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How to face the audit in pharma

Auditing is a part of any industry .but when it comes to the pharmaceutical company it became very wide detail because the drug which we are manufacturing is directly consuming by human  .as we know that now a day lot of Indian pharma company struggling to face the audit .some of the company even shut down by US FDA. You might have herded recently some of the pharma company was forcefully removed there, staff. specially the company which is having a business in the US, EUROPE, OR any other regulatory agencies. and this is happening is not because doing any wrong thing but the expectation of every regulatory agency are going high nowadays due to the advancement of technology in all over the globe. And the people also are very conscious about the health now a day’s .so it is important for regulatory agencies to taking care of people health. And fulfill their requirement.
Basically, we all are very familiar with the terms of financial audit only but in the pharmaceutical industry, there are several types of audit every the company have to face before getting approval from any regulatory agency there is no basic audit that every regulatory can follow blindly and give you approval .every regulatory will conduct their own audit and we will get the final approval on the basis of the outcome of all audit.

HOW TO FACE AUDIT IN PHARMA

TYPE OF AUDIT IN PHARMA-
11)    FACILITY AUDIT =
-     once you  have submitted the new drug molecule for  approval than before giving final approval FDA or another regulatory will inspect the facility from where you go to the manufacturing of the drug. in facility audit auditor will visit them each and every part of the facility and inspect the premises. During the facility audit auditor mostly focus on the facility such as building .equipment instrument and premises
.
22)    GMP AUDI T = 
      During the conducting of GMP audit, the auditor will inspect all over the practices .document .record.facilty of the company .there are the various norm given in guideline about GMP called as good manufacturing practices .but how we will determine the GMP so there are several commandments in GMP it includes your .health .hygiene .equipment.clothing.premises.personnel.cleaning.material handling. Document and all so including all those things we can achieve the GMP. It includes all over your company practice.

33)   POST APPROVAL AUDIT =
      so after GMP audit regulatory will give approval for the manufacturing of drug from a particular facility. Once you start the manufacturing of drug the immediately within few months regulatory will conduct one more audit and that is the post-approval audit.in this audit, the auditor will cover everything again freshly.

HOW TO FACE THE AUDIT =

 As we really do not know what are the questions the auditor is going to ask. But it doesn’t mean there is no point in planning and preparing for the audit.
Generally, any regulatory agency will give prior information before they come to conduct audit .but now last few years we have heard the news of surprise audit. Now a day’s regulatory auditor is doing surprise audit at any time because they find some hiding or scraping of data before audit. but most of the time auditor will give prior notice before coming for audit.so will get time to prepare for audit.
How and what prepare before audit.                                                                                                                                                                                                                               
 It is natural for anyone who face the auditor to get tense. but can we avoid the audit obviously not  so face it with confident actually we have to prepare any time for the audit our GMP and practices should be like that if any time if the auditor can come spuriously than you can face it easily

PREPARATION BEFORE AUDIT =

Once you get notify that next month you are going to face audit then what precaution you have to take.
1 ) facility = on the first day after the completion of introductory meeting auditor will go for facility round generally .so the firstly we have to maintain and get it done any work related to facility most of the time we will avoid some small thing by thinking this is not important but that small thing also can make a very bad impact on your audit. There are some important checkpoint we have to check before audit.
External premises-
-          all the external premises of our facility should be clean and well maintained such as building walls and paint should be proper there should not be any scratches on building all the wall color should be good in condition.
-          all the road inside the premises should be good condition and have proper sins such as speed limit and all.
-          All the safety equipment should be in working a condition such as fire exit, fire alarm, assembly point, fire hydrant line, etc.
-          All the facility should be neat and clean there should not be an accumulation of any dirt and waste material .please keep in mind that auditor can put their hand in such places that you think it's difficult to reach. I personally have experienced this thing. In one of the audit person cleaned racks in the warehouse up to the middle level by thinking that auditor cannot reach up to the top racks. But the things happen exactly apposite auditor has checked one downside rack cleaning and ask to check one top side rack cleaning and he went to the top rack by using a hydraulic trolley and he found dust there.  So be careful that reach every corner of your the facility should be properly cleaned.
-          There should not be any gap or point where dust can get accumulated. all gaps should be closed properly.

