Procedure :

Intimation / Conformation of Inspection :

• Intimation for the inspection from Regulatory Authority shall be received by Corporate Office and shall be communicated to Unit Head and or Quality Head of the respective site or location.
• The confirmation for the inspection programme with Regulatory Authorities should be done by Corporate Quality Assurance.
• The itinerary and staying of Inspector (s) during inspection should be arranged by Corporate Office or Plant Administration Department of the respective site or location.

Co-ordination :

• The Inspector(s) appointment to conduct the inspection should be accompanied from the Hotel/Airport to the location by a company representative.
• On reaching the unit, the Inspector (s) should be taken to the conference room where they should be introduced to the entire concerned department Heads.
• After the introduction, presentation should be made by the Unit Head/Quality Head which include about organization, Product, Plant layout and approvals etc.
• The Unit Head/Quality Head should present the Site Master File, if required to the Inspector and brief him/her of the activities at the site.

Answering of Questions during Inspection or Audit :

• Any questions raised by the Inspector(s) should be answered either by Unit Head / Quality Head.
• In case further clarification is required the respective department head should be called to answer the query.
• In case the Inspector(s) desire to ask question to any other person the respective Department Head should call a responsible department person to answer the query.
• The respective department person who has done the activity or the doer shall also responsible to answer or explain to the Inspector if asked by him/her.

Provision of Documents and Records :

• The documents asked by the auditor shall be available without delay.
• The subject matter expert or the doer of the respective department shall be responsible to explain the documents to the auditor.
• In case the Inspector(s) desire to check any document / records, that would be provided either by Respective Department Heads / QA-Head / Unit Head.

Tour of the facility :

• The Inspector(s) may split and start audit in more than one departments at the same time with or without audit agenda or intimation.
• The Inspector(s) should be accompanied by the Unit Head /Quality Head during the tour of the facility.
• The respective department head should join them when they arrive at the department.
• The Inspector(s) shall accompanied or guided by the respective department head before entering to the change room.

Response to any non-compliance during Audit :

• In case any point of non – compliance is made by the Inspector(s), the same should be addressed on top priority by the QA-Head / Unit Head for corrective action.
• Non compliance should be addressed immediately or within the time frame of respective statutory authority.
• Non compliance which are addressed immediately shall be shown to the inspectors in the closing meeting.
• Follow up on above should be done till all points are compiled with and firm response should be sent.
• Site is applicable to inspection for any working days within 8:30 to 17:30 (Except Holiday / Weekly Off). If required audit can be planned with prior authorization of Unit Head and or Quality Head.
• Photographs /video shooting within company premises are not allowed (If required prior permission of Unit Head / Quality Head shall be taken.)
• Related Topic https://pharmaceuticalupdates.com/2019/01/29/self-inspection-or-internal-audit-and-its-requirement-in-pharmaceuticals/

Conclusion :

When is someone ready for the inspection the following questions may be useful as follows :

• Have you identified, evaluated and tackled all internal and potential compliance risks.
• Are you aware of the current inspection trends and possible focuses specially related to your product.
• Have you informed and prepared all the colleagues involved and are all the roles clearly assigned.
• Are you sure that all your colleagues are competent enough to answer the inspectors’ questions and provide clear information about the processes and documentation.
• Have you established procedures about how to handle the inspection and answer the inspectors’ questions .

Deviation : Any unwanted event that represents a departure from approved processes or procedures or instruction or specification or established standard or from what is required. Deviations can occur during manufacturing, packing, sampling and testing of drug products.

Examples of Deviations:

Temperature and RH of area goes out of limit during manufacturing, Typographical error observed in approved documents, Standard operating procedure not followed, Breakdown of equipment, Spillage of material during unloading, Instrument calibration results goes out of limit etc.

Critical deviation: A Critical Deviation is an unplanned event that affects a quality attributes a critical process parameter, an equipment or instrument critical for process control and has an immediate patient safety risk, life threatening situations. 

Major deviation: A Major Deviation is an unplanned event that potentially affects a product’s quality, safety or efficacy or its ability to meet specification, or regulatory or documentation requirements which may not have direct impact on patient.

Minor deviation: A Minor deviation is an unplanned event that potentially has GMP impact (e.g. an event affecting a utility, equipment, materials, components environment or documentation) but does not affect product quality and / or the physical state of the product, intermediate or component, or its labeling .

Observer or Initiator : The person identifying the occurrence of deviation shall be termed as observer and the person initiating the documentation of deviation in deviation form shall be termed as Initiator.  

Corrective action : An action taken to eliminate the cause of the existing deviation , incident or problem in order to prevent its recurrence (occurring again).

Preventive action: An action taken to eliminate the cause of potential deviation, incident or problem in order to prevent its occurrence (an incident or event) .

