detection limit (DL) can be expressed as DL = 3.3 σ/S where
σ is the standard deviation of the peak response
S is the slope of the calibration curve formed concentration vs response

Limit of Quantitation

The lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. And is used particularly for the determination of impurities and/or degradation products

Determination of the S/N ratio is done by comparing measured signals from known low concentrations samples of an analyte with those of blank samples and by establishing the minimum concentration at which the analyte can be consistently quantified. 

A typical S/N ratio is 10:1 The quantitation limit (QL) may be expressed as: QL = 10 σ/S where
σ is the standard deviation of the peak response
S is the slope of the calibration curve formed concentration vs response

Linearity

Ability to get test results within the given range  that are proportional to the concentration (amount) of the analyte in the sample

Guidelines specify a minimum of five concentration levels, along with certain minimum specified ranges. 

For the assay, the minimum specified range is from 80-120% of the target concentration. 

For an impurity test, the minimum range is from the reporting level of each impurity, to 120% of the specification. (For toxic or more potent impurities, the range should be commensurate with the controlled level.)
 For content uniformity testing, the minimum range is from 70-130% of the test or target concentration, and for dissolution testing, +/- 20% over the specified range of the test.

Range

lower and upper concentration (amounts) interval of analyte in the sample (including lower & upper concentrations) for which it has been proven that the analytical the procedure has a suitable level of precision, accuracy, and linearity.

Robustness

The measure of analytical method capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage.

The robustness of an analytical  method is assessed by deliberately varying method parameters such as temperature, ionic strength, pH & % organic etc., and evaluating the effect (if any) on the results of the analytical method.

Ruggedness

The degree of reproducibility of the results obtained under a variety of conditions, expressed as %RSD.

These conditions include different laboratories, analysts, instruments, reagents, days, etc.
  

Solution Stability

To establish the stability of the sample and standard solutions

Sample & Standard solutions to be analyzed at periodic times.

System Suitability

To verify the system suitability parameters

All system suitability parameter to be verified as per respective testing procedure.

Analytical method Transfer: 

Analytical method transfer is a documented process that qualifies a laboratory to use an analytical test procedure that originated in another laboratory thus ensuring that the laboratory has the procedural knowledge and ability to perform the test. 

If the receiving laboratory participated in the collaborative study (Reproducibility as part of the precision study) during the validation of the analytical method, then the same shall be reported as Co-Validation and the laboratory can be considered as qualified for use of analytical test method. 

If the receiving laboratory has not participated in the Validation study then method transfer activity shall be performed as follows to qualify a lab to use the test method. 

In-direct method Transfer (Inter Lab): 
Analysis of the same samples (Single batch), six times at both the transferring unit & receiving unit by using the same analytical method. However, the transferring unit can consider data from the method validation study. 

Direct method Transfer (Inter Lab): 
Analysis of the same samples (Single batch), six times by both the analyst of the transferring unit & receiving unit by using the same analytical method at the receiving laboratory. 

Analytical method Verification: 

Users should have the appropriate experience, knowledge, and training to understand and be able to perform the compendial procedures as written. 

Verification should be conducted for all compendial procedures in a way such that the verification results will provide assurance that the procedure will perform consistently as intended. 

Verification requirements should be based on an assessment of the complexity of both the procedure and the material to which the procedure is applied. 

Although complete revalidation of a compendial method is not required to verify the suitability of the method under actual conditions of use, some of the analytical performance characteristics listed at the analytical method validation section may be used for the verification process. 

Only those characteristics that are considered to be appropriate for the verification of the particular method need to be evaluated. The degree and extent of the verification process may depend on the level of training and experience of the user, on the type of procedure and its associated equipment or instrumentation, on the specific procedural steps, and on which article(s) are being tested. 

Routinely performed basic compendial test procedures do not require verification unless there is an indication that the procedure is not appropriate for the article under test. Examples include, but are not limited to, residue on ignition, loss on drying, several wet analysis procedures such as simple instrumental methods such as pH measurements & acid value. However, for the application of already established routine procedures to compendial articles tested for the first time, it is recommended that consideration be given to any new or different sample handling or solution preparation requirements. 

Analytical method Equivalency: 
Equivalency demonstrates the sameness of two analytical methods. 

Method equivalency comes in to picture whenever you want to use different methods against to monograph method and/or already filed methods during product registrations. 

The goal of method equivalency is to demonstrate acceptable method performance by comparison of a specific set of results (e.g., an assay). I.e. the method proposed is equally capable as a monograph / already filed method to analyze the interesting samples.

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OTHERS

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JUMBO JOBS - A JOB SCAMMER - BE CAREFUL

As you all know, every day a new job scam come in to picture and lots of people caught up with these job scams and loss so much money due to unawareness whether the offerings was of a scam or really good opportunity

As an example, in January 2019 a big job scam of www.wisdomjobs.com was blasted out that has cheated more than one lakh people (Approximately 70 cores) and the wisdom management was got arrested.

Now, similarly Jumbo jobs is doing the same again and cheated and trying to cheat so many people just by offering fake jobs and collecting money from the victims.

Refer following as few examples.

I personally had experience with this Jumbo jobs. One day ‘Geetha’ from Jumbo jobs called me and told that they looking for good candidates for position that exactly matches my current job profile. 

Later i verified in the web and found it is scam and same was discussed during call from jumbo jobs and immediately they said its ok... its ok and disconnected the call.