2 ) Equipment and instrument =
-          All the equipment and instrument you are using in the company should be good condition.
-          All the equipment and instrument should be properly label and number. And all the equipment which you are using there the number should be included in the equipment master list.
-          All the equipment and instrument should be validated and calibrated .label related to calibration done date and next due the date should be present on the equipment. And all the data related to equipment validation should be in the proper place.
-          All the equipment and instrument-related usage the record should be check properly .there should not be any pending or unwanted entry without proper justification. If any missed or done wrongly it should be handled through proper way or deviation if required. Because if any entry caught by the auditor which you cannot justify than you will be in trouble.
-          All the critical instrument and equipment which is generating electronic data such as HPLC.INTEGRITY MACHINE. AUTOCLAVE.BALANCE CALIBRATION.CIP and SIP SYSTEM . should be matched with the 21CFR guideline  .the data of such equipment should not be deleted and all thing should be available for audit trial.
-          If there are any equipment which is not working should be labeled as under breakdown with proper justification.

3 ) Document and records =

-           Document= document consist of procedure of the company eg- sop. Protocol,
-          In all our document you have to write what you want to do with the checking of adequacy and regulatory compliance.
-          Do exactly as per written in the document.
-          Instantly record the deviation if it goes wrong or not mention in document .doNT try to hide anything.
-          Check all the critical document before audit at list last 5 year.
-          Keep all the important document at one place where you can access easily.
-          Record= record is having proof of have done the activity as per the relevant document.
-          All the record such as logbook BMR etc should be check regular basis to avoid any mistake or any gap in the record.
-          Take the deviation if any discrepancy observed in the record and give proper CAPA to avoid the mistake in the future.

4 ) sops and practice =

-          The main focus of the auditor nowadays is on actual practices.
-          All the person who is working on the process should be trained in their respective sops as well as they should follow the same what is written on sop.
-          All the sops should be prepared on the basis of practical representation .most of the time we will   prepare some sop which is difficult to follow or not possible to work with that sop
-          Find out that sop which is having a theoretical and practical gap and change it with proper justification.
-         Make sure that there is no practice you are doing but not mention in sop.

CHECKPOINT FOR QUALITY CONTROL DEPARTMENT =

The following checkpoint should be taken into consideration by the quality control department before going to face the audit
-          Are all the record related to equipment calibration is available or not.
-          Make sure all the equipment should be within calibration due date.
-          Check all sample of stability and the finished product should be separated with proper storage condition and labeling. And the reconciliation of the sample.
  •           Check the document related to IQ.OQ.& PQ of any new instrument as well as an old instrument.
  •           Check the proper labeling of expire sample.
  •           Check all the instrument record should be maintained properly without miss any entry.
  •          Check that all the document should be indexed properly and it should be in lock and key.
  •           Check the all temperature study product row data should be available.
  •           Check the personnel protective equipment should be available.
  •           Check the disposal procedure and disposal record should be available.
  •           Check the availability of all chemical MSDS report.
  •           Check all the data related to any major incident should be available.
  •           Check all the report of analytical method validation should be available.
CHECKPOINT FOR PRODUCTION DEPARTMENT=

Following checkpoint should be taken into consideration by the production department before going to face the audit.
  •           Check and make sure all the point related to the last audit has complied.
  •           Check the point related to internal audit has complied.
  •           Check all the CAPA related to every deviation has implemented.
  •           Check the cleanliness of all the area and maintain it on a daily basis.
  •           Check all the area related logbooks and their entry with respect to procedure.
  •           Check all the current version of the SOP and make sure it should be available in the place.
  •           Give proper on the job training to every person related to there are and procedure.
  •           Give some practical demonstration of critical sop and make sure everyone should train on it.
  •           Check all the equipment and instrument should be clean and well-labeled such as calibration. validation.etc.
  •           Check all the door opening and interlock working is working properly.
  •           Check all the records and training file of every individual who is working in process should be completed on the current version of a sop.
  •           Make sure all the person should be aware and trained about cGMP and DATA integrity.
  •           Make sure the qualification and validation of all the equipment should be done and within the limit.
  • -          A person who is working in a critical area such as filling should be qualified on the process and practice.

CHECKPOINT FOR ENGINEERING DEPARTMENT =

The following checkpoint should be taken into consideration by the engineering department before going to face the audit.
  •          Check and make sure all the point related to the last audit has complied.
  •           Check the point related to internal audit is complied
  •           Check all the CAPA related to every deviation has implemented.
  •           Check the cleanliness of all the area and maintain it on a daily basis.
  •           Check the preventive maintenance activity and the plan has executed periodically.
  •           Check all the record related equipment such as IQ.OQ.PQ. Should be available in the place.
  •           Check all the area related logbooks and there entry with respect to procedure.
  •           Check all the current version of the SOP and make sure it should be available in the place.
  •           Check the document related to deviation and record of any change.
  •           Check all the detail of machine breakdown and the justification  should be available
  •           Give proper on the job training to every person related to there are and procedure.
  •           Give some practical demonstration of critical sop and make sure everyone should train on it.
  •   Check all the equipment and instrument should be clean and well-labeled such as calibration. validation.etc.

