QUALITY MANAGEMENT OF COMPLAINTS AND RECALL OF PHARMACEUTICALS AS PER GLOBAL GMPs

About Authors:
Nilesh Sovasia, Prof.Sanjeev Thacker, Tarun Patel
Seth G.L.Bihani S.D.College Of Technical Education,
Institute Of Pharmaceutical Science & Drug Research,
Sri Ganganagar,
Rajasthan, India

ABSTRACT
Despite a company's best efforts to design, manufacture and sell safe and reliable products, the possibility still exists that dangerously defective products may reach the customers. These products may cause accidents,leading to adverse verdicts in product liability litigations.There for Quality management of Complaints and Product recalls are essential to ensure the safety of customer.

Reference Id: PHARMATUTOR-ART-1258

1 INTRODUCTION:

1.1 COMPLAINTS
- Guidelines recommend that a person should be designated for handling complaints and to decide the measure to be taken.
- Supporting staff should be provided to him.
- Guidelines also recommend SOP for complaint handling. Person responsible for quality control should normally be involved in the study.⁸

IMPORTANT IN THIS ARTICLE:

* COMPLAINTS AND RECALL OF PHARMACEUTICAL AS PER INDIAN GMPs

* COMPLAINTS AND RECALL OF PHARMACEUTICAL AS PER USFDA

* COMPLAINTS AND RECALL OF PHARMACEUTICAL AS PER THERAPEUTIC GOODS ADMINISTRATION (TGA)

1.1.1 Objective: Objective of the guidelines under this element is that a defective product is immediately recalled ,matter is investigated & remedial measures are taken.
All verbal or written complaints or reports received by the manufacturer are complaints.
Complaints may be of three types:
- Quality complaints
- Adverse Reaction complaints
- Other Medically Related complaints

Quality complaints usually originate at consumer level and concern with physical, chemical and biological properties or condition of labeling and/or packaging of the product. Adverse drug reaction (ADR) may be allergic reactions or any other untoward reaction or fatal reaction. Other medically related complaints include such as lack of efficacy or clinical response.⁸

1.1.2 Handling Of Complaints:
A written record should be maintained for all complaints received.The quality complaints should be forwarded to the quality control department of the manufacturing unit.Reports of adverse reaction should be handled by a member of this committee.Usually the Medical Advisor of the company is the competent person to handle ADR.
Upon receipt of complaints,quality control unit should review all the incoming information.If a sample has been received along with complaint,the sample should be examined and tested.If need be,retained reference sample should be examined,tested/analyzed.All the relating data and documentation should be reviewed.When investigation is complete,conclusion on the cause and action should be reported to the management.If it has been found,out that the complaint is result of defective production then a copy of completed report should be sent to the production department to take corrective action.
If formulation or process of manufacture is required to be amended.Master formulation record should be amended accordingly and should be authorized.If it is found,on investigation,that the complaint is result of defective, ingredients or packaging materials.a copy of report should be sent to the purchasing unit for corrective action.It may also be examined whether any other batch(es) should be recalled.
A mention has been made under the WHO GMP text that special attention should be given to establish whether complaint was caused because of counterfeiting.
It is the responsibility of the In-charge,Quality control to see that each complaint is recorded, evaluated and reported to the management.Records of complaints should include the following information:

(Ι) Contents Of complaint

These should include

* Name,dosage form,package form,batch no.;

* Date and the place of occurrence of complaint;

* Cause of complaint;

* Name & address of complaintin detail.

(ΙΙ) Results of investigations

These should include:

* Result of investigation regarding market place, circulation condition and condition in which the defect was observed;

* Result of investigation of retained reference sample;

* Result of investigation of analysis and testing records, production and storage records;

* Result of investigation should be referenced to the BPR of the product

(ΙΙΙ) Evaluation

(ΙV) Follow up measures

Follow up measure include:

* Reply to the complainant

* Remedial action so that complaints of this type do not recur and or drug recall

* Competent authorities should be informed of any serious defect or problem.⁸

1.2 RECALL
Despite a company's best efforts to design, manufacture and sell safe and reliable products, the possibility still exists that dangerously defective products may reach the customers. These products may cause accidents,leading to adverse verdicts in product liability litigations. Product recalls are certainly expensive, but attempting them without adequate planning can be much more costly.¹⁴

1.2.1 Objetives:
Once the quality of a batch of the product is primafacie doudtful, it is intended that the product is no more consume and is recall for more investigation and decision.
Complaints and product recall are inter related. in most of the cases of complaints, it may be necessary to recall the products. The purpose of the drug recall is to ensure that the drug is effectively and rapidly withdrawn from the market.

1.2.2 Primary Reasons for a Product Recall
A product recall may be:

* Mandated by a regulatory agency as a result of a violation of a government act, standard or other mandatory regulations, such as toy recalls ordered by the Consumer Product Safety Commission.

* Required to avoid potentially serious additional product liability claims or losses.

* Indicated by the analysis of field monitoring reports and feedback that may point to product tampering, nearmiss incidents, accidents or consumer complaints.

* Suggested by new information based on additional research and product testing.

* Needed when characteristics of the product don't measure up to the advertised claims for safety or effectiveness.

As indicated earlier, some product recalls come under federal regulations. For example, the Consumer Product Safety Act (CPSA), Section 15(b) requires that the Consumer Product Safety Commission be notified within 24 hours of the time it is discovered that a consumer product presents a "substantial" hazard. The Food, Drug & Cosmetics Act administered by the Food and Drug Administration (FDA) classifies recalls into three classes:

* Class I: Involves a life-threatening situation. FDA will mandate a consumer recall, a 100 percent effectiveness check and appropriate public announcements.

* Class II: Involves a potentially hazardous situation, but not a life-threatening condition. FDA will usually mandate a recall to the retail outlets and will not require a 100 percent effectiveness check. A press release may be required, depending on the reasons for the recall.