Requirements :

• Each deviation related to a batch production, to materials used during processing, to test procedures, to warehouse/ storage and transport conditions, to re calibration / re-qualification activity or to the rejection of a defective product, etc., must be identified, evaluated, investigated and documented, it may be for commercial batch or regulatory dossier preparation batches (e.g. scale up / tech transfer / pre-exhibit / exhibit / registration etc.).
• The person identifying the deviation shall immediately inform to supervisor and department head and QA after discovery of any deviation.
• Necessary immediate actions must be taken in consultation with QA and department head to avoid the recurrence of observed deviation.
• The deviation form for reporting all types of the deviations shall be initiated and investigated immediately.
• Deviation shall be notified to the concern department and QA for review, evaluation and logging within one working day after occurrence.
• Each deviation must initiate appropriate corrective and preventive actions as necessary.
• All deviations shall be closed within 30 calendar days. If not closed, then fill the deviation extension form justifying the delay. Each extension (maximum two) shall be allowed for next 30 days only.
• Trending of the deviations shall be done on Quarterly basis.
• All products related deviations (critical, major, and minor) having impact on product quality, safety, and efficacy, validated status of process & equipment shall be circulated to the customer/Qualified Person/Marketing Authorization Holder for notification and approval.
• deviations shall be sent to CQA for approval if required

Procedure :

• A person identifying the deviation (observer) shall inform to initiator for documenting the deviation details in the deviation form with the description of the deviation, Batch no. / A. R. No., name of the product / Material. date, time and other details related to deviation as per deviation form
• Observer/Initiator shall take immediate actions in consultation with QA and head of responsible department to contain the deviation.
• Initiator shall address all immediate actions taken in deviation form and shall analyze the risk and evaluate impact of deviation in consultation with HOD of responsible department and subsequently mention it in the deviation form . After completion of details initiator shall submit deviation form to QA for review, evaluation and login.
• The products intended for the regulatory dossier preparation / submission purpose; the overall risk as a concept must be considered differently for the following reasons like Products considered at the development stage, Product knowledge is under development phase and the products are not intended for commercial purpose at this stage till approved by the respective regulatory authorities.
• Wherever applicable, quality risk assessment shall be performed for suspected product defects, potential impact on other batches or on other products etc.
• QA shall review & evaluate details of deviation mentioned in deviation for correctness & completeness along with the immediate actions taken, risk & impact assessment of deviation and supporting documents (if any). Additional supportive data and documents can be requested from responsible department for evaluation.
• After review and evaluation, QA shall assign unique reference number to the deviation form and update the deviation number in the deviation log book.
• After evaluation of details mentioned in deviation form, risk, impact assessment of deviation, QA shall categorize the deviation in to Critical, major or minor as per nature of deviation.
• QA shall also check whether similar type of deviation was happened in past one year.
• Investigation of Critical, major deviations and minor deviations which are repetitive in nature shall be performed using investigation report and deviations which are minor in nature or deviations having obvious or known root cause, investigation shall be performed as per deviation approval form .
• The responsible department head/designee shall initiate the investigation as per the SOP for Investigations as applicable, considering history & trending, root cause evaluation, risk and impact assessment and comments from other departments within the site along with QA department.
• The cross functional investigation team shall be formed for the investigation of deviations and shall consist of Head of the department or designee where deviation has occurred and members with sufficient knowledge on current matter for investigation.
• The investigators must have appropriate knowledge and training to perform an investigation.
• The team shall include members (depend upon nature and Applicability) from QA, QC, Manufacturing, Packaging, Regulatory, Engineering, Safety and Warehouse etc.  
• The tools like Ishikawa diagram analysis (fish bone diagram), 5 why’s, fault tree analysis (FTA) failure mode and effects analysis (FMEA), Flow charts, Process flow etc. shall also be used for detection of the root cause, if necessary.
• If actual root cause is not identified, potential root cause shall be identified based on history of repetitive deviation, deviation trends, vendor assessment, scientific knowledge and actions shall be taken to prevent the potential from occurring.
• Investigations where human error is suspected or identified as a root cause shall be justified. The procedural or systems based errors must be thoroughly reviewed before concluding for human errors.
• Responsible department along with QA shall evaluate the following information (but not limited to) for the impact / risk  assessment for the deviation as mention below: 

1. Scope of the deviation – batch affected (both in-process and previously released).
2. Potential quality impact.
3. Trends relating to (but limited to) similar products, materials, equipment and testing processes, product complaints, previous deviations, annual product reviews, and /or returned goods etc. where appropriate. 
4. A review of similar causes.
5. Regulatory commitment impact.
6. Other batches potentially affected.
7. Market actions (i.e. recall etc).

• Investigation of critical deviations shall be completed within 15 working days & investigation of major deviations shall be completed within 20 working days and investigation of minor deviations shall be completed within 30 working days from the day of deviation occurrence.
• The deviations (wherever applicable) shall be communicated to the customer / QP / MAH immediately after the completion of the investigations as per timelines mentioned .
• Depending on the impact assessment / risk assessment, identified root cause, and comment received from various sources, CAPAs shall be defined by responsible department head in consultation with QA.
• Based on the investigation results and derivation of CAPAs, Quality Assurance shall determine the disposition of the affected material/product as applicable.
• The final evaluation of root cause, CAPAs and the conclusion of the investigation shall be performed by head QA/designee and shall be recorded in the investigation report.
• Appropriate CAPA’s shall be identified and subsequently logged into CAPA log book and the deviation report shall be closed.
• QA shall check the implementation and completion of the corrective and preventive action and update the Log book.
• The implemented corrective & preventive actions shall be monitored periodically for its effectiveness as per SOP for CAPA management.
• At the time of batch release, QA representative shall ensure that the investigation for the deviations is carried out and closed.
• QA shall review the deviation logbook after every month to identify the open deviation report and follow- up for the same with respective responsible department & HODs.
• All deviations shall be timely reviewed to close within 30 calendar days of occurrence of deviation & Justification for delay in closure shall be filled by the responsible department in case deviation is not closed in 30 days .
• Only two extensions, of 30 days each, shall be allowed for Investigation & deviation closure, if failed to complete the activities after two extensions, then QRA shall be prepared by responsible department.
• Periodic review of deviation system or Trending of deviation shall be conducted quarterly to check the effectiveness of deviation system and shall be documented . Periodic review shall include (but not limited to) total no. of deviations during review period as per category (e.g.  Critical, Major and minor), as per department, as per nature of deviation (e.g. Product related, Process related, equipment related, calibration validation failure, testing related etc.), no of repeat deviations (e.g. as per nature and as per root cause etc). 
• The trending or Periodic review of deviation system shall include Department wise classification of deviation, Category wise,Type wise, Review of similar root cause,Review of previous open, Summary and conclusion etc.