CHECKPOINT FOR QUALITY ASSURANCE DEPARTMENT =

HOW TO FACE AUDIT IN PHARMA

Following checkpoint should be taken into consideration by the engineering department before going to face the audit.

  •           Check and make sure all the point related to the last audit has complied.
  •           Check the point related to internal audit has complied.
  •           Ensure the cleaning of the overall facility.
  •           Ensure the health and hygiene practice of every individual.
  •           Check all the CAPA related to every deviation has implemented.
  •           Ensure all the BMR is compiled before releasing of the batch.
  •           Ensure all the yield in every stage is in within limit.
  •           Ensure all the procedure and practices are being followed daily by every department.
  •           Ensure that there is no cGMP violation of any department.
  •           Ensure that there is no DATA integrity in practice.
  •           Ensure all the CAPA and deviation has been implemented within the timeline.
  •           Ensure all the document related to batch and the procedure has been verified each and every stage.
  •           Ensure that there is proper issuance of each and every document.

THE AUDIT DAY AND HOW TO FACE =

HOW TO FACE AUDIT IN PHARMA

  •           It’s natural to get stressed while interacting with auditor .but the employee who going to faces the auditor should have self-confidence.
  •           There are the difference between universal gesture and cultural gesture.so give universal gesture.it helps to create a good impression on the auditor.
  •           After the proper welcome give a brief introduction about plant design. Layout. Procedure and line product description in the welcome meeting.
  •           Ask auditor how they want to plan and what they want to see.
  •           Don’t give plan as per your convenience it seems you’re trying to show something that you want to show.
  •          A person who going to give an answer to the auditor should have proper knowledge about related process.
  •           Communication knowledge and presentation is very important to face the audit.
  •           For effective communication its better to speak consistent tone and pitch.
  •           Effective listening is more difficult than effective speaking.so listen carefully before giving the answer.
  •           If there is more than one person from our company facing the audit at a time. than we should strategize as to who should speak with which topic.
  •           While speaking with the auditor we should never say I don’t know. Instead of that, you should say I will get the proper information about this from the respective person and get back to you.
  •           The auditor is more interested to know about clarity and fool proofness of our system.so don’t try to give a false statement and half knowledge.
  •           The observation and comment pointed out by auditor need to be attended and close effectively and promptly.
  •          Never try to interrupt the auditor when he is speaking.
  •           Nowadays auditor increasingly interacting with down the line employees and line operator. So the line operator and employee also need to be trained in their practice. and aspect of facing the audit.
  •           If we develop a positive attitude and good culture than audit can be a pleasant learning experience rather than the nightmare.


what is lyophilization meaning process and principle 

lyophilization meaning

lyophilization is also known as freeze-drying it is the dehydration process general;y  use to preserve the perishable material to increase the shelf life or to make the material more convenient during transportation .in pharmaceutical industry lyophilization process use to increase the shelf-life of the drug.in the lyophilization process, first material gets frizzed followed reducing the pressure and slowly adding the heat to convert frozen water evaporate. also called sublimation.

 Lyophilization history:-

 modern freeze-drying was developed during world war 2 .during the world war serum being sent to Europe from the US for the medical treatment of the wounded required refrigeration.but because a lot of refrigeration and transport many serum spoiling before reaching to there recipient. the freeze-drying process was developed as a commercial technique that enabled serum to chemically stable and viable without having to refrigerated.within a short period of time freeze-dry process apply for penicillin and bone.and thereafter lyophilization technique as an important for the preservation of biological product and medicine.
triple point 

Lyophilization principle:-

principle of lyophilization is based on thermodynamic which also called as sublimation.in the sublimation stage solid is converting into the vapor phase under high pressure without passing to the liquid phase.
the eutectic point-eutectic system is the mixture components or elements that having a single composition that solidifies lower temperature than any other composition.this composition known as Eutectic mixture. the triple point of water gas-liquid-solid corresponds to the minimal pressure at which liquid water can exist. at a pressure below triple point, solid ice when heated at constant pressure the ice get convert directly to the vapor phase is also called sublimation. and nowadays this technic broadly used in the pharmaceutical industry to remove the water from the product without high heat and to increase the product shelf life.

