5/10/2010

1

FDA-Investigator’s Perspective on Review of Supplier Qualification Programs During Audits

José E. MeléndezConsumer Safety Officer

Drug SpecialistFood and Drug Administration

CommunicationØA process of

transferringinformation from one person to another.

ØCommonly defined as "the imparting or interchange of opinions, or information by speech, writing, or signs".

5/10/2010

2

CommunicationEffective communication between the manufacturer and the supplier will improve the decision making process related to:

ØNon-conformance events

ØComplaint investigations

ØDistributed products

ØCritical Change Control requests

ØRelease and in-coming controls

Overview • Background• General Principles• Supplier Management System• Investigator’s Perspective• Quality Assessment• Supplier Questionnaire• Audit Process• Quality Agreement• Case Study• Change Controls• Supply Chain Activity• Delivery and Monitoring

5/10/2010

3

BackgroundThe cGMP regulations for final drug products are defined in each country and region. The content of the regulations may vary but the purpose is the same:– To deliver high quality and safe medicines.

– To prevent deaths, serious illnesses, adverse events or products recalls resulting from deficiencies in the manufacturing and distribution processes.

There are many cases known where the standards expected from manufacturing companies have not been maintained.

Background

Contamination of Glycerine raw material with diethylene glycol that led around 300 deaths in Panama (2006) due to lack of controls in the distribution system of Glycerine and in the drug product manufacturing site involved.

5/10/2010

4

Background

A supplier is anyone that is independent from the manufacture’s Quality Management System.

If the supplier is not part of the manufacture’s internal audit scope is considered an internal supplier.

General PrinciplesRegulatory authorities evaluate the Active Pharmaceutical Ingredients (API) and/or drug product manufacturers to confirm that evidence of control over products and services from suppliers is present, at the manufacturer’s site.

5/10/2010

5

General Principles

Manufacturers of API and Drug products have the ultimate responsibility for approving and qualifying their suppliers and to monitor on an ongoing basis the performance of their critical suppliers.

General PrinciplesObjective evidence may include:

ØManufacturer and/or supplier correspondence

ØReceiving, inspection, acceptance records

ØRecords of Results of any preventive and corrective actions

5/10/2010

6

Supplier Management SystemTypically consists of the following:

ØIdentification of Potential Suppliers

ØSupplier Selection

Ø Supplier Quality Assessment

Quality Assessment

Approval underchange control

Yes/No

Remediation and Assessment of the Remediation

Change ControlEvaluation

Production &Validation

Assessment

SuppliesApproval

QualificationYes/No

Supply ChainSecurity

OngoingMonitoring &

Evaluation

Quality ContractAgreement

Development

Supplier Management System

5/10/2010

7

Investigator’s Perspective ØEstablish a Control Procedure for the

qualification of the suppliers.

ØConduct periodic evaluation.

ØMonitoring the changes made by the suppliers with possible quality impact.

Investigator’s Perspective

ØEvaluate and reviewing the distribution and Supply Chain controls related to transportation, storage conditions, traceability of the material, container closure and labeling.

5/10/2010

8

Quality AssessmentThe approach is based on risk, the level of communication and manufacturer in house analysis.

Some of the requirements are:– Supplier Questionnaire– On site Supplier audit– Supplier cGMP Compliance History– Supplier 3rd party Certification

(e.g. MHRA, EME)– Quality Agreement

Supplier QuestionnaireShould be tailored to the supplier of the raw material.

Lines of Inquiry:

ØHas a Quality Assurance Program in place?

ØHas an established qualification requirements for operators?

5/10/2010

9

Supplier Questionnaire

ØDoes the supplier have in place resources for identification of quality problems?

ØHas the supplier fully implemented a document and management record control system?

Supplier Questionnaire

ØDoes the supplier have a process in place for identifying suspect/counterfeit items?

ØDoes the supplier follow an adequate program for calibrating and maintaining equipment used for inspection and tests?

5/10/2010

10

Audit Process

The audit must be performed taking into account the supplier quality system and the customer requirements.

References Q7A, Q9, Q10 and Quality System Inspection Guidance

Quality Agreement

The manufacturer should agree with the supplier on their individual responsibilities.

While the manufacturer is responsible for the drug product, the supplier also has responsibility such as exchange of information.

5/10/2010

11

Quality Agreement

Regulatory requirements call for validated process.

Regardless of who actually performs the process validation, it is the manufacturer responsibility to ensure that the validation is properly performed.

Quality Agreement

The manufacturer and the supplier should have an agreed in advance for evaluating any changes to a validated process and for identifying when a re-validation of the process is necessary.

5/10/2010

12

Quality Agreement

For internal suppliers is expected to establish and define a formal arrangement.

Standardize processes will ensure coverage of all relevant regulatory requirements.

Quality Agreement

Ø Handling of complaints received

ØHandling of non-conformities

ØCorrective and Preventive actions

ØLabeling requirements

ØTechnical documentation

ØProduct Recall

5/10/2010

13

Case Study

A manufacturer received approximately 29 broken glass syringe consumer complaints for a combination drug product . In all cases, management confirmed the association between the complaints received with a no pre-existing syringe defect.

A barrel defect was identified as the most probable root cause for broken syringes.

5/10/2010

14

Case StudyThe manufacturer’s incoming inspection did not identified the syringe defect.

A supplier’s investigation was initiated and disclosed that there was no indication that the complaint sample lots deviated from its standard process.

Case StudyThe syringes were found to be within the supplier’s acceptance limits for the identified defect.

The acceptance criteria were based on the supplier’s manufacturing controls, and it was not developed based on the firm’s critical controls parameters.

5/10/2010

15

483 Items21 CFR 211.22(d)-“The responsibilities and procedures

applicable to the quality control unit are not fully followed”.

