Thursday, October 29, 2015

Regulatory expectation and guidance on Pharmaceutical market complaints

On way to manufacturing process end number of steps, tests, check, audits and evaluation is there combined with other quality system elements such as qualification validation and many more. All these impart confidence that the system or process is functioning as intended and assurance of safety, identity strength and quality. The last hurdle is that the product must successfully marketed: to the consumer or healthcare provider.
Still consumer complaints are unavoidable circumstances. It may range from “don’t smell right” to “insect parts are there inside the bottle during packaging” and the list can continue for pages and pages.
Complaints are generally thought of as communications concerning a real or perceived defect in the product or that the product fails to meet the expectations of the consumer. US FDA defines as “all scientific and data gathering activities relating to the detection, assessment, and understanding of adverse events”.

GMP Expectations

1. There is a defined system for collection of complaint-related information.
·         A procedure needs to be in place that describes roles, responsibilities, and the process related to complaints.
·         Everyone, from technicians to senior managers needs to know how to respond in preliminary if they are told about a potential product defect or adverse event.
·         Those charged with collecting information from patients or consumers must collect that information in a timely, consistent way, using some sort of form or on-line checklist.

 [EU 8.2].

 [WHO Annex 3- GMP, 5.1]; [WHO Annex 3- GMP, 5.3].

[Q10, 3.2.2]

2. Investigations are performed to determine the significance of the compliant and the cause(s) and potential affect(s) of the defect or product quality issue
·         Typically there are different levels of responses based on the complaint. For example, a cosmetic defect (the label is not perfectly straight on the primary container) is less serious than a while tablet in a container of green and white capsules.
·         Often firms will have numerical criteria that, if exceeded, prompt a new intensity in investigations. Criteria can be based on the ratio of complaints to units of product, ratio of complaints to dosage forms, or an increase in the rate of complaints. It may be useful to merge data in different ways, for example, looking at the complaint rates for all of the product’s dosage forms or presentations or complaints on all products made at a particular manufacturing site.
·         It is critical that investigations be taken seriously. Investigators always need to consider if the complaint could be an early signal of a more serious issue.
·         There are situations where it is legitimate to not investigate a compliant. A requirement, however, is to document that the complaint was received but provide a legitimate rationale why the compliant was not investigated.

21 CFR 211.192; 21 CFR 211.198(a); 21 CFR 310.305; 21 CFR 514.80; 21 CFR 211.198(b)(3)
C.02.012#3.3; C.02.015#5
EU 8.3; EU8.7; EU6.1
WHO Annex 3-GMP, 5.2; WHO Annex 3- GMP,5.4
Q-10 3.2.2; Q-9 I.4

3. Records are kept of the complaint, investigation process and outcome
·         As with other GMP activity, records provide evidence of an event, action or decision.
·         Complaint files are of high interest ti inspectors and auditors. These files need to be complete and end up to date
·         It is not uncommon for an investigation to remain ”open” for a time, for example while awaiting the return of a complaint sample from a consumer. Firms need to be able to show that they were diligent in trying to obtain information and close the case. Clear records customer contacts can help.

21 CFR 211.137; 21 CFR 211.198(b); 21 CFR 211.192; 21 CFR 211.180(c); 21 CFR 211.198(b)(1)-(2)(3)
EU 8.3; EU 8.5
WHO Annex 3- GMP,5.5; WHO Annex3- GMP 5.8
ICH Q9; ICH Q10 3.2.2
4. The investigation extends to other lots/products that could possibly be affected.
·         A frequent question from inspectors and auditors is , “How do you know that the problem wasn’t present in other lots of the same product or in similar products?”
·         Regulatory authorities want to be sure that all potentially affected products are included in the investigation
·         Often, in the initial stages of the investigation, you will be including and excluding lots and products into the scope of the investigation, that is things may be affected by the unwanted event.
·         Understanding the root, contributing, and direct causes- the chain of events that were involved in the problem- is important. The more you know , the higher your confidence can be that you identified the lots and products that were affected.

21 CFR 211.192
EU 8.4
WHO Annex 3 –GMP, 5.6

5. Solutions are taken to minimize risks to consumers
·         Risk assessment tools can be very useful to describe the potential harm to the patient and also the likelihood that it could occur. The assessment should be done in a formal way that is with a defined scope and risk question. Risk questions could include,  “ What is the risk that the patient may exposed to a dosage form that has this effect”; “What is the risk to the patient if they use a product with this defect?”; “What is the risk to all patients using this product if X number of lots are recalled?”
·         Understanding the product, how it is used, the patient population, and the defect is critical.
·         Often, the only remedy is to recall the product from the market.
21 CFR 211.150(b)
  C.0.012 Rationale; C.02.012#1,1.1-1.11
 EU 8.2; EU 8.11; EU 8.9
WHO Annex 3-GMP, 5.7; WHO Annex 3-GMP 6.8 
 6. Data from complaints and complaint information are monitored, communicated and used for improvements
·         An important component of risk management is risk communication. If there are potential risks to patients, it is critical that the drug manufacturer’s senior management team is fully aware of the issue.
·         Regulatory agencies often have additional requirements (i.e., Beyond GMP) that they notified problems. [Example: US FDA’s Field Alert Report for drugs and Biological Product Deviation Report for biological products]
·         Complaint data is important to both national authorities and the manufacturer. Inspectors and auditors will want to know if and how you are using it to gain new insights about potential product issues.
·         Some firms are “Mashing-up” complaints data with other tools, for example plotting complaint data on map to see if there are geographical trends, perhaps related to temperature conditions or distribution practices.

21 CFR 211.180(e),e(2), (f) ; 21 CFR 211.198,198(a); 21 CFR 211.192; 21 CFR 211.204; 21 CFR 208; 21 CFR 310.305; 21 CFR 514.80
C.02.012#1.1; C.02.012#1.10; C.02.012#1.11; C.02.11#51, 51.6
EU 8.8; EU 8.12; EU 1.4 and 1.4 (vii)
WHO Annex 3- GMP, 5.2; WHO Annex 3- GMP, 6.5; WHO Annex – GMP, 1.3
Q10, 4.2.4

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