Goals
When you have completed this unit, you should be able to:
a. Perform an internal, supplier or contractor audit of a complaint system.
b. Know and understand which of the worldwide requirements apply to managing complaints.
c. Use a range of information tools, including the contents of this module and the Internet in support of a complaint audit.
d. Recognize compliance or non-compliance to regulations pertaining to complaints.
Definitions
Adverse Event (AE): The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product.
An undesirable medical condition can be symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the abnormal results of an investigation (e.g. laboratory findings, electrocardiogram). In clinical studies an AE can include an undesirable medical condition occurring at any time, including run-in or wash-out periods, even if no study treatment has been administered.
An adverse event can also be failure of expected pharmacological action.
Complainant: The person or organization who files or notifies the manufacturing company or FDA about a complaint involving a drug product.
Demographics: Information about the complainant which could include age, address, etc.
Product Quality Complaint: All manufacturing and/or packaging-related complaints involving samples and trade products. Customer may be a patient, pharmacist, doctor or other health professional, pharmacist, wholesaler or regulatory authority. A product quality complaint (PQC) may represent a physical defect in the formulated product or its packaging, but does not include customer complaints regarding accounts, billing, transportation or shipping.
Emergency Complaint : A complaint that could represent a serious defect or non- conformity with specifications, methods and current GMP, Good Manufacturing Practice, which may lead to injury or harm to a customer. The complaint has the potential to result in a recall if justified. Investigations of emergency complaints shall be expedited.
Major Quality Incident: An event that could adversely affect the safety, identity, strength, quality or purity of a product such that it could have an actual or potential adverse impact on the health of a patient, and if the product had reached the market, may have had the potential to result in a Product Recall.
New Drug Application (NDA): Application to the US regulatory agency (FDA) to allow the sponsor to market a drug product in the US.
National Drug Code (NDC): Product identifiers for human drugs, which include a unique NDC number (US term).
Product Quality Complaint (PQC) Notification: Any report involving 1. The possible failure of a drug product to meet any of its specifications. 2. Non typical product characteristics: color, odor, embossing, labeling etc. 3. Dissatisfaction with the design of the product or the package or labeling.
Recall: A Major Quality Incident that leads to the removal of the entire affected batch or batches of material from the market, or if clinical trials, from a study.
Explanation of Topic
Introduction
Every effort is made to ensure that drug products that reach the market are safe, pure, effective and of the highest quality. However, a company may receive complaints from a patient, pharmacist or physician about a drug product not meeting its specifications.
The company or site must know how to manage these complaints.
The goal of this training module is to describe how to audit a complaint system using the appropriate GMP standards.
Some of the principles outlined in this module can apply to a quality management system based on ISO 9001 or other similar systems as well as GMPs.
Overview
Although regulatory agencies do not specify a standard complaint handling system, the GMP requirements specify certain actions that shall be included in any system.
Manufacturers shall:
a. Document, review, evaluate and file all complaints.
b. Formally designate a unit or individual to perform these activities.
c. Determine if an investigation is necessary.
d. Record the reason if no investigation is made.
e. Assign responsibility for deciding when not to investigate.
The site should have an approved SOP for managing complaints. It should contain the roles and responsibilities of the quality unit regarding complaints, the method for recording and retaining complaint information and the criteria for determining if the complaint should be investigated. The Quality Unit should review the complaint and the subsequent investigation or document the decision not to perform an investigation.
The complaint system is important because it acts as an indicator for the regulators to determine if the manufacturer’s quality system and corrective actions are adequate. It also provides valuable information to the manufacturer regarding quality and performance of distributed product.
The site should also have a system in place to monitor for trends on a periodic basis and to notify upper management of significant incidents and trends.
Notification of Complaint
A finished drug product manufacturer may be notified of a complaint via telephone, facsimile or written correspondence by sales representatives, pharmacists, patients and physicians. API manufactures may also be notified using the same methods. When the complaint is received, the following information must be recorded, if available:
a. Name of complainant and demographics
b. Batch number
c. Product name/strength (local product code is useful in the US for finished dosage forms)
d. Description of the problem
Each complaint record should have a unique number or code assigned to it. The site should have a method to track the status of the complaint and to trend complaints.
