Month: January 2020

Processing Controls to be followed During Manufacturing of Drug Products

Procedure to be followed (But Not Limited to ):

  1. Access to the Manufacturing Area is restricted to Authorized personnel only
  2. All personnel entering the Drug Product Facility shall follow the gowning Procedure mentioned in the SOP   Procedure for Entry and Exit from Change  room to Process and Packaging Area.
  3. Before entering the process area, the personnel shall understand the responsibilities of their positions and individuals entering inside the manufacturing area are responsible for themselves and others to follow the Current Good manufacturing practices rules and regulation.
  4. Personnel Who have an apparent illness or open lesion that may adversely affect the quality of a material or product must be prevented from direct contact and shall not be allowed to enter the process area, until the condition is recovered.
  5. Persons who are sick shall not be allowed to enter in the process area. They shall be examined by the registered medical practitioner and must be certified fit and only then they shall be allowed inside the process area.
  6. Visitors shall be allowed only after authorization from the area in-charge and they shall always be accompanied inside the manufacturing area by company employee.
  7. Where raw materials, active pharmaceutical ingredients (API) and intermediate, finished products are exposed, personnel must remove all unsecured jewellery and other objects that may fall off and must take adequate precautions to secure watches, identity tags or other loose items.
  8. Clean protective garments must be worn when working with or near exposed raw materials, API and in-process materials.
  9. When wearing the garments checks that the garment is clean and no loose threads and or damage is observed.
  10. Personnel working in areas and with processes where intermediate products is exposed must wear gloves and must cover excessive facial hair (beards, moustaches, side-burns, etc.).
  11. All personnel involved in manufacturing operations must wear personal protective equipment appropriate to the need to protect these materials from contamination.
  12. Inside the production area, there must be no eating, chewing, smoking, drinking or keeping of plants, food, drinks, smoking materials and personal medicines in any production areas.
  13. There must be no direct contact  between a person’s ungloved  hand or any other unprotected body part and a material, API, in-process materials or a primary packaging component or equipment product contact surface.
  14. Inside the production area, unnecessary personnel movement in the corridors is restricted.
  15. Before starting the operation, environmental conditions such as Temperature, Relative Humidity and Differential Pressure shall be checked as per the respective product batch record. The operation shall be continued if the environment conditions are within the acceptance limit, else the information shall be given to the Concerned person to take necessary action.
  16. Ensure that all lights of the room are working. In case any tube light is not working, get it rectified. 
  17. Inside one processing room only one batch of the product shall be processed.
  18. Ensure that all the equipment, containers and rooms shall bear the dully filled labels as appropriate.
  19. Ensure the Cleanliness of the area and the equipment before starting the operation. If a new batch is to be started, then get the equipment/ room/line clearance from QA.
  20. Weighing balances shall be verified on prior to use as per the respective SOP and recorded in Balance verification record before starting the weighing operation.
  21. All steps during process shall be strictly followed as per the written instructions in Batch manufacturing record and respective Standard Operating Procedures.
  22. All the in-process checks during the process shall be done as per the specified frequency mentioned in the respective batch record.
  23. All entries of time in Equipment Log book, Batch record and all GMP related documents shall be done on 24 hours time basis. The date shall be entered in DD/MM/YY or DD/MM/YYYY format.
  24. All the Reject bins and Waste bins shall be kept with properly labeled as per the respective SOPs.  Rejects and Waste bins shall be emptied and cleaned on daily basis.
  25. The Area / Equipment which is under maintenance shall have the maintenance label duly signed by the Engineering.
  26. Online entries shall be made in respective documents with permanent Blue ink pen. Correction of wrong entry on the document shall be carried out by striking off with the single line .After cancelation and necessary correction the concerned person shall put the sign and date with justification. The reason such as entry error, calculation error, printing error, transcription error, typographical error etc. can be used as applicable and as suitable.
  27. All materials, containers, equipment shall be labeled for identification and status at all stages.
  28. Intermediate (tablets & capsules) and finished product shall be stored in a double poly lined High-Density Polyethylene containers and shall be labeled both inside and outside the container.
  29. Process area floors, walls and ceilings shall be subjected to a regular cleaning and sanitation as per the respective SOP at specified frequency interval.
  30. Drug Product in all stages such as starting material, Intermediate and Finished Product shall be stored in the respective designated area after completion of activity.
  31. At the end of the shift or at the end of the day, equipment power supply, room lights shall be switched off to save energy.
  32. Before closing the operation for the day, all product containers shall be closed properly and transferred to respective quarantine which is maintained at controlled temperature.
  33. All keys shall be placed in the key board of the production office. The key of the key board shall be with the area in charge.  
  34. All containers of a batch shall be stored on pallets and all shall be stretch wrapped.
  35. No container shall be opened in the quarantine area for any reason. If the container needs to be opened for sampling or any other purpose, it shall be done in non-operational clean room. The line clearance shall be taken from IPQA and shall be recorded in the batch manufacturing record.
  36. Pest control activities shall not be carried out inside the warehouse, manufacturing, packaging, quality control labs and change rooms.
  37. After Cleaning of SS Bin, check the outer surface of SS Bin visually and check internal corners of the SS Bin and other difficult area to see, with the help of ‘Mirror’ and ‘Torch’.
  38. Nylon brush/scrubber and lint free cloth which are used for cleaning of equipment’s and area are for single use. Discards these cleaning aids after cleaning of the equipment/area.   