* Class III: Involves no serious haz-ard. It is usually limited to the wholesale level with no effectiveness checks and no press release requirements.

Depending on the seriousness of the situation, the company may have a choice whether to repair or modify the product (no cost or reduced cost retrofit by customer or the company), refund the purchase price, or initiate a total or partial recall (voluntary or mandatory).

In case of a mandatory recall, the company can contest the notice of recall from a regulatory agency. This should be done only after a thorough review of the situation and with appropriate legal counsel.¹⁴

1.2.3 The Goals of a Product Recall
A product recall is intended to protect the health of the public. As a meat processor, you are trying to meet two goals during a product recall. The first goal is regain control of all hazardous products. If this goal is met, the recall is successful. In some cases, all products can be successfully recalled without the public ever knowing that a recall occurred. Many times, though, even the best planning and record keeping, will not enable you to retrieve all product. In such situations, your second goal should be to inform the public about the hazardous product so that they do not eat it. This secondary goal is most important for retail operations. For wholesale processors, informing the public becomes more important as time goes by and product gets farther into distribution.⁹

1.2.4 Product Recall procedure:
The following steps may be taken while executing the drug recall.These Steps may be included in the written procedure for the drug recall.

· Determine the degree of recall.There are three degree of recall

* Degree Ι:Product with high health risk requiring freezing of stock within 24 hours.

* Degree ΙΙ:Product with minor health risk or substandard requiring freezing of the stock within 72 hours.

* Degree ΙΙΙ:Product with other reason for recall

Disseminate recall instructions using telephone, telegram, postage, mass media, radio TV, depending upon the seriousness of the defect.
-Freeze the internal stock of the product.
-Establish the record and report of recalled product.
-Organize the return of the recalled product.

Information/data given below will be useful to perform the recall of drug product:

* Reason for recall

* Details of what is covered by recall and what is not covered ,for example individual batch or dosage form-the nature of risk, if some patents are at risk,advice has to how they should be managed

* The cause of defects, if known

* Organisation of return of the defective product

* Address, telephone number of persons to be contacted at national, provincial levels

* Addresses, telephone, telex number of distributors, wholesalers and hospitals etc…⁸

1.2.5 Recall Triggers

There are a number of different ways in which a recall situation can be triggered.

· Customer complaints: if a complaint reveals evidence of a critical or major defect,it can lead to a recall. This could also happen if there were a significant number of complaints about one particular product or process.

· GMP deviations or results of a failure investigation: if a company carries out an investigation as a result of problems during processing of a particular batch, it might lead to the discovery of problems with earlier batches that were not detect prior to release.

· Result from the QC stability programme: for example, if the stability studies showed unusual deterioration of activity within the normal shelf life of the batch.

· Information from the regulatory authorities: on occasion, complaints are sent to the authorities rather than directly to the company; in addition, random samples are taken from time to time from various parts of the distribution chain.

· Result of an inspection: if a regulatory inspection uncovers a problem with the manufacturing process that casts doubt on the validity of the release for a given product.

· Known counterfeiting or tampering with the product: if it is known that counterfeit product has been released on the marketplace, it may be necessary to withdraw all the product until it can be established which is the genuine product.

· Adverse drug reaction (ADR): ADRs, reported as part of a pharmacovigilance programme, can but will not automatically lead to a recall situation.⁷

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2. COMPLAINTS AND RECALL OF PHARMACEUTICAL AS PER INDIAN GMPs

2.1 Complaints and Adverse Reactions.
2.1.1 All complaints thereof concerning product quality shall be carefully reviewed and recorded according to written procedures. Each complaint shall be investigated /evaluated by the designated personnel of the company and records of investigation and remedial action taken thereof shall be maintained.
2.1.2 Reports of serious adverse drug reactions resulting from the use of a drug along with comments and documents shall be forthwith reported to the concerned licensing authority.
2.1.3 There shall be written procedure describing the action to be taken, recall tobe made of the defective product.

2.2 Product Recalls.-

2.2.1 A prompt and effective product recall system of defective products shall be devised for timely information of all concerned stockists, wholesalers, suppliers, upto the retail level within the shortest period. The licensee may make use of both print and electronic media in this regard.

2.2.2 There shall be an established written procedure in the form of Standard Operating Procedure for effective recall of products distributed by the licensee. Recall operations shall be capable of being initiated promptly so as to effectively reach at the level of each distribution channel.

2.2.3 The distribution records shall be readily made available to the persons designated for recalls.

2.2.4 The designated person shall record a final report issued, including reconciliation between the delivered and the recovered quantities of the products.

2.2.5 The effectiveness of the arrangements for recalls shall be evaluated from time to time.

2.2.6 The recalled products shall be stored separately in a secured segregated area pending final decision on them.⁸

3.COMPLAINTS AND RECALL OF PHARMACEUTICAL AS PER WHO GUIDELINES AND PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME (PICS) AND NEW ZEALAND FOOD SAFETY AUTHORITY AND EUROPEAN COMMISSION (MHRA)

3.1 Complaints
3.1.1 Principle. All complaints and other information concerning potentially defective products should be carefully reviewed according to written procedures and the corrective action should be taken.

3.1.2 A person responsible for handling the complaints and deciding the measures to be taken should be designated, together with sufficient supporting staff to assist him or her. If this person is different from the authorized person, the latter should be made aware of any complaint, investigation or recall.

3.1.3 There should be written procedures describing the action to be taken, including the need to consider a recall, in the case of a complaint concerning a possible product defect.

3.1.4 Special attention should be given to establishing whether a complaint was caused because of counterfeiting.

3.1.5 Any complaint concerning a product defect should be recorded with all the original details and thoroughly investigated. The person responsible for quality control should normally be involved in the review of such investigations.

3.1.6 If a product defect is discovered or suspected in a batch, consideration should be given to whether other batches should be checked in order to determine whether they are also affected. In particular,other batches that may contain reprocessed product from the defective batch should be investigated.