Deviation Approval form Attached for Reference

Flow chart for Deviation :

The following terms and definitions are provided to assist the reader in using this guidance Documentation.

Batch Number  : A distinctive combination of numbers or letters from which the complete history of  the manufacture, processing, packaging, coding and distribution of a batch can be determined.

Documentation that provides the history of a batch from the raw material dispensing stage to completion of the batch or lot which include Dispensing of raw material, Granulation, Blending Compression, Capsule Filling, Coating, Inspection and yield at different stages. It also includes the details of the activity performed by whom, checked by whom, at what time activity was performed, at what date activity was performed and signature of the personnel involved in the batch or activity.

Batch Packaging Record : Documentation that provides the history of a batch from packaging material  dispensing, Blister packing, Bottle packing, Jar packing, Dry syrup Filling, labeling, Carton packing and shipper packing up to  Dispatch of a Batch or Lot. It also includes the details of the activity performed by whom, checked by whom, at what time activity was performed, at what date activity was performed and signature of the personnel involved in the batch or activity.

Active Ingredient :A substance or a bulk pharmaceutical chemical that is intended to furnish pharmacological  activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of  the disease or to effect the structure or any function of the body of man or other animals.

Actual Yield : The quantity that is actually produced at any appropriate phase of processing of a particular product.

Theoretical Yield :The quantity that would be produced at any appropriate those of manufacture, processing or  packaging of a particular drug product based upon the quantity of components to be used in  the absence of any loss or error in actual production.

Acceptance Criteria :The specifications and acceptance/rejection, such as acceptable quality level and  unacceptable quality levels, with an associated sampling plan that are necessary for making a decision to accept or reject the material. This term can also be applied to validation.

Analytical Methods Validation : The Process by which it is established by laboratory Studies, that the performance characteristics of the method meet the requirements for the intended Analytical Applications.

Calibration :The demonstration that a particular instrument or device produces results within specified limits  by comparison with those produced by a traceable standard over an appropriate range of   measurements.

Certificate of analysis : A document relating specifically to the results of testing a representative sample drawn from  the material to be delivered.

Cross-Contamination : A contamination of material or product with another material or product.

Expiry/Expiration Date : The date usually placed on the containers /labels of material designating the time during which the material is expected to remain within the established self  life specifications if stored under defined conditions and after which it should not be used.

Finished Product : Any pharmaceutical product that has undergone all stages of production, including packaging and labeling.

In-process control :Checks perform during production in order to monitor and if necessary to adjust the process to ensure that the product conforms its specifications. The control of the environment or equipment may also be regarded as a part of in-process control.

Medicines :A manufactured, sold placed for sale or recommended substance or mixture for Treatment, relief, prevention or diagnosis of a disease, abnormal a physical state or the symptoms of one or another one in man or animals or the reestablishment, correction or the organic functions modification in man or animals.

Qualification :The action of proving that any equipment or process work correctly and consistently and  produces the expected result. Qualification is part of, but not limited to a validation process, i.e. Installation Qualification (IQ), Operation Qualification(OQ) and Performance Qualification (PQ).

Operational Qualification : Operational qualification consists of verification and documentation, of the parameters of the subjected equipment.

Performance Qualification : Performance Qualification is designed to prove the process, can consistently produce a product that meets the stated requirements and specifications.

Quality Assurance :The sum total of the organized activities performed with the intent to ensure that all the activities are of the quality required for their intended use.

Quality Control : All activities such as measuring, examining, testing, or gauging one or more Characteristics of  a product (including raw materials) and comparing the findings with specified requirements to determine conformity.

Production :All operations involved in the preparation of a pharmaceutical product, from receipt of raw materials through the completion of a finished product.

Validation : Documented program or evidence, that provides a high degree of assurance that a specific process method or system consistently produce a result indicating predetermined accepted criteria.

Validation Protocol :A written plan starting how validation will be conducted and identifying specific acceptance criteria.  For example the protocol for a typical manufacturing process identifies processing equipments, critical process parameters/ operating ranges, Critical Quality attributes and product characteristics. Sampling and test data to be collected, number of validation runs and acceptable test results.

Prospective Validation :Establishing documented evidence that a system dos what it  suppose to do prior to the commercial distribution of the new product or an existing product made by  a new  or modified process.

Quarantine : The status of starting or packaging materials, intermediates, Bulk or finished products isolated  physically or by other effective means whilst awaiting a decision on their release or refusal.