Pl refer

Pl refer

Handling of Products during Power stoppage in Manufacturing and Packing Process

On the event of Power Failure :

  • Once the production is stopped due to power failure during manufacturing and  Packing Process, switch off the equipment’s immediately after power failure which are having moving parts and directly connected to main supply.
  • Record the stoppage time in the respective record wherever required. If power failure is less than one minute, interruption start and stop time can be same as time is being recorded in hour & minute format.
  • Cover the material with polythene bag which is exposed in the machine and close all the product containers available in the room or cubicle or area.
  • Restrict man movement and opening of doors in manufacturing and Packing area during the period of power failure.
  • If power resumes after 20 minutes then raise deviation with proper Corrective action & preventive action and risk assessment study if required and continue with manufacturing and packing operation. The disposition of the lot or the batch which are affected due to power failure will be decided with the consultation with Quality assurance and ‘Production Head’ and ‘Technical Head’ etc.
  • Power failure study shall be performed to decide the time.

After Resuming of the Power:

Once the power resumes, wait for 10 minutes, for condition to restore consistently, before restarting activities ensure that temperature and RH, Differential air pressure of area is achieved as per batch record and restart the procedure as outlined below. Follow all applicable individual SOP’s for operation and start-up of equipment’s.

Power stoppage can happen, at various stages of operation, Intention of the instruction below is to cover critical step, to assist a uniform, restart procedure, which takes in to the requirements.

During Sifting of Material:

Ensure that all the materials pass from the top hopper and the bottom hopper, if  materials are present in the top and bottom hopper then pass materials after recovery of power supply then Check the vibration of the sifter and then start the process as per batch record instruction. In Multimill check the RPM of the blade and the direction of the blade after recovery of power supply & then start.

During Drying in Fluid Bed Dryer :

Ensure that the sealing gasket pressure before continuing the operation.

Ensure that set inlet and outlet temperature is as specified in BMR.

Rake the materials to break any lumps formation and draw sample for LOD  checking.

Air dry the lot at intervals as mention in the batch record to ensure proper fluidization. Once fluidization is normal, resume drying as per instructions given in the batch record.

Rapid Mixer Granulator :

If the power failure occurred during the dry mixing and if RMG is running in “PLC”mode then select “MANUAL” mode run after power recovery and enter required parameters as per batch record and for remaining time depending upon the power failure time.

In the event, power failure occurred during the binder addition process then weight the remaining quantity of paste and record , then rake the wet mass thoroughly and ensure that no binder is sticking to  chopper and the agitator, then Before starting the wet mixing, ensure that the binder solution is visually checked and is fit for use and then  addition of remaining binder as per batch record instruction.

If the power failure occurs during the wet mixing but after addition of binder  solution then Manually rake the wet mass thoroughly and free the chopper and agitator from any adhered mass and then Knead the wet mass for 30 seconds with the chopper off.

Roll Compactor :

Ensure that any adhered materials are not stick in the auger, and in the hopper of the Roll compactor then Check all the parameters of the Roll compactor like hydraulic pressure of   the roller, roller RPM, auger position, etc… then after ensuring the above, restart compaction process.

During Blending:

Ensure that timer is showing remaining time of blending then switch ‘ON’ the blender to restart the operation for remaining time and If timer is not showing remaining time of blending, then check the start time of blending in HMI and calculate the remaining time of blending depending up on the power failure time. Run the blender only for remaining period e.g. Initial setting of blending  time is 30 minutes: power failure occurred after blending for 25 minutes and run the blender only for remaining 5 minutes.

