1. Basic Principles of GMP
Complaints and Recalls
We are going to deal with an area of very great importance.
The plan for this session is that we will present to you the critical aspects of complaint and recall handling for about 1 hour. You will then go into your groups to work there for about 1 hour. We will then reconvene for a plenary session and feedback, which will last about 1hours. There then a test paper followed by an answer session.
This session will conclude the QA/QC aspects of the programme and we will have about half an hour for discussions on any of the issues raised.
Part One, Sections 6 and 7

2. Complaints and Recalls
Product Complaint Principle
“All complaints and other information concerning potentially defective products must be carefully reviewed according to written procedures.”
(WHO GMP)
The product complaint principle is defined in the WHO GMP.
The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization, and do not place the patient at risk because of inadequate safety, quality or efficacy.
Complaints must be handled positively and carefully reviewed, and corrective actions must be taken as necessary. This can mean amending a manufacturing process as well as implementing a recall of a defective product from all markets where it has been distributed.
Part One, 7.1

3. Complaints and Recalls
Objectives
To identify the key issues in product complaint and recall handling
To understand the specific requirements for organization, procedures and resources
To understand and develop actions to resolve current issues applicable to you
During this review we will look at the very specific requirements placed upon the organization, the procedures that are required and the resources that are needed, in particular, the people involved.
We will also highlight the proper use of information regarding complaints as a tool for overall quality improvement.
We then want you to look at some examples of current practice and to look at them with the advantage of hindsight. We expect that you will identify weaknesses in the way that these examples were handled and thus learn from these experiences.

4. Complaints and Recalls
Complaints Handling Principle
All complaints and other information concerning potentially defective products must be carefully reviewed according to written procedures
Handled positively and carefully reviewed
Must be seen as important work
Managed by a senior staff member
Thorough investigation of the cause is essential
A major source of information and learning
Enable possible production defects to be remedied before they lead to a recall.
Necessary actions taken -- even a recall decision
Quality management is defined in the WHO GMP.
One necessary but not always pleasant aspect of quality management is dealing with complaints.
It is important that complaints are handled in accordance with a written procedure, and that the results of the investigation are used to improve the situation and prevent recalls and complaints in the future.
Complaints must be handled positively and be carefully reviewed.
The handling of complaints must be seen by all areas of the company as being important work, which is the responsibility of a senior staff member.
Thorough investigation of the cause for the complaint is essential before decisions can be taken as to how it should be resolved.
Complaints can be an important source information and learning for the company and enable potentially serious defects to be remedied before they become so serious as to initiate a recall.
Actions must be taken as necessary, possibly even leading to a recall decision.
Part One, 6.1

5. Complaints and Recalls
Complaints Procedure - I
Designated responsible person
May be authorized person
If not, must advise authorized person of results
Sufficient support staff
Access to records
Written procedure describing action to be taken
Acknowledge and respond to complainant within a reasonable period
Record written and verbal comments
First of all a written complaints handling procedure should be available.
The basic requirements for such a procedure are:
A designated person must be appointed with authority to conduct complaints reviews in accordance with the SOPs. The person designated may be the authorized person responsible for quality control. If not, then that QC person must be kept informed of all complaints being investigated. The designated person must have sufficient staff to be able to review all the complaints received in an effective and rapid manner. They must to be able to access all the relevant records concerning the product under discussion.
Required actions are described.
The complaint is acknowledged and a response to the customer is provided.
Written and verbal comments are recorded.
Part One, 6.2 – 6.9

6. Complaints and Recalls
Complaints Procedure - II
Investigate and review
QA review complaint
Appropriate follow up actions
Review of trends
Written complaints handling procedure (continued).
Investigations and reviews are done as a result of a complaint.
Complaints are reviewed on a regular basis by the QC/QA department.
Appropriate follow-up actions are taken. These will be both corrective and preventative and may include reviewing of other batches of the product.
Trends of complaints should be reviewed.
Part One, 6.2 – 6.9