Authorities need to be notified of major quality issues, which are required by EU GMP, for medical devices and for Comparator manufacturers for R&D. All complaint records must be readily available for review by regulatory agencies. If the complaint is recorded into an electronic system, the system must be validated.
Types of Complaints
The company may receive many types of complaints. These complaints can be classified into four categories. For example, 1) Supply & Logistics complaints, 2) Product quality complaints, 3) Adverse drug events and 4) Medication errors.
Supply & Logistics complaints
Examples of supply and logistics complaints are complaints raised due to damage during the transportation or distribution. Also, temperature excursions during a temperature controlled distribution.
Product Quality Complaints (PQC)
Product quality complaints may include product mix-ups (two different types of tablets in one bottle), empty product containers, broken product, product container labeled with one strength but the actual product labeled with a different strength and other quality problems. Emergency complaints are those complaints that include serious defects or
GMP violation that may lead to patient harm. They are considered urgent and assume priority. Examples of Emergency PQCs are:
a. Mislabeled or Product Mix-up. This may include a package that contains two different products or a package where the drug or strength on the label does not agree with the contents of the market pack.
b. Overfilled blister packet.
c. Empty capsules.
d. Inhaled mouthpiece of an inhaler
e. Extraneous material in a sterile product
f. Possible microbial contamination
g. Alleged tampering
h. Questionable authenticity of product
i. Issue of product quality causing a patient death
j. Investigation of Emergency complaints must be expedited.
Adverse Event
If the complaint is categorized as an adverse drug event, the NDA holder must report the event to the FDA. In the EU the Adverse Event will be managed by the local Drug Safety Unit. All information associated with adverse drug events must be kept for 10 years. Adverse events may be related to a product quality issue. The company needs to have a process in place that ensure that potential quality defects are considered, when handling adverse events.
Medication Errors
Medication errors are any preventable events that may cause or lead to inappropriate medication use.
Causes of these errors include:
a. Similar labeling or packaging.
b. Similar sounding drug names.
c. Poor communication.
d. Ambiguities in product names, directions for use, medical abbreviations or writing.
e. Poor procedures or techniques.
f. Patient misuse because of poor understanding of the directions for use of the product.
Investigation
Once the status of a product quality compliant has been established, it should be investigated using the site investigation procedures. If a product defect is discovered or suspected in a batch, consideration should be given to checking other batches in order to determine whether they are also affected. In particular, other batches which may contain reworks of the defective batch should be investigated.
If Quality determines that the complaint does not need a complete investigation, the reason must be documented. The QA unit should approve the investigation reports.
When the investigation is completed, the complainant may receive a letter indicating the results of the investigation. Results of the investigation should be recorded and
“Corrective Actions/Preventive Actions (CAPA), if determined, tracked.”
Retention of Complaint Files
Complaint files should be retained for 10 years.
Contractor responsibilities
Contractors who provide a service or product, have a responsibility to manage internal or external complaints about the products they supplied. Their complaint systems should include:
a. A documented complaint procedure. It should include information on how to manage complaints received from the contract giver and directly from customers.
b. An easily retrievable record of follow-up actions.
c. A system to notify the contract giver of complaints, within 48 hours or immediately, if a Emergency complaint is received.
Available personnel, usually from the Quality unit, responsible for all Quality related complaints.
The should be nominated person or function responsible for reviewing all quality related complaints and filing a report. If an investigation is not justified, the reason should be documented in the report. If a true defect is found that occurred while under control of the contractor or subcontractor, a full investigation should be performed. The investigation should include:
a. Identification and investigation of probable causes
b. Determination of root cause
c. The extent of the problem
d. Corrective and preventive actions based on the root cause
The report should include:
a. A complaint reference number
b. A description of the complaint.
c. Test, specification and result for the test, if complaint investigation requires analytical testing
d. Results of the investigation, if conducted, including probable causes, root cause, extent and CAPAs .
e. An indication if the complaint is justified.
f. Review by Quality
In principle, any sponsor requires contractors to retain their complaint files for 10 years and samples for 2 years unless stated otherwise in the Quality Assurance Agreement.