During Tablet Compression:

After resumption of power, challenge test for metal detector should be performed and recorded in batch record before start the compression activity then Switch “ON” the machine and Ensure that at least two round of the tablets are rejected. Ensure the group weight variation of tablets is as per limits specified in batch record. If group weight variation of tablets is not in the limits as specified in Batch record, then reset the machine and reject the tablets obtained.

During Tablet Coating:

Check for coating defects of tablets, action to be taken in case of defected tablet during coating’ if found raise deviation then Start coater and ensure that actual RPM of pan, inlet and product/exhaust temperature and atomization air pressure are as specified in HMI and start spraying then Stir the coating solution for 5 min before start of spraying if it’s no continuous stirring. 

During Capsule Filling:

Ensure running of plate sorter, metal detector, empty capsule loader and vacuum pressure before continuing the operations after resumptions of power supply then perform Metal Detector challenge Test and capsule sorter challenge test after power resumption. Collect the one round of capsules and reject the same & ensure group weight variation of capsules is as per limits specified in batch record and If group weight variation of capsules is not in the limits then reset the machine and reject the capsules obtained.

During Blister Packing:

In case of blister packing activity, check sealing and forming temperature, compressed air pressure once the power is resumed then run the machine and ensure blisters below sealing plate should be rejected. Check coding quality of blisters. Non filled detection if available shall be challenge and Leak Test shall be performed after power resumption.

Bulk and Bottle Packing :

In case of bulk pack Reject the bottle under induction sealer, metal detector & screw capping heads. Wait until the sealing temperature is achieved before proceeding for sealing perform the challenge test. After sealing of pack, check the sealing quality. Perform metal detector challenge test after resumption of power failure and before start of the operation.

During dry Syrup Filling and Packing:

In case of dry syrup filling activity, all the bottles under the filling stations,Metal Detector, check weigher, screw capping & induction Sealing shall be rejected. After power resumption perform challenge test for metal detector, check weigher, screw capping & induction sealing (as applicable) and check net Fill content of individual bottles, sealing quality of cap and leak test of filled bottles.

Sticker Labelling machine:

In case of labelling, remove the bottles in coding section & conveyor belt Check the continuous 05 bottles/Packs once the power resumed and check visually printing matter of bottles/Packs prior to continuing the operation.

Cartoning Machine:

In case of cartooning, remove the cartons in front of coder, challenge test for code reader system (Pharmacode) and challenge test for Blister, Carton and leaflet shall be done after resumption of power failure and when all tests are Ok then continue the operation.

Checkweigher System:

In case Checkweigher operation, remove the carton on checkweigher, balance & conveyor belt, challenge test for Checkweigher shall be performed after resumption of power  and when all tests are Ok then continue the operation.

Preparation of Site Master File (SMF)

What is SMF :

A Site Master File (SMF) is a document that describes the structure of the organization which includes the site, the manufacturing activities carried out, the facility and premises, number of employee with their Qualification, Production system, Quality Control System and also details of the quality management system which are in place.

Reference : WHO Technical Report Series, No.961, 2011. Annex 14 WHO guidelines for drafting a site master file 7 and EudraLex Volume 4 GMP Guideline

Content of Site Master File :

1. General Information on the Organization
2. Quality Management System
3. Personnel
4. Premises and Equipment
5. Documentation
6. Production System
7. Quality Control System
8. Distribution, Complaints, Product Defects and Recalls
9. Self-inspection system
10. Site Inspection History

1. General Information on the Organization :

Brief Information of Firm which include site location, surrounding environment, and size of the different section in square meters and other relevant information. Name and address of Manufacturing Site and Head Office including 24 hr’s contact Number. Brief information of type of Dosage forms manufactured at the site. (e.g. Solid Oral, Liquid, Parental or any other) and details of pharmaceutical manufacturing activities as licensed by the national authorities. Details of product manufactured at the site and information about any specifically toxic or hazardous substances handled.

2. Quality Management System :

It shall include the responsibility of various quality functions describing the role of Corporate Quality Assurance (CQA) and Site Quality Assurance (QA). Describe the detailed elements of Quality System, Audit Programs, Product Quality Review, Management review and Vendor Approved System. Responsibility and functions of Quality assurance in brief including Batch release System, Quality Risk Management system,Out of specification, Out of Trend, Incident, Change control, Deviation, Market Compliant and VMP,etc. Quality management system also includes audit programmed of supplier & contract laboratories list covering name & Address etc.