Refer below communication . Please be careful

Dear Mr. Kiranreddy Munnangi,
Greetings from Jumbo-Jobs,
Jumbo-Jobs based in India is a global leader in successfully connecting job opportunities and people. Jumbo-Jobs main Purpose is to improve the efficiency of recruitment. The recruitment process has four stages such as sourcing, engaging, selecting, and hiring. We’ll look at the market for recruitment tools from the point of view of recruitment stages We use the world's most advanced technology to help people in finding better job opportunities via digital, social and mobile solutions including Info@jumbo-jobs.com

Our primary business focuses Recruitment & Job Enhancement in 7 countries (Gulf, India, Canada, Australia, USA, Singapore, Malaysia).

Jumbo jobs is the India’s latest online search engine with new technologies which provides relevant profiles to employers and relevant jobs to job seekers across industry verticals, experience levels and geographies. Our international reach helps in dealing global employment services at domestic as well as at international level. We serve our clients keeping all their requirements and parameters into consideration and help them in getting relevant yet best responses in required time.

There is a position available for (Sr.Manager - QA/ Senior Level Position) in one of the leading (Pharma / Biotech / Clinical Research) industry based in (United Arab Emirates, Qatar) which suits your qualifications and experience as demonstrated by your resume on one of the job boards.

We have short-listed your resume to the above mentioned requirement directly with our client. If your are open for a change, we will forward your resume to prospective clients in above mentioned location.

Below are the details of Salary & Benefits:

Date Posted
15th  Oct 2019
Position Type
Permanent
Designation
Sr.Manager - QA
Nationality  
Any English Speaking
Industry
Pharma / Biotech / Clinical Research
Years of Experience
(13) Years+
Functional Area
Quality / Testing / QA / QC / Inspector
Availability To Join
90 days or less 
Number of Vacancies
2
Salary Range
USD  (5500 to 6500) Basic Negotiable + Benefits.
Work Location
United Arab Emirates, Qatar


Additional Benefits
Housing Allowaces
Subsidized Healthcare Package For You And Your Family
Medical & Life Insurance (As per Country’s Law)
Transport Benefits
Education Allowance For Children
Excellent Bonus Schemes
Paid Annual Leave (30 - 45 Days)
Round Trip – Annual Leave Family Air Tickets Per Year To Your Point Of Hire

Organization Type

MNC































T& C:-

1. The total cost of the services and the entire recruitment process including the registration charges is USD 600 out of which you have to pay 50% upfront which is USD 300 for the registration process, and remaining USD 300 you have to pay from your 1st month of salary after joining the client.
2. If Jumbo-Jobs fails in providing the relevant job opportunities in 90 days, the whole amount which you have paid for the services will be refunded.
3. The Client details will be disclosed only after registration process.


Awaiting for your immediate Response.


Thanks & Regards,
Geetha HR Manager
Contact number :+917093712674

Jumbo-Jobs - Agreement Form

SERVICE TERMS &CONDITIONS
Agreement (“Agreement”) is made by and between Jumbo-Jobs (“Recruitment Consultant”) and Mr. Kiranreddy Munnangi with its affiliates and subsidiaries.
First Party: Jumbo-Jobs
And
Second Party: Mr. Kiranreddy Munnangi
IT IS HEREBY AGREED AS FOLLOWS:

This Agreement shall commence on 16thOct 2019 (the “Start Date”) and Jumbo-Jobs shall provide the services detailed below for a period of 90 days from the Start Date i.e. 16-10-2019 till 15-01-2019.

Jumbo-Jobs will provide the candidate with the name of the client they have already approached and will also provide details of any other clients who are interested in the resume for the duration of 90 Days.

Terms and Conditions
Jumbo-Jobs select and apply on behalf of candidates for either permanent/temporary employment on the following terms and conditions:
It is client who acknowledges and agrees that they are solely responsible for the recruitment decision they make. It is important that the client is entirely satisfied with a candidate before engagement.
Jumbo-Jobs will spot current job openings from various sources and we share job opportunities with the candidate with his/her accord. The details of the job roles and responsibilities along with a brief depiction about the prospective companies will be shared.

CONFIDENTIALITY
Any information supplied to a client by Jumbo-Jobs regarding a candidate is done so on a strictly confidential basis to enable the client to assess a candidate’s suitability for the position and except where authorized or required by law shall not be disclosed to any third party without the express written consent of the candidate.
Jumbo-Jobs endeavors to obtain accurate details on all candidates including their qualifications and experience. Jumbo-Jobs is however reliant on the integrity of information supplied to it by potential candidates placed by Jumbo-Jobs.• The total cost of the services and the entire recruitment process including the registration charges is USD 600 out of which you pay only USD 300 upfront, remaining USD 300 will be charged after you complete your probation period in the company.
The client shall be solely responsible for any failure in the interview. No liability is accepted by Jumbo-Jobs for any errors, expenses, loss and damage.

Jumbo-Jobs will ensures further and will arrange an alternate opportunity without any additional charges.• If Jumbo-Jobs fail in providing job Opportunities within 90 days, total amount which the Job Seeker has paid in advance for the services will be refunded.
We see our company as a bridge between jobseekers and employers adding value, productivity and a happy environment and career for all involved. We also help promote your profile to a wide range of people who know the value of your profile.

Jumbo-Jobs Date: 16th Oct 2019

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