7. Complaints and Recalls
Records of Complaint Investigation
Name of product
Name of active substance (INN) if necessary
Strength, dosage form
Batch number
Name of complainant and nature of complaint
Records, retention sample investigated, other batches reviewed and staff interviewed
Result of investigation: “Justified” or “Not justified”
If “justified”, actions taken to prevent reoccurrence
Sign-off upon completion
Besides the complaints procedure itself, records should be kept to document each incident. The records should be kept for the time specified in the procedure. It must be emphasized that:
1. The investigation process is extremely important.
2. Action taken to prevent reoccurrence is also important.
The records should contain:
Product name,
Active ingredient name INN if necessary, (International Non-proprietary Name)
paper on INN at , no more available 2003), strength, dosage form
Batch number
Name of complainant
Nature of complaint
Records investigated and the details recorded from these documents.
Staff interviewed
Result of investigation — is the complaint justified or not justified?
Actions taken
Sign-off upon completion.
This record can then be used by staff in authority to change the necessary processes within manufacturing or quality assurance to ensure that the cause of the complaint does not arise again.
It may be necessary to consider whether other batches should be checked to see if they too should be subject to detailed investigation.
The investigation should be thorough enough to identify the fundamental cause of the complaint. Only then will the opportunity arise for corrective action to be taken.
Part One, 6.4

8. Complaints and Recalls
Decision from a Complaint Investigation
Complaint justified
Actions to prevent reoccurrence
Ongoing observation of process
Recall product may be required
Complaint not justified
Advise customer of findings
Appropriate marketing response
There are 2 decisions possible when a complaint has been evaluated.
The first is that the complaint is justified. In this case the company should have developed a plan of action that should work towards eliminating the cause of the problems. In addition, there should be a plan for observation of product performance to ensure that the defect does not arise again.
The second possible decision is that the complaint is not justified. For example, when the product has expired for a long time or the product was not kept at the storage conditions stated by the manufacturers.

9. Complaints and Recalls
Other issues
Regular review of trends required
Reoccurring problems
Potential recall or withdrawal
Inform competent authority of serious quality problems
As complaints are investigated and records are built up, then trends may start to become clear. A regular review of complaint records to establish whether there is a trend for a particular product, dosage form, customer, distribution channel or similar should be undertaken. This is where the true value of a good complaints handling procedure shows. It may be that a particular formulation or particular machine is giving rise to complaints. This trend analysis process is an opportunity for continuous improvement.
It may be that a particular customer is engaged in fraudulent behaviour.
The competent authority must be informed of any serious quality problems that are revealed by the complaint investigation
Let us now move on to look at recall procedures.
Part One, 6.8

10. Complaints and Recalls
Classification of Defects
If complaint is justified, then there has been a failure of the quality system
Once defect has been identified, company should be dealing with it in an appropriate way, even recall.
The definition of defects is useful.
The following system has been found in some countries (but it is not a WHO guideline):
Critical defects
Major defects
Other defects
During complaints handling and especially in recall situations it is important to have clear guidance to define the magnitude of the problem. If an investigation into a complaint proves that the complaint is justified, then there has been a failure of the quality system resulting in a defective product becoming available. Once a very serious defect has been identified, it is important to be sure that the company is dealing with the recall in an appropriate way. How quickly should the company be responding to the problem?
The definition of defects therefore is important. We are suggesting here a system of classification that may be helpful. Some countries have different approaches. This system has been in use in a number of countries and found to be useful.
Classification of defects:
Critical defects
Major defects
Other defects.
This is a very difficult area requiring professional judgement in coming to the correct decision. The company should have procedures to call into operation to decide whether a recall is required and how quickly it should be implemented. These procedures should be discussed and agreed with the regulatory authority.