3. Personnel :

The details related to number of employees with their qualification, experience and responsibility of key personnel and organization chart showing reporting structure for Manufacturing, Packaging, Quality Control, Quality Assurance, Engineering and other departments at facility.

4. Premises and Equipment :

Elaborate about nature of construction and fixures or fitting, Built-up area with plant layouts and Outline about Air handling units (AHU), Air cooling units (ACU) & Air Ventilation Units at facility with their quantities and description of filter details used with various  tests carried out etc. Details about pre-treatment, water purification, Sanitation of water generation & distribution system and details about compressed Air system, steam etc. Details about list out the manufacturing, packaging & quality control Instruments/ equipment etc.

5. Documentation :

Documentation for all the activities starting from the receipt of material to conversion into finished goods and transfer to Finished Goods Store (FGS).

It includes the information related to documents received from Corporate Quality Assurance (CQA).

It also gives information related to handling of various documents like SOP’s, OOS, Market Complaints, Deviation, Incidents, Self-Inspection and other relevant information of documentation practices. Preparation, revision  and distribution of necessary documents and their controls.

6. Production System :

Brief description of production operations with process flow charts.

General policy for process validation & inter-departmental role for its execution and details of material management and warehousing & about starting material, semi finished, finished product, rejected raw material, rejected packing material & rejected drug products etc.

7. Quality Control System :

Information on different aspects and functions of Quality control department at the site which include information related to Raw material and Finished Product and information related to testing of the material/ product, review of the documents and release system etc.

8. Distribution, Complaints, Product Defects and Recalls :

Brief information related to storage condition of the Finished Product at the site, temperature condition requirement, stacking of goods, labeling for easy identification and other dispatch details. Procedure for handling of market complaint , categorization of complaint & closing of the same and also give the procedure for handling of product recall, Mock recall, investigation of the product, reconciliation of the goods etc .

9. Self-inspection system :

Periodic self-inspection is carried out to assess the compliance with Good Manufacturing Practices (GMP) and Good Laboratory Practices (GLP). The Self-Inspection (Internal Audit) System should be followed at the site which helps for identifying the non-compliance and verifying the compliance within the target completion date.

The observations during the audit are noted down and are addressed by the responsible personnel in a set time frame. The implementation of the Corrective actions and Preventive action are done within a defined time frame which are resulted in Internal audit.

10. Site Inspection History :

Site inspection includes regarding approval of the regulatory agency for the facility or inspection of the site etc. with Name of regulatory audit, date and certificate required to be attached to SMF.

General Information :

  1. Site Master File shall be prepared by Quality Assurance, reviewed by Head Production, Head Quality Control and Head Engineering and Approved by Quality Head.
  2. The annexes or the attachments like FDA Product approval license copy, Site drawings and schematic layouts, schematic diagram of water, Floor Plans, Organogram of employee, Process flow diagram of product, List of Equipments & instruments of Manufacturing and Quality control and site regulatory approval copies shall be attached to SMF.
  3. SMF shall be revised at a interval of 02 years & when ever required.
  4. Site master file is a important documents for the organization and this is first documents which can be presented to the Auditors during audits.

Most common 483s Observation in USFDA

What is Form 483 :

Form FDA 483 Inspectional observations is a form used by the FDA to document and communicate concerns observed during inspections of the site or firm or organization. It is also reffered to as Form 483.


Most of 483 observations in FDA inspections are repeated frequently in different pharmaceutical companies. The same observation is reported many times in a year but companies or the organizations are not focusing on the elimination of these issues. These common issues/ mistakes could be easily eliminated before any inspection.

1. Absence of Written Procedures :

FDA did not find written procedures 197 times in last one year in different pharmaceutical manufacturing facilities. Companies were not following the thumb rule of pharmaceuticals i.e. “Write what you do, do what is written.” About 50% of these were related to stability studies. Documents like Standard operating Procedure, protocols, Standard Test Procedure and especially for stability studies must available for every procedure and product in the company. Most of the companies have written procedures but people don’t follow those procedures and caught in the inspection. To eliminate this issue proper training of the procedures must be provided to all concerned. Employees must be clearly instructed to refer to Standard Operating procedure and Good Documentation practices before starting any operation.


2. Data Integrity Issues :

Data in computer systems was not found secure 125 times during inspection in last one year. Master production and control records and other documents like Standard operating Procedures, Standard Test Procedures and records must be accessible to authorized personnel only. Digital or physical records must be protected and backed must be taken as per schedule.  Data integrity is a common issue in pharmaceuticals now a days . FDA and WHO recently published their data integrity guidelines. This is a frequent issue but very easy to eliminate and don’t require to work hard.