Raw material :Any substance used in the manufacture of pharmaceutical drugs excluding Packing material.

Reconciliation : A comparison between the amount of product or  material theoretically vs actually produced or used.

Retest Period : The period of time during which the material can be considered to remain within specifications and therefore acceptable for use in the manufacturer of a given drug product provided that it has been started under defined conditions.

Retrospective Validation :Establishing documented evidence that a system does what it purports to do based on a review and analysis of historic information. It is normally conducted on the drug material already being commercially distributed and is based on accumulated production, testing and control data.

Working Standard :A substance of established quality and purity as shown by comparison to a primary reference standard/used as a reference for routine lab analysis.

Standard operating procedure (SOP) :A written authorized procedure that gives a set of instructions for performing the operations.

Reprocessing : The reworking of all or part of a batch of product of an unacceptable quality from a defined stage of production so that its quality may be rendered acceptable by one or more additional operations.

Product Lifecycle : Stage through which a product moves from its inception till its discontinuation. It includes pharmaceutical development, technology transfer and commercial production up to product discontinuation.

What is Disintegration:

It is the time required for the Tablet / Capsule to break into particles, the disintegration test is a measure of the time required under a given set of conditions (environmental) for a group of tablets/capsules to disintegrate into particles.

Disintegration is to be Performed to determine whether tablets or capsules disintegrate within the prescribed time when placed in a liquid medium at the experimental conditions.

Since its inception in the 1930s, disintegration testing has become an important quality control (QC) test in pharmaceutical industry, and disintegration test procedures for various dosage forms have been described by the different pharmacopoeias.

In 1948, the British Pharmacopoeia (BP) adopted a disintegration test for tablets based on observing the disintegration behavior in test tubes.

The basket-rack assembly apparatus, first adopted by the United States Pharmacopoeia (USP) in 1950.

Basket-Rack Assembly Parameters & Specification :

Parameters	Specification
Beakers	1000 mL each
Height of beaker	138 – 160 mm
Inside diameter	97- 115 mm
Frequency of shaft raising and lowering basket	29 – 32 CPM
Distance of shaft for raising & lowering the basket	53 – 57 mm
Diameter of tube holding plates	88 – 92 mm
Thickness of tube holding plates	5 – 8.5 mm
Six open-ended transparent tubes of length	75 – 80 mm
Inner tube diameter	20.7 – 23 mm
Stainless steel wire cloth (square weave aperture)	1.8 – 2.2 mm
Wire diameter	0.57 – 0.66 mm

Disks : The use of disks is permitted only where specified or allowed in the monograph.

MOC (Material of construction)  = Plastic material having a specific gravity between 1.18 – 1.20

Thickness & Diameter = 9.5 ± 0.15 mm & 20.7 ± 0.15 mm

How to perform Disintegration test :

Place 1 dosage form in each of six tubes of basket and add a disk (if prescribed)

Operate the apparatus using water or specified medium as the immersion fluid, maintained at 37 ± 2º C.

At the end of the time limit as specified, lift the basket from fluid and observe the tablets, all the tablets have to disintegrate completely.

Disintegration Time :

• Uncoated Tablet 15 min as per BP & 30 min as per USP
• Sugar Coated Tablet 60 min as per BP
• Film Coated Tablet 30 min as per BP
• Plain Coated Tablets DT in specific medium for 30 min as per USP
• Enteric Coated Tablets DT in  simulated gastric fluid (0.1 M HCl) for 1 hr and then in simulated intestinal fluid (Phosphate buffer 6.8 pH) until disintegrate as per USP.
• Dispersible Tablets 3 min ( 15- 25º C ) as per BP.
• Effervescent Tablets 1 tablet in 200 mL water  for 5 min ( 15- 25º C )
  as per BP
• Buccal Tablets 4 hrs as per USP.
• Soluble Tablets 3 min ( 15- 25º C ) as per BP.
• Chewable Tablets are not require to comply with test.
• Gastro resistant capsule DT 2 hrs without disk in 0.1 M HCl  and phosphate buffer pH 6.8 for further  60 min as per BP.
• Hard gelatin capsule DT 30 min as per BP & USP.
• Soft gelatin capsule DT 30 min as per BP .
• Oral lyophilizates DT disintegrate within 3 min Using a beaker containing 200 mL of water at 15 °C–25 °C. Six units tested, 1 at a time as per BP & phEur.

Calibration:

• Cycles of shaft holding the tube basket (1 min) = Limit 29-32 Cycles Per Minutes
• Distance covered by the shaft = Limit 55 ± 2 mm
• Beaker Temperature (60 min) = Limit 37º ± 2º C
• Sieve integrity check (Aperture opening) = Limit 1.8 – 2.2 mm

Timer :

• Time in 3 min = Limit 3 min ± 3 sec
•  Time in 15 min = Limit 15 min ± 18 sec
• Time in 30 min = Limit 30 min ± 36 sec
• Time in 60 min = Limit 60 min ± 1 min 12 sec
• Time in 120 min = Limit 120 min ± 2 min 24 sec
• Start the instrument and record the time with calibrated stop watch

Sieve integrity check :

• Intactness of each sieve opening
• any cracks, abrasion
• Aperture opening a = L – 5W/6  where L= Length of 6 opening and W= Wire diameter and No. of opening =6
• Acceptance Criteria 1.8 – 2.2 mm
• Measure the length of six aperture of basket mesh with the help of calibrated vernier calliper
• Measure the Diameter of basket mesh wire with the help of calibrated vernier calliper.

