Month: February 2020

Acceptable Quality Level (AQL) in Pharmaceuticals

What is Acceptable Quality Level (AQL) :

Acceptable Quality Level (AQL) is a percent defective that is the base line requirement for the quality of the product. The sampling plan required to be prepared or design in such a way that there is high probability of accepting a lot that has a defect level less than or equal to the AQL.

Background of Acceptable Quality Level (AQL) :

The AQL was popularized by Harold F. Dodge and Harry Remig for US military  during World War II. The military faced a problem with the need to test bullets for quality and function. So the military had find a way to test enough bullets to give them assurance about the quality of a lot without testing all bullets. Sampling with AQL addressed these concerns. By pulling a sample of bullets randomly from a lot, the military was able to test part of the lot and use those results to estimate the quality of the total lot. 

Procedure of AQL :

AQL Shall be performed for Packing material ( Printed cartons, Leaflets, Aluminium Foil, PVC/PVDC, Bottles, Caps etc. and for Empty capsule also before sampling or during sampling. AQL shall be performed at different stages of manufacturing like for Compressed tablet, Filled Capsules and Coated tablets after visual Inspection. Both Production and Quality Assurance shall performed the AQL activity .

After getting satisfactory AQL result tablets or capsules shall be further processed to the next stage.

Samples for AQL Inspection shall be collected from each container of the batch or Box.

For Tablets, Capsules and Caplets etc. the Lot Size is equal to the total No. of Tablets, Capsules and Caplets available in respective container.

To determine the “Code Letter” & “Sample Size” corresponding to the “Lot Size” for AQL inspection refer below table A as Single sampling plan for normal inspection and refer below Table B as Single sampling plan for tightened inspection.

Collect the approximate sample into the separate sample bag with the help of “Code Letter”. Refer the Single sampling plan for Normal inspection (Refer table A) and Single sampling plan for Tightened inspection (Refer Table B).

Acceptable Quality Level (AQL) inspection shall be carried out in the “Inspection area” on the SS tray lined with polythene bag and record the result in Acceptable Quality Level (AQL) Report . Inspection shall be carried out on the basis of Classification of Minor, Major & Critical defects.

The Accepted units shall be kept in respective container and only Rejected units shall be kept separate for reference purpose till decision of release or rejection of the batch. These units shall be kept in secured container.

In case of Major or Minor category if numbers of Rejected units are equal / less than the Acceptable criteria, the respective container(s) are accepted and the lot or batch shall be released for further process.

In case of Major or Minor category, if number of Rejected units are equal / more than the Rejection Criteria, the respective container(s) shall be given for 100 % inspection to remove defective units. In case the Rejection is Critical category, then all containers shall be given for 100 % inspection.

On completion of 100 % inspection, again sampling shall be carried out from respective container(s) or all container(s) and AQL Inspection (Tightened) shall be performed.

In case of failure of AQL, Investigation shall be carried out to find out the root cause of failure .

After completion of AQL Inspection, Acceptable units of sample shall be kept in container & Rejected units of sample shall be destroyed.

AQL Inspection Report shall be attached with Batch Manufacturing Record (BMR).

Sampling plan for Normal inspection (Table A)

Sampling plan for Tightened inspection (Table B)

AC Stands for Accepted and RE Stands for Rejected

AQL Calculation :

Suppose we have to perform AQL for Coated tablet or Filled capsule or Compressed tablets and calculated average weight of tablet or capsule after Inspection is 700 mg and Weight of HDPE drum or container with capsule or tablet is 20.00 kg then the calculation will be as follows.

20 kg/700 mg x 1000 x 1000 = 28571 capsules or tablets in Nos.per container. Refer the Lot size (in Nos) & code letters from Table A and B. Refer Serial number 12 whose lot size is mentioned 10,001 to 35,000 and code letter mentioned M that means we have to collect 378 tablets or capsules from each container or drum to perform AQL and based upon the result we have to released the batch.

What is Critical Defects :

It is one that will affect the quality of the finished product (unsafe) and cause a potential risk to the patient. The AQL for critical defects is very low i.e. 0.0%.

What is Major Defects :

It is one that will likely to cause non-conformance of product during manufacturing/packaging, testing, shipment, storage, or use. Such failures do not constitute a potential risk to the patient. The AQL for major defects normally ranges from 0.0 to 2.5 %.

What is Minor Defects :

It is one that will not affect the quality of the finished product (unsafe) and cause no potential risk to the patient. The AQL for minor defects normally ranges from 0.0 to 6.5 %.

Conclusion :

AQL is the additional control to know the defects of any Batch or Lot or container or Box but every employee or manufacturer or the organization should focused on quality of the drug products or materials during performing the activity online in order to have a better control on defects or Rejects which are generated from machine.

It means that we have to identify and correct the problems which may affect the quality of the compressed tablets, capsules and coated tablets during compression, Coating and capsule filling activity and management should be involved and take this seriously to avoid any market compliant or failure of the batch or Lot.