3.1.7 Where necessary, appropriate follow-up action, possibly including product recall, should be taken after investigation and evaluation of the complaint.

3.1.8 All decisions made and measures taken as a result of a complaint should be recorded and referenced to the corresponding batch records.

3.1.9 Complaints records should be regularly reviewed for any indication of specific or recurring problems that require attention and might justify the recall of marketed products.

3.1.10 The competent authorities should be informed if a manufacturer is considering action following possibly faulty manufacture, product deterioration, counterfeiting or any other serious quality problems with a product.

3.2 Product recalls

3.2.1 Principle. There should be a system to recall from the market, promptly and effectively, products known or suspected to be defective.

3.2.2 The authorized person should be responsible for the execution and coordination of recalls. He/she should have sufficient staff to handle all aspects of the recalls with the appropriate degree of urgency.

3.2.3 There should be established written procedures, which are regularly reviewed and updated, for the organization of any recall activity.

Recall operations should be capable of being initiated promptly down to the required level in the distribution chain.

3.2.4 An instruction should be included in the written procedures to store recalled products in a secure segregated area while their fate is decided.

3.2.5 All competent authorities of all countries to which a given product has been distributed should be promptly informed of any intention to recall the product because it is, or is suspected of being, defective.

3.2.6 The distribution records should be readily available to the authorized person, and they should contain sufficient information on wholesalers and directly supplied customers (including, for exported products, those who have received samples for clinical tests and medical samples) to permit an effective recall.

3.2.7 The progress of the recall process should be monitored and recorded. Records should include the disposition of the product. A final report should be issued, including a reconciliation between the deliveredand recovered quantities of the products.

3.2.8 The effectiveness of the arrangements for recalls should be tested and evaluated from time to time.^1,2,12,15

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4. COMPLAINTS AND RECALL OF PHARMACEUTICAL AS PER USFDA

4.1 RECALL ENTERPRISE SYSTEM
The Recall Enterprise System (RES) is an electronic data system used by FDA recall personnel to submit, update, classify, and terminate recalls.
Basic recall guidance and procedures remain essentially unchanged from those used prior to the initiation of RES. RES User Guides contain the detailed information needed for the use of RES. Electronic copies of the guides have been provided to field and center recall coordinators. The RES application currently has some help information available for each screen. Additional detailed guidance will be developed and added to the application.

The RES increases efficiency in processing recall information by:
1.      allowing field coordinators to input recall information via an on-line, Intranet system;
2.      combining five separate documents for a recall event into a single system, allowing users to build a record of the entire recall by entering information as it becomes available thus reducing preparation time and providing consistency throughout the agency;
3.      reducing duplication of efforts between the Field Offices, OE, the centers, and Office of Public Affairs;
4.      increasing communication of recall information between the field, headquarters, and the appropriate center(s) offices;
5. providing a central, searchable database to more efficiently track information      and generate and disseminate reports of recall activities
6.using a uniform Health Hazard Evaluation (HHE) form or a form equivalent to the HHE form to promote consistency in evaluating potential health hazards and/or risks agency-wide while supporting wider use of electronic precedent health hazard assessment files to expedite recall classifications; and,
7.Providing the public with “real-time” information about the FDA recall process

The information entered in RES is gathered from various sources, including the field, the firm, ORA and the CRU. ORA is the business owner for the RES database.¹¹

4.2 INITIATION OF A RECALL
A manufacturer or distributor may voluntarily initiate a recall at any time. Under certain urgent situations, FDA may request that a manufacturer or distributor recall a product. Under certain authorities, FDA may mandate a recall.¹¹

4.2.1 Firm Initiated Recalls
if a recall is firm initiated, the agency will obtain and review the information provided by the recalling firm under 21 CFR 7.46(a). This includes reviewing and suggesting changes to the firm’s recall strategy, to its recall communication, and to its press release (if necessary). The agency will conduct a health hazard evaluation (HHE), (precedent HHEs or written classification policies may be used), classify the recall, and advise the firm in writing of the assigned recall classification. FDA will also assign audit checks as appropriate, monitor the effectiveness of the recall communication, correction or removal, verify appropriate product disposition, and terminate the recall.¹¹

4.2.2 FDA Requested Recall
FDA requested recalls are most often classified as Class I. Generally, before FDA formally requests recall action, the agency will have evidence capable of supporting legal action, i.e. seizure. Exceptions include situations where there exists a real or potential danger to health, or in emergency circumstances such as outbreak of disease involving epidemiological findings. The completion of either a firm initiated or FDA requested recall does not preclude FDA from taking further regulatory action against a responsible firm.¹¹

4.2.3 FDA Ordered Recalls
Various sections of the law authorize FDA to order a firm to recall a product. If the recall is FDA ordered, the agency will issue a written order to the firm to recall. This order should state the violation and the section of the Act or regulations that gives FDA the authority to order the recall. It should clearly describe the product, lots, serial numbers, etc. to be recalled and provide a time frame for the firm's reply.¹¹

4.3 RECALL CLASSIFICATION AND STRATEGY
The Center Recall Unit (CRU):
1.      initiates a health hazard evaluation;
2.      finalizes a recall strategy;
3.      classifies the recall and, for Class I recalls, prepares an Action Memorandum for Center Director or his/her designee concurrence before forwarding it to OE/DCMO and the ACRA; and,
4. updates RES with classification, audit strategy, and any recommendations, and posts the             information to the Internet.¹¹

4.3.1 Health Hazard Evaluation
The agency will conduct or obtain health hazard evaluations (HHE) for each recall scenario. Precedent HHEs will be used where the product is identical or similar with basically the same defect or violation as a recall action previously classified. Precedent HHEs will be re-evaluated and updated periodically.
Upon receipt of each recall recommendation or other information, from any source, which indicates a recall may be necessary, the CRU determines whether an up-to-date health hazard precedent exists covering the situation. If not, it forwards the appropriate information to the Center Health Hazard Evaluation Committee for review. Additional information received during the progress of a recall should also be forwarded to the committee for timely health hazard reevaluation.
The Health Hazard Evaluation Committee must promptly reevaluate the initial health hazard when additional data regarding injury, illness, medical, or scientific findings is received by the center. Where additional data are being received on a continuing basis, the committee is to routinely meet and reevaluate the health hazard at least biweekly.¹¹