11. Complaints and Recalls
Critical Defects
Those defects which can be life threatening and require the company to take immediate action by all reasonable means, whether in or out of business hours
Examples
Product labelled with incorrect name or incorrect strength
Counterfeit or deliberately tampered-with product
Microbiological contamination of a sterile product
Critical defects are those defects which can be life-threatening and which require the company to take immediate action by all reasonable means, as soon as the defect becomes apparent, whether in or out of business hours. This means that all wholesalers must be alerted and the necessary actions taken to commence recalling the product throughout the distribution chain. This illustrates how important distribution records are, including those of the wholesaler.
Examples of critical defects are:
Product labelled with incorrect name
Counterfeit or deliberately tampered with product
Microbiological contamination of a sterile product.
It can be seen from the examples that it is critical to patient health that immediate action is taken. It may mean using radio and television news broadcasts to conduct the recall.

12. Complaints and Recalls
Major Defects
Those defects which may put the patient at some risk but are not life threatening and will require the batch recall or product withdrawal within a few days
Examples
Any labelling/leaflet misinformation (or lack of information) which represents a significant hazard to the patient
Microbial contamination of non-sterile products with some risk for patients
Non-compliance to specifications (e.g. active ingredient assay)
Major defects are those defects which may put the patient at some risk but which are not life-threatening. They will require the recall of the batch or product withdrawal within a few days. In some countries this is specified as within 48 hours.
Examples of major defects are:
Any labelling/leaflet misinformation (or lack of information) which represents a significant hazard to the patient
Microbial contamination of non-sterile products with some risks
Non-compliance to specifications (e.g. active ingredient assay close to limits but out of specification).
A country may decide on different time-scales for recalls, depending on the appropriate response for the product or defect concerned.

13. Complaints and Recalls
Other Defects
Those defects which present only a minor risk to the patient — batch recall or product withdrawal would normally be initiated within a few days
Examples
Readily visible isolated packaging/closure faults
Contamination which may cause spoilage or dirt and where there is minimal risk to the patient
Other defects are those defects which present only a minor risk to the patient. Any batch recall or product withdrawal would normally be initiated within a few days. In some countries this is specified as within five working days.
Examples of such defect are:
Readily visible isolated packaging/closure faults
Contamination which may cause spoilage or dirt and where there is minimal risk to the patient.
Again this shows a less speedy response to the situation which is in balance with the level of risk for the patient.
Let us summarize at this point:
It is important that complaints as well as potential recall situations result in the proper categorization of the problem. This means that the company will then undertake recalls or complaints handling with the correct level of urgency and not unduly alarm patients or the public.
It is essential that the public retain a high level of confidence in the supply of pharmaceuticals. This confidence, however, must be justified.

14. Complaints and Recalls
Reasons for Recall
Customer complaint
Detection of GMP failure after release
Result from the ongoing stability testing
Request by the national authorities
Result of an inspection
Known counterfeiting or tampering
Adverse reaction reporting
A recall situation can result from information entering a company in various ways:
Customer complaints – these may be so serious as to initiate a recall. An example could be the evidence of a lack of sterility
GMP deviations/results of a failure investigation
The result from the QC stability programme
Request by the regulatory authorities
Result of an inspection
Known counterfeiting or tampering
Adverse drug reaction (ADR) reported, leading to a recall decision (however, an ADR does not automatically lead to a recall).
The company must have a procedure in place that can be operated at all hours to decide how serious a defect is and whether it warrants a recall.

15. Complaints and Recalls
Detection of GMP failure
The photo shows an active tablet in the row of placebos in a bi-phasic oral contraceptive blister pack.
An example of a defect that can lead to a recall

16. Complaints and Recalls
Product Recall Principle
“There should be a system to recall from the market promptly and effectively, products known or suspected to be defective.”
(WHO GMP)
The product recall principle is defined in the WHO GMP.
The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization, and do not place the patient at risk because of inadequate safety, quality or efficacy.
Recalls must be handled positively and carefully reviewed, and actions must be taken as necessary leading to an effective recall of defective product from all markets where it has been distributed.
Part One, 7.1

17. Complaints and Recalls
Definition
Recall
Removal from the market of specified batches of a product
May refer to one batch or all batches of product
To deal with the topic of recalls we should first review some definitions:
Recall is the removal from the market of specified batches or all batches of a product.
Some countries refer to the recall of all batches as “withdrawal”.