Lyophilization process stages:-

there are mainly four stages in the process 
1) pretreatment
2) freezing
3) primary drying  
4) secondary drying

pretreatment:- pretreatment is the method of treating the product before freezing.this may include concentrating the product, the formulation of the product. formulation include the addition of components to increase stability or improve processing. the decision of pretreat a product is based on theoretical knowledge of freeze-drying and the requirement or product quality consideration.

freezing:-

sin large scale, especially in the pharmaceutical industry freezing is doing by using a machine called as lyophilizer. in lyophilizer machine having an automatic recipe that will move automatically product and lyophilization requirement.it is important to the material below its triple point at which the solid and liquid phases of the material can coexist. larger cristal is easier for sublimation to produce large crystal the product should be cooled slowly or can be cycled up and down in temperature. this process called annealing.but in case of food or component which is having a living cell we should not form the large cristal because it ca break the cell wall so in this case the freezing is done rapidly below its eutectic point to avoid the formation of cristal.generally the freezing temperature is between -50 c to - 80 c the freezing phase is the most critical phase in the lyophilization process .becase the whole product quality depends on the evaporation of water from product and whole product can be spoiled if done improperly.

Primary drying:-

During the phase of the primary drying phase, the pressure is slightly lower rage to a few millibars and the required heat provide to the material so the water gets sublimate. the amount of heat can be calculated using the sublimating molecule. called latent heat of sublimation.in this initial drying phase about 95% of water can be removed from the material. this phase is very slow its 90 to 110 hour to sublimate. because if you add to much fast speed then the material structure can change and it can impact the final product nature quality and action.in this phase, the pressure is controlled by a vacuum pump by applying a partial vacuum. the use of vacuum speed up the process of sublimation.in other side of the machine having cold condenser which collects the vaporize form of water on it.the the main role of condenser is to prevents the water vapor from reaching the vacuum pump which could reduce the pump performance .condencer temperature is normally between -50 to -60 c . it is important to note that in this range of pressure the heat is brought by conduction or radiation the convection is negligible due to low air density.

  Secondary drying:-

the aim of secondary drying is to remove the unfrozen water molecule. we have seen that the ice was removed in the primary drying phase. this part is based on material adsorption isotherm.in this phase, the temperature is raised higher than the primary drying phase to break any Physico-chemical interaction that has formed between the water molecule and frozen material. the atmospheric pressure is also lower in this phase to increase the desorption.
once the freeze-drying process is complete the vacuum usually was broken with an inert gas as nitrogen before the material is sealed.at the end of the operation the final residual of water in the product is very low around 1%

Lyoprotectant :- 

some of the molecules which are using to protect the freeze-drying material called as lyoprotecant these molecules are typically from polyhydroxy compounds such as monosaccharides and polysaccharides polyalcohol and there derivative.trehalose and sucrose are natural lyoprotectant.

Advantages of lyophilization:-

once you sealed the freeze-dried or lyophilized substance .the substance may be stored room temperature without refrigeration and be protected from spoilage for many years.
preservation is possible because reducing the water content inhibit the action of microorganism that would normally spoil the substance

lyophilization also cause less damage to the substance than another dehydration method that is using a higher temperature.in addition flavors and nutritional content generally, remain the same for making this process popular for preserving food.

lyophilization product can be rehydrated much easily because the process leaves microscopic pores.this is very important when it comes to pharmaceutical uses.

lyophilization can also be used to increase the shelf life of some pharmaceutical product.such as vaccine and other injectables.by removing the water from the product and sealing the product in vial.theproduct can easily stored shift and later reconstituted to its original form for injection.

another advantage of lyophilization in pharma is to produce tablets the advantage is less excipient ane rapidly absorbed and easily administered dosage form.
the lyophilization( freeze-drying) process came in wide public attention when it uses to create freeze-dried ice cream an example of astronaut food.because of its lightweight per volume.and it can be reconstituted at the time of use.freeze-dried fruits are used in some breakfast or sold as snacks.

in the chemical industry, the product is more often freeze-dried to make them more stable or make them more easy to dissolve in water.

in biotechnology, freeze-drying is used to conserve special strains.

freeze-drying is also used for floral preservation. birthday wedding bouquet it's very popular who want to preserve there wedding day flowers.

disadvantage:-

liophilization ( freeze-drying) process is more expensive than other.the cost maintenance and operating cost is very expensive.
lyophilization is also time-consuming process its require a long time to complete.
but the material which is heat sensitive such as protein enzyme and biologic product shuld must required lyophilization.