Conclusion :

• Generally the test is carried out once.
• In case at the end of the time limit if 1 or 2 tablets fail to disintegrate completely, repeat the test on 12 additional tablets.
• The requirement is met if not less than 16 of the total of 18 tablets tested are disintegrated.

What is Friability Test of Tablet ???

Friability is defined as the percentage of weight loss of powder from the surface of the tablets due to mechanical action and the test is performed to measure the weight loss during transportation .

It is a supplement test for Uncoated / Compressed Tablets other than physical measurement e.g. Hardness (Tablet Breaking Force).

Measuring the hardness of a tablet is not a reliable indicator for tablet strength as some formulations when compressed into very hard tablets tend to ‘cap’ or lose their crown portions on attrition. Such tablets tend to powder, chip and fragment.

In friability test the tablets are prone to abrasion hence enabling us to check for the tablet strength under application of force in different manner.

They not only lack elegance and consumer acceptance but also spoil the areas of manufacturing such as coating and packaging.

Who will perform Friability Test ???

• Production ● Quality Assurance (IPQA) ● Quality Control

Friability Drum Specification :

Title	Specification
MOC and Property of Drum	Transparent Synthetic Polymer with polished internal surfaces. Develops minimum Static charge. One side is removable.
Drum attachment	Horizontal to axis of Instrument
Internal  Diameter	283.0 to 291.0 mm (287.0 ± 4.0 mm)
Depth	36.0 to 40.0 mm (38.0 ± 2.0 mm)
Outer Diameter of Central Ring	24.5 to 25.5 mm (25.0 ± 0.5 mm)
Curved Projection with inside Radius (Extends from middle to outer wallof drum)	75.5 – 85.5 mm (80.5 ± 5.0 mm)
Drum Revolution/Minute	24 – 26 (25 ± 1)
Drop Height	154.0 – 158.0 mm (156.0 ± 2.0 mm)
Total Revolution / Test	100 Revolutions / 4 Minutes
Function	At each turn, the Tablets roll or slide and fall onto the drum wall or onto each other

A drum with dual scooping projections, or apparatus with more than one drum, for the running of multiple samples at one time, are also allowed.

How to perform Friability Test ???

Tablets with unit weight equal to or less than 650 mg, take sample of whole corresponding to as near as 6.5 g equivalent.

Tablets with unit weight more than 650 mg, take sample of 10 whole Tablets.

Tablets must be de-dusted prior to and after test.

Calculation :

Friability (%)  =W₁ – W_2/ W_{1  X 100}

Where,
W₁ = Weight of Tablets (Initial / Before Tumbling) &
W₂ = Weight of Tablets (After Tumbling or friability)

  Limit : Friability (%) = Not More Than 1.0 %

Conclusion :

Generally, the test is run once.

In case cracked, cleaved, or broken tablets are present in the tablet sample after tumbling, the sample fails the test.

In case the results are difficult to interpret or the weight loss is greater than the targeted value (NMT 1.0 %), the test is repeated twice and the mean of the 3 tests determined. A maximum loss of mass (obtained from a single test or from the mean of 3 tests) NMT 1.0 % is considered acceptable for most products.

Incase Tablet Size or Shape causes Irregular Tumbling & why it happens & What to do :

Tablets bind together when lying next to each other, which prevents them from falling freely.

Adjust the drum base in such a way that the base forms an angle of about 10° with the horizontal surface.

In the case of Hygroscopic Tablets A humidity-controlled environment is required for testing.

Calibration Limit :

Parameters	Specification
Revolution / Minute	24 to 26 RPM (25 ± 1 RPM)
Time / Test	3 Minutes & 50 Seconds                   to 4 Minutes & 10 Seconds (4 Minutes ± 10 Seconds)
Frequency	Quarterly

Objectives :

1. Review measures to ensure Good Sanitation in:

• Premises and Personnel
• Equipment and Apparatus
• Processes, Materials and Containers

2. To review measures to ensure Good Personal Hygiene

Scope :

High level of Sanitation and Hygiene practiced – in every aspect of  Manufacturing.  It covers:

• Personnel
• Premises
• Equipment and Apparatus
• Production Materials and Containers
• Products for cleaning and disinfection
• All potential sources of cross-contamination

General points to be Followed :

• Take daily bath
• Cut nails and comb hair neatly
• Use hair covers in all areas (Cap, beard cover, etc.)
• Do not keep open wounds
• Person having contagious diseases should avoid contact with other persons and product.
• Follow the Entry and Exit SOPs strictly while entering in each area
• Gowning of personnel shall be followed to maintain departmental hygiene
• Ornaments, Make up, Watches, Perfumes and other Chemicals shall not be used in Production Facility

Basic Principles of GMP :

1. Written procedures and instructions and signs – e.g. to wash hands before entering Production Areas .
2. Disinfectants are also used e.g. IPA, Sterilium.
3. Wash hands before entering Production Areas.
4. Toilets should not open directly into Production or Storage Areas.
5. Wash hands after each usage of Toilet

Personal Hygiene :

1. Health Examinations :

• Before joining and during employment periodically
  
• After long illness

2. Training :

• Practices in personal hygiene
• Written procedures and instructions
• Signs and captions in areas