18. Complaints and Recalls
Designated Responsible Recall Person
May be authorized person
If not, must advise authorized person of results
Sufficient support staff for urgency of recall
Independent of sales and marketing
Access to records
A designated person must be appointed with authority to conduct recalls in accordance with the procedures. The person designated may be the authorized person responsible for quality control. If not then that QC person must be kept informed of all recalls being conducted. The designated person must have sufficient staff to be able to undertake recalls in an effective and rapid manner with appropriate urgency. The designated person should normally be independent of sales and marketing departments and must have the status and authority to be able to carry out the procedure.
Part One, 7.2, 7.3

19. Complaints and Recalls
SOP for Recall
Established, authorized
Actions to be taken
Regularly checked and updated
Capable of rapid operation to hospital and pharmacy level
Communication concept to national authorities and internationally
The recall procedure must be written, authorized by at least the quality control manager, describe clearly the actions to be taken, and include a requirement that it is regularly checked and updated. It must be capable of rapid start-up, out of business hours if necessary. It should include a communications plan to enable all key personnel, and deputies in case of absence, to be contacted outside normal business hours.
It is essential that all the authorities in all the countries to which the relevant batch or batches have been sent are informed of the recall. This contact may be done at government level (government-to-government) but not necessarily. It is the manufacturer’s responsibility to ensure that the competent authorities in each country are informed. The manufacturer should also inform importers of the product. The importers will probably be the holders of any product registration and will also know where the product has been distributed.
Key contact telephone numbers for all authorities that may need to be contacted should be listed.
Part One, 7.2, 7.3

20. Complaints and Recalls
Distribution Records
Available to designated person for recall purposes
Accurate
Include information on:
Wholesalers
Direct customers
Batch numbers
Quantities
Essential to the success of any recall is the quality of information contained in distribution records. The company is required to maintain in its records, accurate information on the quantity and batch number of any product it sends to wholesalers or its own direct customers. Full details must be kept of the names, addresses and telephone numbers of all customers.
This point raises issues about the records that must be kept by distributors. We have plenty of examples where distributors fail to keep records that can be essential for a product recall. National authorities and manufacturers must continue to exercise pressure to ensure that distributors maintain records at batch number level.
Part One, 7.4, 7.5

21. Complaints and Recalls
Written progress report and reconciliation
Record progress as procedure followed
Reconcile delivered with recovered products
Issue final report
Effectivemess of procedures checked
Test effectiveness from time to time
Secure segregated storage of returned goods
Essential to keep returned goods away from other goods
As the recall progresses in accordance with the written procedure, written progress reports must be kept showing that all stages of the recall procedure have been adhered to.
A reconciliation must also be prepared, showing the total product quantity distributed and the total quantity returned, by batch. It should identify any areas where reconciliation has not been achieved and offer reasons why. A final report must be issued to cover all aspects of the recalls including lessons to be learnt for the future conduct of such recalls.
The effectiveness of SOP must also be regularly checked and procedures modified accordingly in the light of any lessons learned. The effectiveness of the recall procedure can be tested by conducting a dummy recall of a particular product. This involves identifying a batch and then conducting a paper recall only to test out the systems. Such dummy recalls should be undertaken not only in normal office hours but also at the weekend and in the middle of the night.
As goods are returned, they must be stored in secure storage away from all other goods until their fate is decided. Remaining stock of the suspect batch in the warehouse should also be moved into this secure storage. This is very important because there must be no risk of confusion with other batches that are good.
Part One