4.3.2 Classification Process
For ongoing recalls, the CRU will normally classify recalls within two days after receiving the health hazard evaluation or confirming the classification through precedent review. They will add classification information to the recall document in RES and transmit the classification electronically to the monitoring district and OE/DCMO.
The CRU will then review, correct, edit or add information necessary for the FDA Recall web page and then submit it for updating.
The ACRA has approval authority for all Class I recalls. However, the ACRA has delegated approval of certain Class I recalls to center directors. This has been done to streamline the recall classification process in the center, expedite the handling of the recall by industry and FDA district offices, and in certain situations, to have it universally understood that these recalls represent otentially serious to life-threatening health hazards. The center director may further delegate within the center compliance office the authority for review and classification of recall actions previously established by the ACRA as Class I. Specifically, for CFSAN, this includes precedent situations such as Listeria monocytogenes, salmonella species, various allergens, and pathogens in ready to eat foods.
The CRU will prepare the recall Action Memorandum in all situations requiring ACRA or center director approval. Attach copies of the following: health hazard evaluation, the firm's or FDA's recommended recall strategy, FDA audit program, and the initial recall recommendation. As appropriate, attach product analytical results, medical records, evaluations, etc., which are pertinent to the hazard evaluation and subsequent recall classification. In the case of FDA requested or ordered recalls, propose a course of action in the memorandum to be taken if the firm elects not to recall. Submit the Action Memorandum to the center’s compliance director for review and concurrence in all Class I recall recommendations prior to submission to the center director. The center director approves all Action Memoranda required to be submitted to the ACRA for concurrence with Class I recommendations and FDA requested recalls.
OE/DCMO may review the Action Memo and discuss it with the CRU before submitting it to the ACRA. When the center and ORA/OE disagree on aspects of a recall or when the ACRA believes the health hazard evaluation or recall classification warrants additional medical review, OE/DCMO may request that an ad hoc committee be formed to review and recommend changes to the health hazard evaluation or recall classification.
NOTE: FDA will normally evaluate, prepare, and approve necessary action memorandum on infant formula manufacturers' notifications submitted in compliance with section 412 of the Act within five calendar days.
The CRU may classify Class II and III recalls without management review. However, unusual and/or potentially high profile recall issues should be brought to center management’s attention.¹¹

4.3.3 Classification Notification And Routing
When the ACRA approves the Recall Action Memorandum, the center and the district office is informed by OE/DCMO (via phone) of the ACRA's decision. The classification letter when signed by the ACRA will be mailed to the firm by DCMO. Distribution copies of the final approved documents will be sent to the center and the district office as soon as they are available. The original action memorandum with appropriate signatures and comments will become a permanent part of the center's recall file.¹¹

4.3.4 Recall Strategy
Each recall is unique and requires its own recall strategy. The CRU will review the firm's recall strategy for voluntary recalls and will develop a strategy for FDA requested recalls. The recall strategy includes the type notification and depth of the recall. It also contains the depth and level of audit checks and the need for public warning. Recall strategies are based on the individual recall circumstances and are not necessarily dependent on the recall classification.
For FDA requested recalls, the center’s compliance director ensures that the regulatory strategy cited in the recall recommendation and the action memorandum is supportable in the event the firm refuses the ACRA’s request to recall or fails to complete the recall effectively or in a timely manner.
If the agency approves an industry Corrective Action Program (CAP) for a radiation emitting electronic product, the agency will notify the responsible firm that its CAP is classified as a recall and will stress the need for prompt corrective action. These corrective actions are taken to correct either product defects or non-compliance with standards.¹¹

1 Elements of a Recall Strategy
A recall strategy should include a statement on and the reasons for recommending the desired option under each of the following elements:
a. Depth of recall. The recall may extend to the consumer or user level, the retail level, or the wholesale level.
b. Public warning. In urgent situations, consideration should be given to the need for a press release that could be nationwide or to affected geographical areas only. In some cases, special communication with specific segments of the population (e.g., physicians, pharmacists, veterinarians, and hospitals) may be appropriate. When the CRU believes that there is a need for a FDA press release or a Talk Paper, in addition to the FDA Recalls web page posting, they should coordinate with the appropriate press officer on OPA’s Media Relations Staff (HFI-20). Similar Information may also be posted on Med Watch.
c. Effectiveness Check Level. This includes the method(s) to be used for and depth of recall effectiveness checks.

The recall strategy should consider the disposition of recalled products (e.g., carcinogenic products) when normal disposition means, landfill, crushing, denaturing, etc., are inadequate.

2 Recall Strategy Review or Development In reviewing or developing a recall strategy, the CRU should take into account the health hazard evaluation, type or use of the product, the ease in identifying the product, the degree to which the product's deficiency is obvious to the consumer or user, the amount of product remaining unused in the marketplace, distribution pattern, validated salvage or rework plan, and the continued availability of essential products.¹¹

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5.COMPLAINTS AND RECALL OF PHARMACEUTICAL AS PER THERAPEUTIC GOODS ADMINISTRATION (TGA)
The Uniform Recall Procedure for Therapeutic Goods (the 'Procedure') is the result of an agreement between the therapeutic goods industry and Commonwealth and State/Territory health authorities. Its purpose is to define the action to be taken by health authorities and sponsors when therapeutic goods for use in humans, for reasons relating to their quality, safety or efficacy, are to be removed from supply or use, or subject to corrective action.
Each sponsor of therapeutic goods should advise the Australian Recall Co-ordinator of the names, after-hours addresses and telephone numbers of two persons in the sponsor company who have authority to discuss and, if necessary, implement a recall.
When the need for a recall has been established, the sponsor of the affected goods assumes the responsibility for recovery of the goods, or corrective action, while the Australian Recall Co-ordinator assists by advising the sponsor of the procedures, by notifying agreed third parties and by monitoring the overall action.

