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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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