Difference between sterile and non-sterile dosage forms



In our day to day life we are we all are taking medicine number of time .generally we know the medicine by its physical appearance only like liquid .cream .tablet.poweder or injection. most of us don’t know what medicine inside their nature and action .there are several dosage form available in medicine. they mainly divided into some categories

Dosage forms available for different administration route

     Administration route                                                                         dosage forms
Oral
Solution .suspension .emulsion.poweder.granile.tablet.capsule.syrup,
Rectal
Supossitories.ointment,
Topical
Cream .ointment. poweder.gel.lotion.paste.
Parenteral
Injection. ( liquid.solution.suspension forms.)implants irrigation.
Respiratory
Aerosol. spray .gases.
Nasal
Solution .suspension.inhalation.
Eye & Ear
Luqied.solusion.cream.

 In the above chart, PARENTERAL EYE & EAR is sterile dosage forms. and remaining all are the NON STERILE dosage forms. So what is the difference this two mainly used dosage forms?
STERILE  – Parenteral dosage forms are intended for administration as injection or infusion. A common type is  intravenous IV-(into a vein), subcutaneous ( under the skin) and intramuscular(into the muscle),
All parenteral dosage the form is directly coming to contact of blood circulation immediately and hence it gives fast action .but we can not give any liquid as a parenteral route . as it requires sterile liquid or drug. 
WHAT IS STERILE- the simple definition is free from a living organism.
now you may have a question that how do you say that there is no living organism in sterile dosage forms. So to assume that there is no living organism in dosage form the terminology we are using is SAL ( sterility assurance level) sal is defined as the probability of viable organism that survived the sterilization process. The probability of viable organism after the sterilization SAL is 106  it means the probability of a viable organism is 1 in 1,000,000. This is called a sterility assurance level.
Primary requirement for sterile formulation-
1-      it requires a highly controlled environment to produce a sterile unit. GRADE A class as per cGMP it means the size of 0.5-micron the particle  should not be more than 3500 per cubic meter. and the size of 5-micron particle should not be more than 1 per cubic meter.
2-       Biosafety cabinet.
3-      Laminar airflow.
4-      Cleanroom with barriers.
5-      Soft walls.
6-      Validated cleaning and sanitization.
7-      Contamination control.
8-      Environmental monitoring and validation.
9-      Aseptic gowning monitoring method.
10-   Personnel monitoring program.
11-   Room air exchange studies.
12-   Smoke study.
13-   Aseptic techniques.
14-   HEPA filter grid pattern and testing.
15-   Filling room validation.
16-   Define autoclave and autoclave load validation.
17-   Operator proficiency and qualification .
18-   Aseptic process simulation (media fill)ly
19-   Sterility testing.
INJECTION- injection should be given by using sterile equipment and it should not be reused it should be single-use. but most of the countries still some people using the injection multiple time with multiple patients so it became dangerous for some disease such as.
   - HEPATITIS B –
                           Highly infectious virus .the number of infection 21 million annually.
  - HEPATITIS C –
                         Highly infectious virus .more than 2 million annually.
   - HIV-            more than 250000 infections annually.
But in some cases, we should give the injection such as  - fever, asthma, diarrhea, urinary tract infection. Pneumonia, old age .and unconscious condition.
- ADVANTAGE-
                           - faster In action.
                           - no nausea vomiting or gastric irritation.
                           - it can be given unconscious or non-cooperative patient.
- DISADVANTAGE-
                               - it required sterilized equipment and is costlier.
                               - chances of cross-infection.
                               - we can not take it to own it required assistance.
                               - and it's painful in some cases
.   
-NON STERILE DOSAGE FORMS-
( Solution .suspension .emulsion.poweder.granile.tablet.capsule.syrup ) these all are the nonsterile dosage forms  which are not directly coming in contact with blood circulation. oral administration is the common route of administration of non-sterile dosage forms.
1-      not much highly control area require
2-      clean room.
3-      Validated cleaning method.
4-      Contamination control
5-      Room air exchange.
6-      Class C & D AREA for manufacturing.
7-      The HEPA filter and testing.
- ADVANTAGE-
                               - Oral route of administration is the common and oldest route of the administration dosage form.
                               - it is safer convenient does not need a special assistant.
                               - no need to sterile hence it cheaper.
                                - often painless
- DISADVANTAGE –
                                 - action is slower hence to suitable in emergency cases.
                                 - may cause nausea and vomiting can not be used for an unconscious patient.
                                 - some drug may not absorb through the oral route.
                                 - some may destroy by digestive juices such as insulin.




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