3. Illness or open lesions :

• May affect the Quality of Products
• Should not handle starting Materials, Intermediates or Finished Products, etc.
• Instruction and encouragement to report to Supervisors

4. Direct contact between Product and Operator :

• Should be avoided
• Starting Materials, Primary Packaging Materials, Intermediate and Bulk Product

5. Protection of product from contamination:

• Clean clothes appropriate to personnel activities
• Including hair covering (e.g. Caps, Beard Covers)

6. Check change rooms/changing facilities :

• Hand washing, signs, drying of hands
• Used clothing stored in separate closed containers while awaiting cleaning
• Laundering of clean area clothing according to an SOP and in an appropriate facility
• Procedure for disinfecting and sterilizing when required
• Smoking, Eating and Drinking not allowed in Production areas, laboratories and storage areas
• No chewing (e.g. gum), or keeping Food or Drinks allowed
• No Plants kept inside these areas
• Rest and refreshment areas should be separate from Manufacturing and Control areas.

7. Personal hygiene procedures including wearing protective clothing apply to all persons entering into production areas:

• Full-time employees
• Temporary workers
• Contractor’s employees
• Visitors
• Managers
• Inspectors

What is Batch Packing Record (BPR)

Batch Packing record is a written document of the batch from dispensing to dispatch stage which tells about the procedure and step wise instruction to be followed during the Packing of each batches. It contains actual data of the Packing and it is like a proof that batches were properly made and checked by the production and verified by Quality Assurance personnel. It also contains the details like Who has done the activity, when the done the activity etc.

Dispensing Stage :

1. Ensure the Line clearance is verified by QA.
2. Ensure the balance calibration date and due date is recorded.
3. Ensure the label of ‘Dispensed Material’ is as per packing material requisition.
4. Ensure the Sign & date of Weighed By and Checked By is completed.
5. Quantity of material issued with respect to quantity as per packaging material requisition
6. Ensure the Checklist of required equipment and area is attached with BPR.
7. Check the ‘Clean label’ of required equipment is attached with BPR.

Dry syrup filling stage :

1. Check the QA person is signed on the ‘Release for packing’.
2. Ensure the date of ‘Lubricated Blend’ should not be exceeds the hold time.
3. Ensure the ‘Environmental Condition Log’ is written as per Instruction given in BPR.
4. Check the Line clearance is verified by QA.
5. Check frequency of metal detector performance checks is as per BPR.
6. Check speed of filling machine.
7. Check the ‘Clean label’ of required equipment is attached with BPR
8. Check the all inprocess checks like weight of powder, capping quality and leak test is done as per Inprocess Control Specification frequency.
9. Check the checklist of required equipment and area is attached with BPR
10. Ensure the quantity of labels required to packed as per BPR.
11. Ensure the request for issuance of printed label is attached with BPR.
12. Ensure the printed label specimen is signed and dated.
13. Check yield reconciliation of Bottles, Caps, Labels and shipper etc.
14. Check the yield reconciliation of powders & bottles etc.
15. Ensure the Finished Goods transfer note and packing material Returned Note is attached with BPR.
16. During packing process, if any process history, deviation should be attached with BPR.
17. During review, if any discrepancy observed it must be mentioned through the QMS system.
18. Ensure the additional pages is mentioned in BPR.
19. Ensure the ‘Checked By- packaging’, Reviewed By- packaging’, Reviewed By- QA’ and ‘Approved By- QA’ is signed and dated.

Blister Packaging Stage :

1. Ensure the Line clearance is verified by QA.
2. Ensure the ‘Environmental Condition Log’ is written as per Instruction given in BPR.
3. Ensure the date of Blend , Compression and Capsule Filling’ should not be exceeds the hold time.
4. Ensure the change part number and packing configuration is as per BPR.
5. Ensure the blister/carton specimen proof as per BPR and is signed and dated.
6. Ensure the written parameter and inprocess checks like forming temperature, sealing temperature, leak test , camera challenge test etc are performed as per BPR.
7. Ensure the pharmacode challenge test is performed as per BPR.
8. Ensure the speed of machine is mentioned as per specified limit.
9. Ensure the actual temperature of Bundling, is as per specified limit.
10. Calculate the total weight if Shipper is correct within limit.
11. Ensure the Sign & date of Weighed By, Done By and Checked By is completed.
12. Reconciliation should be calculate as per particulars.
13. Ensure the Finished Goods transfer note and packing material Returned Note is attached with BPR.
14. Check the checklist of required equipment and area is attached with BPR
15. Check the ‘Clean label’ of required equipment is attached with BPR
16. During packing process, if any process history, deviation should be attached with BPR.
17. During review, if any discrepancy observed it must be mentioned through the QMS system.
18. Ensure the additional pages is mentioned in BPR.
19. Ensure the ‘Checked By- packaging’, Reviewed By- packaging’, Reviewed By- QA’ and ‘Approved By- QA’ is signed and dated.

Related topic : https://pharmaceuticalupdates.com/2019/02/10/procedure-for-review-of-batch-manufacturing-record-bmr-or-batch-processing-record-bpr/

Conclusion :

1. Review is a important part of during and after Manufacturing and packing operation.
2. Any missing part in the document should be identified by the reviewer during review.
3. Any observation identified shall be compiled before release of the batch to the market and if required deviation shall be raised in order to rectify the observation.
4. Before release of the batch to the market both Production and Quality personnel shall ensure the completeness or closing of the documents and deviation or change control or investigation if any.