Failure to implement adequate supplier controls to ensure that received components conform to their quality requirements.

Failure to develop and establish specification and/or inspection criteria in collaboration with your manufacturing supplier to ensure that quality commitments are met.

Regulatory ActionThe manufacturer initiated a voluntary recall of thirty eight (38) lots of the affected drug product due to a potential syringe breakage problem.

5/10/2010

16

Case Study

Figure B shows a deviation from baseline at the area near the flange. The syringes were manufactured in sister sites, using the sameparent glass supplier.

483 Item21 CFR 211.22(d)

“The responsibilities and procedures applicable to the quality control unit are not fully followed”.

Specifically, the firm failed to implement incoming controls to evaluate the conformance of the device used in the manufacturing process of drug product.

5/10/2010

17

Change ControlsAll changes that have the potential to impact product quality must be evaluated (e.g. identity, strength, purity, regulatory filings)

The types of changes requiring notification should be defined and agreed by both the manufacturer and the supplier.

Change ControlsThe request may include:

ØTracking numberØDetailed description of the changeØSpecification for the materialØProducts impactedØThe reason for the changeØSupporting documentation

5/10/2010

18

Case StudyIn 2007, a supplier of APIs conducted a modification to a non-dedicated manufacturing equipment.

In 2008, a customer complaint was received by the the supplier due to foreign materials present in tablets.

The supplier’s investigation disclosed that during the re-assembling operation, one of the screws were not appropriate centered with the mechanical seal.

Case StudyA mixture of metallic particles, crystals of different products and residual solvent was found inside the threads of the screw.

The investigation was only focused in the process of the affected API, and prepared for the evaluation and concurrence of the complainant customer.

5/10/2010

19

483 ItemsFailure to prevent cross-contamination among APIs manufactured at manufacturing facilities.

Failure to have validated cleaning procedures to detect contamination in process steps where contamination poses the greatest risk to the API quality.

Regulatory ActionDrug product manufactured for domestic market wasaffected by this cross-contamination event. The firm initiated a voluntary recall of one hundred forty eight (148) lots

5/10/2010

20

Supply Chain ActivityThe whole supply chain from the manufacturer of an API or a critical raw material to the customer should be assessed and qualified from a quality perspective.

Supply Chain Activity

Transportation, storage and related conditions as well as traceability of the material have to be evaluated.

5/10/2010

21

Supply Chain ActivityFor temperature/humidity sensitive materials, the use of data loggers should be considered to ensure that the product was stored at the required conditions during the transportation.

Use of tamper-resistant packaging closure and/or manufacturer specific design of the seal.

Supply Chain ActivityEvaluation of the label by the customer; the label on the material matches the reference label provided by the manufacturer.

Label needs to indicate the name, address of the manufacturer, special storage/transportation conditions, name of the product, lot number, quantity of content and the expiry date.

Assessment of the CoA against an authentic manufacturers CoA.

5/10/2010

22

Delivery and Monitoring21 CFR 211.84 – Testing and Approval or Rejection of Components, Drug Product Containers and Closures.

– (a) Each lot of components, drug product containers, and closures shall be withheld from use until the lot has been sampled, tested, or examined, as appropriate, and release for use by the Quality Control Unit.

DeliveryVisual examination of materials on receipt should be conducted to confirm that the correct material has been delivered.

Containers should also be examined for integrity of the seals and physical damage.

Broken seals on containers may indicate that the container has been opened during transit, and that the material may have been exposed to adverse environmental conditions.

5/10/2010

23

DeliveryWhen materials are purchased through agents, supplier names should be requested to identify the actual component manufacturer.

Otherwise, the third-party supplier agent may interchange producers according to availability and price, and without prior notification.

Case StudyIn September 2006, a physician in Panama City observed an unusual number of cases of severe renal failure.

By October 2, health officials from Panama Ministry of Health identified 21 case-patients, of which 12 had died, due to the identified adverse condition.

5/10/2010

24

Case Study

Information about the prescription drugs used among illness patients was documented.

The medications were sent to CDC and FDA laboratories for analysis.

Case StudyThe laboratories identified diethylene glycol (DEG) in several lots of medications with a concentration of approximately 8%.

Investigation disclosed that a raw material used in the formulation of the drug products is the source of the DEG.

Containers of this raw material was labelled as “Glycerine USP”.

5/10/2010

25

Glycerine was one of the major components (around 35%)of the cough syrup formulation.

This cough syrup manufactured by the Government of Panama was identified as the most probable cause for the reported syndrome.

5/10/2010

26

5/10/2010

27

MonitoringControls procedures need to be established to monitor the supplier’s performance and ensure that customer and regulatory requirements are met.The following data should be evaluated:

ØPeriodic full testing of the materialØComplaint situationØAssessment of changesØResponse times for complaints and questionsØRegulatory or/compliance issues

Conclusion

Supplier Qualification Programs constitute a review mechanism to ensure that suppliers routine production activities are consistently monitored by the drug manufacturers.

5/10/2010

28

ReferenceØ 21 CFR 210 and 211

Ø FDA, Compliance Program Guidance manual program, Drug manufacturing Inspections, February 2002

Ø FDA, Guidance for Industry, quality Systems Approach to Pharmaceutical cGMP Regulations, September 2006

Ø FDA, Guidance for Industry: Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, FDA/ICH, August 2001

ReferenceØGHTF, Quality Management System, Medical

Devices, Guidance on the Control of Products and services obtained from Suppliers, Final Document, December 2008

ØHSS, Draft Quality Assurance Criteria Review and Approach Documents Suggested Lines of Inquiry, November 2009

http://www.hss.energy.gov/nuclearsafety/qa/QA_CRAD_SuggestedlinesOfInquiry.html

5/10/2010

29