The Procedure is recognised by the Product Safety Policy Unit, Australian Competition and Consumer Commission (ACCC) as being appropriate to the specialised requirements for the recall of therapeutic goods. Its use is therefore, in effect, obligatory in relation to safety-related recalls of therapeutic goods.

Where recall is refused, or is not carried out satisfactorily, the Minister may order a mandatory recall. Failure to comply with such an order may result in substantial fines.¹⁰

5.1 Definitions
Recall is an action taken to resolve a problem with therapeutic goods for which there are established deficiencies in quality, efficacy or safety.

Two distinct types of recall are included in this Procedure:
a. permanent removal of deficient goods from the market or from use; and
b. correction, which may involve temporary removal from the market or from use.

These are designated Recall and Recall for Product Correction respectively.
Recall - means the permanent removal of therapeutic goods from supply or use for reasons relating to deficiencies in the quality, safety or efficacy of the goods.

It includes:

* requests to pharmacists, hospitals, pathology laboratories, fractionators, operating and research facilities, biomedical engineers or others to check and return goods found to be defective; and

* removal from supply or use of goods with inherent design or manufacturing defects.

It does not include:

* removal of time-expired goods; and

* removal of appropriate numbers of goods to determine whether there are deficiencies relating to quality, safety or efficacy.¹⁰

Recall for Product Correction - means the repair, modification, adjustment or re-labelling of therapeutic goods for reasons relating to deficiencies in the quality, safety or efficacy of the goods. The corrective action may take place at the user's or the sponsor's premises or any other agreed location.

It includes:

* corrections involving a product’s expiry date; and

* changes to any accessories, operating instructions or software, correcting deficiencies relating to the quality, safety or efficacy of the goods or outputs.

* Field corrections

It does not include:

* removal of individual goods for repair in the event of malfunction or failure as a result of normal wear and tear or for appropriate maintenance or due to lack of good maintenance; and

* removal of individual goods for modification due to technical improvements other than when these improvements overcome an inherent design or manufacturing defect.¹⁰

5.2 Stages of recall procedure
The objective of the Uniform Recall Procedure for Therapeutic Goods is to facilitate recall when a deficiency in therapeutic goods is established and warrants such action.

The Procedure is divided into seven stages, which are set out below, with a reference to the Section in which detailed information is given

Recall Stage		See Section
1	Notification to the Coordinator Crisis management This should be to the Australian Recall Co-ordinator.	C
2	Information Required to Assess Recall Information on product, problem and distribution is required, (see also - The Medicine Problem Report Form, Medical Device Incident Report Form and Human Blood and Tissues Report Form at Appendices I, II and III).	E
3	Assessment of Recall Liaison between sponsor and Australian Recall Co-ordinator to assess classification, level and strategy of recall.	F
4	Recall Letters and advertisements are submitted by the sponsor to the Australian Recall Co-ordinator for approval before despatch.	G
5	Notification to the Federal Minister Responsible for Consumer Affairs Where the recall is safety-related, there is a legal requirement to notify the *Minister via the Product Safety Policy Unit, Australian Competition and Consumer Commission (ACCC)*.	M
6	Progress of Recall and Report Progress reports are forwarded to the Australian Recall Co-ordinator.	H
7	Follow-up Action The effectiveness of the recall is monitored by the Australian Recall Co-ordinator.	K

5.3 Notification/initiation of recall
Recall might be initiated as a result of reports referred to sponsors or co-ordinators from a variety of sources. The reports may be referred by manufacturers, wholesalers, retail and hospital pharmacists, blood banks, fractionators, pathology departments, tissue banks, operating and research facilities, medical practitioners, biomedical engineers, dentists and patients. Recall might also be initiated as a result of analysis and testing of samples of therapeutic goods by sponsors and by the Commonwealth and State/Territory testing laboratories; and as a result of advice received from the Australian Drug Evaluation Committee, the Adverse Drug Reaction Advisory Committee, the Medical Device Evaluation Committee, the Medicines Evaluation Committee, the Complementary Medicines Evaluation Committee and other bodies. Recall of goods manufactured overseas might be initiated by reports appearing in FDA Enforcement Reports and similar publications of health authorities, or from information received directly from such authorities.
Certain information is essential to permit the assessment of the validity of the report of a problem with therapeutic goods, the potential danger to consumers and the action appropriate to the situation.
Serious problems which may lead to recall should be reported directly to the TGA for investigation. Reports made to a State/Territory Recall Co-ordinator, with any opinions on toxicological or therapeutic hazards and the action proposed by the State/Territory should be referred on to the appropriate officers in the TGA. These are the Australian Recall Co-ordinator (medicine problems) and the Manager, Medical Device Incident Reporting Scheme (device problems).
When the need for recall has been established, additional information is required so that an appropriate recall strategy may be devised.¹⁰

Special Note on Radiopharmaceuticals
A special procedure is used for the initiation of recalls for short-lived radiopharmaceuticals, some of which are distributed before all quality control tests are completed. If such a product is shown not to comply with relevant specifications or if, for some other reason, doubt exists as to the product's quality, safety or efficacy, the head of the distributing organisation's radioactive products section or a nominated deputy must take immediate action to prevent its use by informing users accordingly by telephone or facsimile and seeking acknowledgment. The Australian Recall Co-ordinator should also be advised immediately.
In the case of telephone advice to users of radiopharmaceuticals or when incomplete facsimile advice has been given initially, a facsimile or medicine recall letter giving full details in accordance with Section G, as appropriate, is to be sent to users. The text of the communication is to be approved by the Australian Recall Co-ordinator.¹⁰

5.4 Crisis management (including tampering of therapeutic goods)
A crisis is an unprecedented set of circumstances which represents an immediate and significant threat to a company, consumers of its products, employees and/or the community. This may include threats to the product, damage to the public image/reputation of a company or its products or a disruption of the production process. Such events are likely to attract media interest.