What is Batch Manufacturing Record (BMR) or Batch Processing Record (BPR) :

Batch manufacturing record is a written document of the batch from dispensing to Inspection stage which tells about the procedure and step wise instruction to be followed during the manufacturing of each batches. It contains actual data of the process and it is like a proof that batches were properly made and checked by quality Assurance personnel. It also contains the details like Who has done the activity, when the done the activity etc.

Procedure for review of BMR or BPR :

Raw material Dispensing Stage:

1. Ensure the ‘Environmental Condition Log’ is written as per Instruction given in BMR.
2. Ensure the Line clearance is verified by QA.
3. Ensure the balance calibration date and due date is recorded.
4. Check the calculation of Potency of API and verified by QA.if applicable.
5. Ensure the label of ‘Dispensed Material’ is as per ‘Bill of Material’.  
6. Ensure the Sign & date of Weighed By and Checked By is completed.
7. Ensure the selection of code of active material is done, if applicable.
8. Quantity of material issued with respect to quantity as per ‘Bill of Material’. 
9. Ensure the Checklist of required equipment and area is attached with BMR.
10. Check the ‘Clean label’ of required equipment is attached with BMR.
11. Ensure the Printout of  Balance is attached, material wise with BMR (If applicable)

Granulation Stage :

1. Ensure the date of ‘Dispensed Materials’ is within the hold time.
2. Ensure the ‘Weight Verification’ of all ‘Dispensed Materials’ is completed and signed prior to manufacturing.  
3. Ensure the ‘Environmental Condition Log’ is written as per Instruction given in BMR.
4. Check the Line clearance is verified by QA.
5. Ensure the Sieve/Screen is used as per mention in the batch record
6. Calculate the total net weight of containers used for binder is as per required quantity.
7. Check the pre-lubrication and Lubrication activity is performed as per BMR.
8. Check the Printout of blending activity with actual Start Time, End Time and RPM.
9. Ensure the calculation of ‘Reconciliation’ of blend is correct.
10. Ensure the Sign & date of Weighed By, Done By and Checked By is completed.
11. Check the checklist of required equipment and area is attached with BMR.
12. Check the ‘Clean label’ of required equipment is attached with BMR.

Compression Stage :

1. Ensure the ‘Environmental Condition Log’ is written as per Instruction given in BMR.
2. Check the QA person is signed on the ‘Release for Compression’.
3. Ensure the date of ‘Lubricated Blend’ should not be exceeds the hold time.
4. Ensure the ‘Environmental Condition Log’ is written as per Instruction given in BMR.
5. Check the Line clearance is verified by QA.
6. Check the actual type of cam is mentioned.
7. Check the written frequency of metal detector performance checks if as per BMR.
8. Check the all In process is done as per In process Control Specification frequency.
9. Ensure the printout time as per In process checks and it should sign with date.
10. Ensure the balance calibration date and due date is recorded.
11. Calculate the total net weight is written correct.
12. Ensure the Sign & date of Weighed By, Done By and Checked By is completed.
13. Calculate the net weight of each container is written correct
    & yield reconciliation
14. Check the checklist of required equipment & ‘Clean label’ of required equipment is attached with BMR.

Capsule Filling Stage :

1. Check the QA person is signed on the ‘Release for Capsule filling’.
2. Ensure the date of ‘Lubricated Blend’ should not be exceeds the hold time.
3. Ensure the ‘Environmental Condition Log’ is written as per Instruction given in BMR.
4. Check the Line clearance is verified by QA.
5. Check frequency of metal detector performance checks is as per BMR.
6. Ensure the Empty Capsules Sorter Challenge test is performed as per BMR.
7. Check all the In process is done as per In process Control Specification frequency.
8. Check the printout time/Manual weight entry time as per In process checks and it should sign with date.
9. Ensure the balance calibration date and due date is recorded.
10. Ensure the Sign & date of Weighed By, Done By and Checked By is completed.
11. Calculate the net weight of each container is written correct & yield reconciliation.
12. Check the checklist of required equipment & ‘Clean label’ of required equipment is attached with BMR.

Coating Stage :

1. Check the QA person is signed on the ‘Release for Coating’.
2. Ensure the ‘Environmental Condition Log’ is written as per Instruction given in BMR.
3. Ensure the date of ‘Compression’ should not be exceeds the hold time.
4. Ensure the actual parameters at ‘Preparation of Suspension’ stage.
5. Calculate the total net weight of coating suspension containers used for required quantity.
6. Ensure the calculation for average weight of core and coated tablets.
7. Ensure the calculation for spray rate of coating suspension & weight gain.
8. Calculate the net weight of each container is written correct.
9. Ensure the Sign & date of Weighed By, Done By and Checked By is completed.
10. Reconciliation should be calculate as per particulars
11. Check the checklist of required equipment & ‘Clean label’ of required equipment is attached with BMR.