Training of Complaint Personnel
All personnel who are involved in the complaint process should be appropriately trained.
This training should include investigation techniques for those personnel involved in performing investigations and other training as needed. If the contractor is responsible for receiving all PQCs, then their personnel should have telephone skills and scripted questions.
Complaint Analysis
There should be a procedure that defines the process for tracking trends, the criteria for a trend and the process for investigating a trend. Complaints should be tracked and trends detected. Trending should take product, batch and defect into account.
Recalls
A product shall be recalled from the market when it has become evident that the product may cause unacceptable risk to the health of the consumer or if further sales of the product may otherwise adversely impact the company.
A person should be designated with the responsibility of executing and co-coordinating recall activities. The recall procedures shall be capable of being implemented rapidly at any time. The procedure should be updated regularly and effectiveness of arrangements checked and evaluated on a regular basis.
There should be distribution records with sufficient information to identify the wholesalers and customers with batches and quantities supplied.
The competent authorities should be informed if a manufacturer is considering action following possibly faulty manufacture, product deterioration, detection of counterfeiting or any other serious quality problems with a product.
Summary
Complaints may be received from various sources. They should be categorized, tracked and analyzed for trends. Quality should be responsible for managing complaints and investigating complaints.
Key Parameters of Auditing a Complaint System
Prior to the Audit
a. Determine the site’s main functions, (manufacturing, packaging, etc.).
b. Request an organizational chart.
c. Review the chart for appropriate separation of Quality and Production units.
d. If the contractor is a manufacturing site, review the site’s record for meeting complaint investigations deadlines.
e. For investigations, obtain both sponsor’s reference number and the contractor’s number.
During the Audit
Ensure that Quality has the responsibility for all product quality complaint investigations.
Ensure that the site has an approved SOP used to manage drug quality complaints.
Ensure that the site SOP includes the following topics:
Ø Where the complaint files are maintained.
Ø What system is used to track complaints.
Ø What information the complaint file should include.
Ø Ensure that there is a system in place to report, evaluate and investigate all Adverse Events.
Ensure that the Adverse Event reporting, evaluation and investigation system mandates notification of Quality Assurance for all Adverse Events that may involve a product quality issue.
Ensure that all Adverse Event complaints with potential quality issues are investigated by Quality Assurance in accordance with the approved SOP that is used to manage drug quality complaints.
Ensure that all product quality complaints determined to be not justified include documented evidence to support this decision.
Ensure that received product quality complaints are reviewed on a regular basis to identify any trends according to complaint type, manufactured lot or other defined categories.
If the site categorizes complaints by type, verify that the SOP defines what the types are.
Ensure that employees who receive complaints by phone are trained to gather the necessary information from the caller.
Ensure that each complaint file includes, at minimum, the
Ø Name of complainant and demographics
Ø Batch number
Ø Description of the reported product defect
Ø Product name/strength (local product code)
Ø All correspondences between the complaint source and the company, including letters and summaries of verbal communications
a. Contractor responsibility for sending a letter to the complainant, if appropriate
b. Documented decision to investigate or not investigate.
c. Investigation report, if appropriate.
d. Review some representative complaints from different types.
Ø Verify that the complaints were fully investigated.
Ø Determine if the “root cause” may impact other product lots.
Ø Verify that the conclusions in the investigation were appropriate and valid.
Ø Verify that appropriate corrective actions were taken.
Ensure that systems are in place to define retention of samples and documentation to include specific time periods.
If an electronic system is used to track and trend complaints, ensure that the system has been validated.
Ensure for formulated contractors where the distribution is the responsibility of the contractor or for internal audits that there is local procedure for recall.
Ø Verify that distribution records are in sufficient detail to provided traceability for exported products.
Ø Ensure the effectiveness of the recall procedure has been evaluated.
Ø Verify that the procedure can be instigated promptly and at any time.