“Crisis Management Guidelines” have been developed by the Australian Self Medication Industry in consultation with Medicines Australia, the Complementary Healthcare Council of Australia, the Medical Industry Association of Australia, Consumers’ Health Forum, the Therapeutic Goods Administration, State and Territory Health Departments and Police Departments.
Companies are urged to implement these Guidelines as quickly as possible and to ensure that the appropriate personnel are trained in their operation.¹⁰

5.4.1 Tampering of Therapeutic Goods - All threats of criminal tampering with a company’s products should be considered to be genuine and therefore serious and be immediately reported to the Australian Recall Co-ordinator. The Australian Recall Co-ordinator will convene a Crisis Reference Group (CRG) which will co-ordinate the activities required to resolve the crisis.
For any tampering crisis, the CRG will comprise:
The Australian Recall Co-ordinator nominated in the Uniform Recall Procedure for Therapeutic Goods;
The State or Territory Health Department Recall Co-ordinator nominated in the Uniform Recall Procedure for Therapeutic Goods;
The appropriate State Police officers nominated for this purpose by the Police Ministerial Council; and the senior personnel of the company concerned.¹⁰

5.4.2 Information required for assessment of recall
Prior to notification of a recall situation to the Australian Recall Co-ordinator or the State/Territory co-ordinator, the sponsor should gather all the relevant information on problem reports, the product and its distribution, and action proposed. Similarly, the Co-ordinator should make available to the sponsor all relevant information on hand. Some of the information (for example, batch size, distribution chains and quantities distributed) will only be known to the sponsor and it is important for it to be readily accessible for use in recall situations.¹⁰

The type of information required may include:

5.4.3 Details of the Problem
- name, telephone and facsimile number of the person reporting the problem;
- date of report;
- physical location of problem;
- nature of the problem;
- number of similar reports received;
- results of tests and other investigations on suspect or other samples;
- availability for investigation of suspect sample or other samples; and
- other relevant factors

5.4.4 Details of the Product
- product name and description including
dosage form, strength, ARTG number, pack size or type;Ø batch, serial number(s), donation number(s) or tissue bank number(s);
- expiry date (if relevant);
- manufacturer/Australian sponsor and contact telephone and facsimile numbers;
- date manufactured;
- date released
- quantity of the batch, date and amount released;
- local distribution;
- overseas distribution of product exported from Australia;
- number of complaints received;
- whether the product is meant to be sterile; and
- sponsor's product/part/order code.

5.4.5 Risk assessment and proposed action
- type of hazard, and assessment of risk to user;
- action proposed by sponsor;
- proposed recall classification;
- proposed recall level; and
- availability of alternative product

It is recognised that some of the information provided may be of a commercially sensitive or private nature and such information will be treated appropriately.¹⁰

5.5 Assessment of recall (strategy, classification, and level)

5.5.1 Strategy
Each recall is a unique exercise. However, in tailoring an appropriate recall strategy, there are a number of factors common to all recalls that need to be considered. These include the nature of the deficiency in the product, the incidence of complaints, consumer safety, distribution networks, recovery procedures, resources for corrective action and availability of alternative products.
In discussing the recall strategy, the sponsor and Co-ordinator should consider the factors which may affect the duration of the recall action, and a completion date should be agreed.
The actual implementation of the recall includes use of the basic steps which are summarised in section B and these will be common to all strategies.
Even when the required information (Section E) is available to the sponsor and to the Co-ordinator, the appropriate strategy may not be obvious and further liaison will then be necessary in order to attain an agreed course of action.¹⁰

5.5.2 Level
As with classification, the level (or depth) of a recall is to be determined by consultation between the sponsor, the Australian Recall Co-ordinator and, where appropriate the State/Territory co-ordinator. In determining the recall level, the principal factors to be considered are the significance of the hazard (if any), the channels by which the goods have been distributed, and the level to which distribution has taken place. Again, expert opinion may be necessary to determine the significance of the hazard.

In this procedure there are four levels of recall: wholesale, hospital, retail and consumer. One of these levels will be assigned to each recall.

Wholesale level
Includes:
- Medicine and device wholesalers
- State purchasing authorities etc.

Hospital level
Includes:
- nursing homes, hostels and other institutions;
- clinical investigators and the institutions in which clinical investigations are performed;
- hospital pharmacists, blood banks, pathology laboratories, operating facilities, fractionators, human tissue banks and personnel in other hospital departments; and
- wholesale level.

Retail level
Includes:
- retail pharmacists;
- medical, dental and other health care practitioners;
- other retail outlets, e.g. supermarkets and health food stores; and
- wholesale and hospital levels.

Consumer level
Includes:
- patients and other consumers; and
- wholesale, hospital and retail levels.

5.6 Responsibilities of sponsors
Sponsors, and persons with responsibilities for the supply of Human Blood and Tissues products, have responsibilities in relation to recall of therapeutic goods in two general areas:
1. in maintaining records and establishing procedures which will assist in facilitating recall should such action become necessary; and
2. in taking the prime responsibility for implementing recall in the situation where it is necessary.¹⁰

5.6.1 Records
In accordance with the requirements of the relevant Manufacturing Principles and the Standard Conditions Applying to Registered or Listed Therapeutic Goods under Section 28 of the Therapeutic Goods Act 1989, sponsors should maintain records for the products manufactured by them in accordance with the following:
1. A system should be in operation whereby the complete and up-to-date histories of all batches of products from the starting materials (in the case of a medical device, all components) to the finished products are progressively recorded.
2. The system should allow the determination of utilisation and disposal of all starting materials (in the case of a medical device, all components) and bulk products.
3. For products having an expiry period, the complete records pertaining to manufacture should be retained for at least one year after the expiry date of the batch; otherwise, the complete records pertaining to the batch should be retained for at least six years after the date of its manufacture noting that other legislature requirements may impose much greater periods.