Inspection Stage :

1. Ensure the ‘Environmental Condition Log’ is written as per Instruction given in BMR.
2. Check the Line clearance is verified by QA.
3. Ensure the quantity of defected tablets/ capsules is as per quantity of each type of defective tablets/capsules observed.
4. Calculate the net weight of each container and total net weight is written correct.
5. Ensure the Sign & date of Weighed By, Done By and Checked By is completed with balance calibration date
6. Reconciliation should be calculate as per particulars.
7. Check the checklist of required equipment and area is attached with BMR.
8. Check the ‘Clean label’ of required equipment is attached with BMR.
9. Check for manufacturing process, if any process history, deviation should be attached with BMR.
10. QA person should sign and date in ‘Manufacturing Deviations’ table provided in BMR if any.
11. Ensure the additional pages are attached in BMR.
12. Ensure the ‘Checked By- production’, Reviewed By- production’, Reviewed By- QA’ and ‘Approved By- QA’ is signed and dated.

Conclusion :

These above mentioned documents shall be reviewed by both production and Quality Assurance step wise i.e With the completion of the step wise activities the documents shall be completed simultaneously and if the documents are incomplete then Production as well as Quality Assurance shall not move to the next step or activity .

Procedure to be Followed as mentioned below (but not Limited to) :

• Before entering sterile area check temperature, humidity and differential pressures.
• Check that the area is kept clean at all time.
• Confirm the sterilization of sterile gowns and gloves by checking the indicators.
• Do not reuse the dress for second entry.
• Before touching any product container, machine parts,  disinfect the hands with suitable disinfectant
• Use sterilized forceps to pick up the fallen vials & stoppers on the machine and turn table.
• Avoid unnecessary movements, excessive activities, Speedy movements, and opening of the doors frequently.
• Exit should be through return change room only.
• At regular intervals check temperature, humidity and differential pressure.
• For reasons of comfort and efficiency, establish a minimum number of people to be allowed in the air locks any one time.
• No personnel articles (purses, bags, jewellery, watches etc.,) are permitted inside the sterile rooms or air locks.
• Person with sickness should not be allowed to enter the sterile area.
• No verbal communication should be done through the pass through box or air locks.
• All doors of the sterile area should be checked for proper closing.
• All materials, containers and equipment introduced into the sterile room must be subjected to sterilization and proper disinfection procedures prior to taking them in sterile areas.
• Use lint free dusters for cleaning in sterile areas. Mops, brooms, and other customary cleaning equipment should not be used in sterile areas.
• Paper in any form is not allowed into sterile rooms.
• No pencils or ball pens should be used in sterile room.
• Maintain the cleaning and disinfection schedule for the sterile area.
• After completion of production, any material from the previous product should be removed from the sterile room to avoid cross contamination.
• Cleaning and / or disposal of all support material should be done after each workday.
• High standards of personal hygiene and cleanliness are essential for the personnel involved in the activity.
• Gloves should be regularly disinfected during operations.
• Masks and gloves should be changed at least every working session.
• The hair and, where relevant, beard and moustache should be covered.
• Protective clothing and appropriate shoes or overshoes should be worn.
• Clothing used in clean areas should be laundered or cleaned in such a way that it does not gather additional particulate contaminants that can later be shed.
• Grade A and B areas where activities are going on should be designed so that all operations can be observed from outside.
• In clean areas all exposed surfaces should be smooth, impervious and unbroken to minimize the shedding or accumulation of particles or microorganisms.
• After entering to the Changing room all personnel should confirm the correct fitting of garments with the help of mirror .
• Consideration should be given to restricting unnecessary access to critical filling areas.

CALIBRATION OF SIEVES:

Calibration of Sieves Below or equal to 30# :

• Check the cleanliness of sieve before start the calibration.
• Affix “Under Calibration” label
• Take the plain paper and mark with pen one linear square inch in the paper with the help of calibrated standard measuring scale.
• Keep the marked paper below the sieve and count the apertures with the help of magnifying glass and count the number of holes in linear square inch in both the directions (Horizontal and Vertical directions).
• Take minimum ten location counts in each sieve.

Calibration of sieve above 30# to 100# by using Densimeter :

• Keep densimeter on the sieve in such a way that the letters are facing us and other side is touching the sieve.
• Move the densimeter so that any one vertical line of densimeter is matching with the vertical line of the sieve.
• Grids will start forming on the densimeter. Peak of grid form like the peak   of the mountain.
• The line of this peak where it matches the sieve / number mentioned on  the densimeter is the actual sieve number of the sieve.
• Take minimum ten location counts in each sieve.

TOLERANCE LIMIT :

Sr No.	Sieve Size	Number of Apertures per Linear Inch
1	10 #	9-11
2	12#	11-13
3	14#	13-15
4	16#	15-17
5	20#	19-21
6	24#	23-25
7	30#	28-32
8	40#	38-42
9	60#	57-63
10	80#	77-83
11	100#	97-103

Note:

1. if any new sieve are received that needs to be calibrated before issue  to the production.

2. Damaged sifter sieve should not calibrate and use.

      
Calibration of Screen using ‘GO’ and ‘NO-GO’ Gauges :

• Insert ‘GO’ gauge in a screen, it should passes though the screen.
• Insert ‘NO-GO’ gauge in the same screen, it should not passes  through the screen.

Note :

1.Calibrate all the sieve and screens once in six months.

2. If any discrepancy observed immediately inform to the executive  production or department head for the necessary action.

3. All the new sieves and screens needs to be calibrated before issued to the    production

4. Damaged sieve and screens should not calibrate and used.