Investigation tools used in Pharmaceuticals

Step-1 Brain Storming:
What is Brain Storming :
Brainstorming is a situation where a group of people meet to generate new ideas and solutions to find a conclusion for a specific problem. In this session people are able to think more freely and they suggest as many spontaneous new ideas as possible. The term was popularized by  Alex Faickney Osborn  in the 1953.
 To be performed immediately upon receipt of complaint/ deviation
 Questions for Brain storming
What happened? Describe actual problem. Provide Details of the defect. What has happened to the product? What patient is trying to say? Convert it to technical language.
When did it happen? When was the defect discovered? What was the condition of the patient?
Where did it happen? What were the situation/ location?
What is the impact? What is the impact over the product? What is the impact over patient? What could be impact over the batch/ other batches in market?
What could be the probable causes that have lead to this defect/deviation? Describe briefly (in short) the probable causes for deviation/ defect. It must be just bullet points (atleast 10 in numbers).
 Additional Questions:
Whether similar nature of defect reported in past?
Whether similar nature of observation was noted during manufacturing in-process checks or in quality control?
Was any breakdown observed in the equipment or instrument during the manufacturing?
Was any deviation reported during manufacturing?
Has any in-process check failed during manufacturing?
 Based upon the brain storming session, Fish bone diagram is to be derived.

Affinity Diagram or Affinity Chart or Affinity Mapping :

The affinity diagram organizes a large number of ideas into their natural relationships. It is the organized output from a Brain storming session.It can be used to generate, organize, and consolidate information related to a product, process, complex issue, or problem. After generating ideas, group them according to their affinity, or similarity. It was created in the 1960s by Japanese anthropologist Jiro Kawakita.

The affinity diagram organizes ideas with following steps:

  • Record each idea on cards or notes.
  • Look for ideas that seem to be related.
  • Sort cards into groups until all cards have been used.
  • Once the cards have been sorted into groups the team may sort large clusters into subgroups for easier management and analysis.

Step-2 Fish Bone Diagram or Ishikawa diagram (Cause and effect diagram)

Ishikawa diagrams were popularized in the 1960s by Kaoru Ishikawa, who pioneered quality management processes in the Kawasaki shipyards, and in the process became one of the founding fathers of modern management.

  • The defect is shown as the fish’s head, facing to the right, with the causes extending to the left as fish bones the ribs branch off the backbone for major causes, with sub-branches for root-causes, to as many levels as required.
Fish Bone Diagram

Analysis of Fish Bone diagram:

  1. Man:
  • Educational Qualification
  • Experience
  • Association with Company
  • Workload

2. Machine:

  • Qualification
  • Preventive Maintenance
  • Breakdown
  • Calibrations

3. Measurement:

  • Inprocess checks
  • Release testing
  • Control sample testing
  • Stability testing

4. Material:

  • Raw material (API& Excipients)
  • Packing materials
  • Semi finished Goods

5. Method:

  • Dispensing
  • Sifting
  • Granulation ( Dry & Wet Granulation)
  • Blending
  • Capsule Filling
  • Compression
  • Coating
  • Visual Inspection
  • Packing ( Blistering, Bottle packing & Dry Syrup Filling etc)

6. Environment:

Details of Temperature, RH and DP during the process & storage

Summary of Fish Bone Analysis:

Provide the probable root causes from above fish bone details.

Step -3 Root cause:

Based upon the probable root cause, conduct a 5 Why?  Analysis to reach to root cause. For example but not limited to

5 Why ?

Step -4 Review of complaint history:

Include details of any similar defect/ deviation reported in past.

What was the root cause of that defect?

What were the CAPA derived?

What is the status of those CAPA? What is the difference between current scenario and the past scenario?

Step-5 Medical Opinion:

What will be the impact of the defect to the patient?

Is any risk involved, if patient has consumed the defective product or patient continues to take the medicine?

What is the recommendation to the patient- Whether to stop taking the medicine or continue?

Step-6 Impact assessment:

Include the impact of this defect over other batches.

Were the batches manufactured in campaign?

Whether the defective RM/ PM used in this batch was used in other batches?

What is the recommendation for those batches?

Include the details of the impacted batches’- batch no. mfg. expiry, customer etc.

Whether any action is required to be initiated for the impacted batches.

Step-7 Conclusion :

Include the actual root causes.

Include the review of complaint history.

Include what is recommended to the patient/ user.

Include details of impact assessment.

Conclusion :

  • All the Investigation tools mentioned above shall be used in case of any Market complaint, Product complaint and in case of any deviation to find out the root cause but not limited to. Other tools also can be used to find out the root cause for any problem. Based upon the root cause Appropriate CAPA shall be taken.
  • Mistakes can be happens by knowingly or unknowingly by the person but it should be reported immediately to take proper action and the person should not hide the problem.
  • Failures are unavoidable in any organization however, it is important that organization shall performed a detailed investigation to identify the root cause for the reported non-compliance or failure in order to take an appropriate corrective action to avoid recurrence.
  • Proactive organizations do not wait for the failure to be reported but take preventive action to improve the system.
  • Proactive organization not only save money by avoiding these batch failures but also avoid potential questions / observations during regulatory audits.
  • Investigation team shall be cross functional team comprising of members from following functions like Initiating department, Quality Assurance, Quality Control, Manufacturing, Engineering, Formulation & Development and Warehouse etc.
  • The investigation team shall list down all the documents which need to be reviewed as part of the investigation like Batch manufacturing record and packing record, Control sample, Analytical data of Raw material, packing materials, In process & Finished products,Instrument / Equipment calibration /qualification status, Personnel training record,Interview of involved personnel & stability data etc.