All sponsors should maintain records of problem reports received about each product. Problem reports should be evaluated by competent personnel and appropriate action taken. The evaluation of each report and the action taken should be shown in the records.

It is a requirement of the Therapeutic Goods Act 1989 for sponsors to retain records of the distribution of registered/listed goods for a period of five years.

All records should be readily available and easy to follow so as to expedite recall whenever necessary.

The Australian Code of Good Wholesaling Practice for Therapeutic Goods for Human Use sets out appropriate procedures for wholesaler distributors so that there is effective, efficient and safe handling, storage and distribution of such products. It is in the sponsor's interest to encourage their wholesalers to follow this Code.

Sponsor Recall Procedure
As mentioned in Section B, sponsors should prepare procedures for recall action which are consistent with this Procedure and which are applicable to their own operations.
All senior personnel should be familiar with their responsibilities in connection with the procedure and of the records system for products.¹⁰

5.6.2 Pre-Recall
Where evaluation of a problem report concerning therapeutic goods indicates that recall may be necessary, the report must be conveyed with the least possible delay to the Australian Recall Co-ordinator, including goods that have been exported – only and not supplied in Australia. Any batch of a formulated product that has been distributed, or any batch of a starting material that is found not to comply with the approved sponsor's specifications or a relevant standard of the Commonwealth Therapeutic Goods Act 1989 (or complementary State/Territory legislation), must also be reported if it has been used in a distributed product.¹⁰

5.6.3 Recall
The sponsor has the prime responsibility for implementing recall action, and for ensuring compliance with the recall procedure at its various stages (Section B). However, no recall, regardless of level, should be undertaken without consultation with the Australian Co-ordinator and without agreement on the recall strategy.
In cases of significant hazard to consumers, company personnel may be utilised to immediately disseminate information on the recall. This includes telephone advice to quarantine stock pending recall or possible recall. This advice should be based on the agreed text of the recall letter or facsimile, which must always be sent as confirmation of oral advice.
Company representatives (medical detailers and sales representatives) may be utilised to recover stock which is the subject of recall, providing the provisions of State/Territory and any applicable Commonwealth regulations are observed in relation to unauthorised possession of certain stock, e.g. medicines of addiction and restricted substances, and suitable recall letters in compliance with Section G are despatched.
For recall in which distribution to outlets such as supermarkets, health food stores and family planning clinics has taken place, the sponsor is to insert, as quickly as possible, paid and approved advertisements in the daily print media of each State/Territory in which distribution may have occurred (Section G), unless complete and accurate distribution lists are available.
For consumer level recall action, the sponsor is to insert, as quickly as possible, paid and approved advertisements in the daily print media of each State/Territory in which distribution may have occurred (Section G). The sponsor is to prepare a recall letter (Section G) for distribution to wholesalers and retailers upon approval of the text by the Australian Recall Co-ordinator.
Sponsors may also be required to notify overseas recipients of recall actions that affect them (Section M).
Sponsors should keep relevant wholesalers advised of the recall. The recall can involve wholesalers in considerable time and expense in issuing credit notes, handling returned stock and forwarding replacements.
Sponsors should be aware that the Commonwealth Minister responsible for Consumer Affairs may, under section 65F of the Trade Practices Act 1974, order suppliers to recall goods if it appears the supplier has not taken satisfactory action to prevent the goods causing injury to any person. This power applies not only to situations where the supplier has not taken any action to reduce risk to the public, but also where a supplier has taken action which is considered inadequate. As section 65F of the Trade Practices Act 1974 empowers the Minister to order recalls for product correction, the power also applies to recalls for correction which are considered to be inadequate.¹⁰

5.6.4 Post-Recall
At two and six weeks after the implementation of recall, or at other agreed times, the sponsor is to provide the Australian Recalls Co-ordinator with an interim and a final report on the recall. The reports are to contain the following information (however, sponsors are not required to repeat information in the final report that has already been given in the interim report, unless there is a change to that information):
1. the circumstances leading to the recall;
2. the consequent action taken by the sponsor;
3. the extent of distribution of the relevant batch in Australia and overseas;
4. the result of the recall - quantity of stock returned, corrected, outstanding, etc;
5. confirmation, where practicable, (eg. hospitals, specialist clinicians) that customers have received the recall letter;
6. the method of destruction or disposal of recalled goods; and
7. the action proposed to be implemented in future to prevent a recurrence of the problem.

These reports establish the effectiveness of the recall and form the basis of reports to the ACCC Product Safety Policy Unit (safety-related recalls) and to the National Co-ordinating Committee on Therapeutic Goods. Unless satisfactory reports are received, further recall action may have to be considered.¹⁰

