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.
US
[211.198]
EU
[EU 8.2].
WHO
[WHO Annex 3- GMP, 5.1]; [WHO Annex 3- GMP,
5.3].
ICH
[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.
US
21 CFR 211.192; 21 CFR 211.198(a); 21 CFR 310.305; 21 CFR
514.80; 21 CFR 211.198(b)(3)
CA
C.02.012#3.3; C.02.015#5
EU
EU 8.3; EU8.7; EU6.1
WHO
WHO Annex 3-GMP, 5.2; WHO Annex
3- GMP,5.4
ICH
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.
US
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)
CA
C02.024#4.1
EU
EU 8.3; EU 8.5
WHO
WHO Annex 3- GMP,5.5; WHO
Annex3- GMP 5.8
ICH
ICH Q9; ICH Q10 3.2.2
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.
US
21 CFR 211.192
CA
C.02.015#5
EU
EU 8.4
WHO
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.
US
21 CFR 211.150(b)
CA
C.0.012 Rationale;
C.02.012#1,1.1-1.11
EU
EU 8.2; EU 8.11; EU 8.9
WHO
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
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.
US
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
CA
C.02.012#1.1; C.02.012#1.10; C.02.012#1.11;
C.02.11#51, 51.6
EU
EU 8.8; EU 8.12; EU 1.4 and 1.4 (vii)
WHO
WHO Annex 3- GMP, 5.2; WHO Annex 3- GMP, 6.5; WHO
Annex – GMP, 1.3
ICH
Q10, 4.2.4
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