3. Failure to Investigate the Discrepancies :

This issue was observed 107 times in last one year during FDA inspections. Firms were failed to investigate batch failure or any component of the batch which was not within the specified limits. FDA says to conduct a proper investigation for each and every incidence, Out of specification, Out of Trend,event, deviation or failure that happened in the manufacturing facility and in quality control laboratory. Each failed batch or test must be thoroughly investigated to its actual root cause even though the batch is not released for the distribution.

4. Cleaning, Sanitizing and Maintenance :

Cleaning issues in manufacturing are observed 81 times in a period of last one year. Proper cleaning of equipment and utensils used in manufacturing is essential to manufacture a quality product. It is also required to sanitize equipment before its use to remove any microbial contamination. A study must be conducted to find out the hold time period for cleaned equipment during which period equipment can be used without re-cleaning. A study also required to be conducted to find out the dirty equipment hold time study. Cleaning validation study must be conducted to identify the worst case product by considering different aspects like equipment chain, No of batches manufactured per year,Solubility, Cleanability and therapeutic potency etc.

5. Environmental Monitoring :

Environmental monitoring was not found adequate 76 times in different companies in last one year. Many companies don’t take environmental monitoring seriously especially in oral dosages manufacturing facilities. But FDA takes it seriously too and expects environmental monitoring to be followed in oral dosages forms like sterile facility. A proper environmental monitoring program must be prepared and implemented in all classified  areas of the facility. Environmental monitoring shall be performed with schedule interval and trend shall be prepared and should be monitored .

Annual Product Quality Review (APQR/PQR) in Pharmaceuticals

What is APQR/PQR :

Annual product quality review is regular periodic quality reviews of all licensed commercial medicinal products which are conducted with the objective of verifying the consistency of the existing process, parameters, the rightness of current specification for both starting materials and finished products to highlight any trend, Deviation, change control, Market complaints and to identify the product and process improvements.

When APQR Shall be prepared:

Annual Product Quality Review (APQR) of the Drug Product shall be prepared for the Calendar Year (Period: January to December).

APQR shall be prepared for the batches which are manufactured for the Commercial purpose.

APQR  shall be prepared irrespective of number of batches manufactured during the year.

APQR Reference Guidelines :

EU-GMP Part – I, Chapter – I and 21 CFR – Parts 210 and 211 Subpart – J Records and Reports 211.180 (e), ICH Q7 and PIC/S.

Contents of APQR (But Not Limited to) :

  • Product Name, Generic Name, Strength, Market, Label Claim, Storage Condition, Shelf life, Primary and complete Packaging Configuration.
  • Product Batch No., Batch Size (Kg. and Units), Manufacturing Date and Expiry Date etc.
  • Data of Active Pharmaceutical Ingredients (API), Excipients, Primary Packaging Secondary packaging materials used.
  • Review of Equipment and Utility like Compressed air, Gases and HVAC system qualification etc.
  • Quality of water used in the process shall be reviewed and data shall be compiled for pH, conductivity, TOC and Microbial limit test.
  • Review of Batch Manufacturing Records and Batch Packing Records which include include following in process parameters (For Ex. LOD during drying, weight variation, Hardness, Friability, Disintegration test and weight gain in coating as minimum) critical process parameters (CPP) and critical quality attributes (CQA). Manufacturing and packing yield.
  • Review of Release Testing data which include in-process control checks and finished product analytical release testing data along with trend and graph.
  • Review of stability studies of commercial batches and review of stability trend and any Out of specification or Out of trend etc.
  • Review of Specification for Raw Material & Packaging Material and Drug Products.
  • Review of Product and Process related Validation activities.
  • Review of Change Controls & deviations & their status i.e open or close.
  • Status of Corrective and Preventive Action (CAPA) related to Process & drug Products.
  • Review of Out Of Specification (OOS) & Out Of Trend (OOT) Results if any.
  • Review of Product Complaints i.e number of complaints received and open & closed status etc.
  • Product Recall and Filed Alerts.
  • Review of Returned Finished Goods.
  • Review of Elemental impurities.
  • Review of Previous Annual Product Quality Review if any.
  • Conclusion shall contains the observations and the finding which are obtained during review of APQR.

The data of In process parameters obtained from manufacturing and packing, Analytical parameters of ( Blend, Filled capsule, Compressed tablets, coated tablets, Finished products, Raw materials and packing materials) and Stability data shall be calculated for Minimum, Maximum, Average and Cpk values .