5.7 Responsibilities of Australian recall co-ordinator
In connection with recall of therapeutic goods, using the Procedure, the responsibilities of the Australian Recall Co-ordinator are:
1. A list of current recall co-ordinators for sponsor companies is to be maintained.
2. The Uniform Recall Procedure for Therapeutic Goods is to be maintained for currency and available on the TGA Website (tga.gov.au) for downloading free of charge.
3. Copies of the Uniform Recall Procedure for Therapeutic Goods are to be available to all sponsors of therapeutic goods and others on request.
4. The Australian Recall Co-ordinator will advise the sponsor immediately of problem reports with therapeutic goods which may necessitate recall. All available information is to be provided in order to facilitate investigation by the sponsor.
5. Where there may be a hazard to the user, expert advice on the classification and level of recalls may be sought by the Australian Recall Co-ordinator.
6. The Australian Recall Co-ordinator will liaise with the sponsor on recall and provide advice and assistance in relation to letters, advertisements and recall strategies. Sponsors will be informed of actions being taken by the Australian Recall Co-ordinator in advising third parties.
7. Where applicable, the Australian Recall Co-ordinator will liaise with State and Territory Recall Co-ordinators in assessing the strategy for recall.
8. In patient or consumer level recalls, where the consumer hazard warrants, the Australian Recall Co-ordinator will liaise with experts within the Therapeutic Goods Administration and with the sponsor to prepare a statement for immediate use by the media (including the major ethnic media). These statements are intended to bring the problem to consumers' attention as quickly as possible as there may be a delay of several days in publication of paid advertisements.
9. Where necessary, the co-ordinator is to liaise with officers of the ACCC on safety-related recall actions.
10. The Australian Recall Co-ordinator will forward for each recall a report in writing (by facsimile and/or email) to the relevant parties listed in Appendix V. Such reports will include identification of the goods for which recall action is being taken, the nature of the problem, an assessment of consumer hazard, the distribution of the goods and the action proposed. For urgent recall action, notification is to be by telephone with confirmation in writing.
11. Where therapeutic goods have been exported to other countries, and are subject to safety related recall, the Co-ordinator will liaise with the sponsor in order to determine:
12. the sponsor’s recall strategy for the exported goods; and

i. the form of the TGA advice of the recall to the authorities in the other countries.
The Australian Recall Co-ordinator will forward copies of sponsors' final recall reports and related papers to the Australian Competition and Consumer Commission, Product Safety Policy Section where the recall is safety-related.
The Australian Recall Co-ordinator will maintain detailed records of individual recalls and a register in which summaries of recalls are entered.
The Australian Recall Co-ordinator will prepare summarised reports of all recalls for review at meetings of the National Co-ordinating Committee on Therapeutic Goods.
The Australian Recall Co-ordinator may accompany personnel from the ACCC, Product Safety Policy Section, on audits of sponsors' records of safety-related recalls.
The Australian Recall Co-ordinator is responsible for the preparation of safety-related recall summaries for publication in the Bulletin of Australian Recalls and Cancellations published by the Therapeutic Goods Administration.¹⁰

5.8 Responsibilities of state and territory co-ordinators
State/Territory Recall Co-ordinators have responsibilities in:

Ø Passing on product problem reports and recall action information to the Australian Recall Co-ordinator.

Ø Any problem which has been reported to a State/ Territory Recall Co-ordinator is to be notified to the Australian Recall Co-ordinator without delay. Advice from sponsors should be referred to the Australian Recall Co-ordinator.

Ø Failures of goods found by State/Territory health authorities in testing for State Government tenders are to be notified to the Australian Recall Co-ordinator.

Ø State/Territory Recall Co-ordinators are to provide details of recalls to other relevant organisations in the State/Territory.¹⁰

5.9 Follow-up action
The follow-up action consists of a check on the effectiveness of the recall and an investigation of the reason for the recall and remedial action taken to prevent a recurrence of the problem.¹⁰

5.9.1 Check on Effectiveness of Recall Action
The Australian Recall Co-ordinator examines the reports received from the sponsor and an assessment made of the effectiveness of recall action. Recall records may be inspected by TGA and in some cases the records may be audited by the ACCC in the company of TGA.¹⁰

5.9.2 Investigation of the Reasons for Recall and Initiation of Remedial Action
On completion of a recall, the sponsor is requested to provide details of the remedial action proposed to prevent a recurrence of the problem which gave rise to the recall (Section H). Where the nature of the problem and appropriate remedial action are not apparent, investigation and in some cases Good Manufacturing Practice audits may be necessary.
It is required under the Therapeutic Goods Act 1989 that therapeutic goods made overseas for supply in Australia shall be subject to levels of good manufacturing practice equivalent to those expected for similar products manufactured in Australia.
Appropriate follow-up action will be taken by the Therapeutic Goods Administration where indicated; this might include, for example, review of the product by the relevant Product Regulator of the Therapeutic Goods Administration.
Where a recall is initiated following a report submitted by a party from outside the Commonwealth or the State/Territory health authorities, the reporter is to be provided, on request, with an outline of the results of investigations and a summary of the recall.
Maintaining a current Rapid Alert System to communicate in an emergency, urgent safety related information to all public and private hospitals.
Assist in the timely provision of critical recalls information to pharmacists and other professional groups.¹⁰

6. CONCLUSION
As per detailed study of Distribution, Complaints and Recall Of pharmaceutical as per global GMPs it is reveled that India follows the GMP norms and regulation as per WHO guidelines, Pharmaceutical Inspection Co-operation Scheme (PICS),New Zealand Food And Safety Authority and Europian Comission (MHRA).Only USFDA Guidelines and Therapeutic Drug Administration (TGA) Guideline gives detailed information about the distribution, complaints and recall of pharmaceuticals.

REFERENCES
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2. EU Guidelines to Good Manufacturing Practice Medicinal Products For Human and Veterinary Use,Volume 4
3. Guidelines on Good Distribution Practice of Medicinal Product for Human Use
4. Guide for Good Manufacturing Practical for medicinal products, Geneva, PIC/S, June-2006, P.N.39-40
5. McCormick Kate “Quality Pharmaceutical Engineering Series” Published by Butterworth Heinemann P.NO.87-91
6. Orange Guide; inspection and standards division of the Medicine and Healthcare products regulatory agency. Rules and Guidance for Pharmaceutical manufacturers and distributors 2007 Chicago (London): Pharmaceutical press; 2007. P,NO.83-84
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13. Willig H. Sidney & Stroker R. James “Good Manufacturing Practices for Pharmaceuticals A plan for Total Quality Control” fourth edition revised & expanded P.NO.-186-256
14. Zurich,Risk topics,Product Recall Program,Zurich Service Corporation Available From URL zurichna.com/internet/zna/SiteCollectionDocuments/en/media/inthenews/RiskTopicsProductRecall.pdf (Accessed on 7-Aug-2011)
15. Pharmaceutical Inspection co-operation Scheme (PICS) Guidelines