jeff broadfoot session 6

11/22/2010

1

CAPA Programs

Managing Supplier Audits Follow-U A ti iti

C C F 2010

0 Cangene Corporation Fiscal 2011 www.cangene.com 1

Up Activities

Cangene Corporation Fiscal 2011 www.cangene.com 2

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Managing Supplier Audits Follow-Up Activities

1. Understanding The Current Regulatory

Climate

2. CAPA Defined

3. Case Studies for Managing CAPA


4. Interactive Exercise

Understanding The Current Regulatory Climate

Challenges in assuring supply chain integrity Complexity and hazardsCo p e ty a d a a ds Lack of traceability

Increased brokerage and trade Repackaging and relabeling

EMA Economically Motivated Adulteration Animal feed - melamine Heparin oversulfated chondroitin sulfate


Heparin oversulfated chondroitin sulfate Over-reliance on CoAs Non-specific ID tests frequently performed on

composite samples.

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FDA Commissioner

Margaret Hamburg


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companies that sell contaminated products

because of loose supply chain oversight need

to face serious penalties and cannot excuse

themselves by blaming their suppliers, blaming

the FDA or blaming anyone else


the FDA, or blaming anyone else.


we are moving from a system that places

most of the regulatory burden on the FDAs

modest inspection force, to one that creates

greater oversight at points further back along

the production chain


the production chain.

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We need to know who is making our foods and

drugs, where they are located, and we need to

be sure that these facilities are being inspected

and are accountable for what goes into their

d t ll th d t th d


products as well as the products they produce.


I can assure you that addressing the problem of

global supply chain safety, and shifting the

existing paradigm from reaction to

prevention, is one of my highest priorities for

FDA


FDA.

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Supplier questionnaire (audit by mail) not considered adequate any more. q y

FDA is looking for on-site audits; site of actual production see the process.

One day audits are suspect. Need to invest time, planning, resources, gain

understanding. The purpose is to gain understanding of your


p p g g ysuppliers manufacturing and quality processes.


The Agency is backing its regulations with

enforcement action in 2009, 12% of 483

observations and 16% of Warning Letters issued

were all related to inadequate supplier

qualification


qualification.

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The quality assurance of starting materials, and

supplier approval, was deficient in thatthere was no

documented evidence of QA follow-up of progress with

remedial actions arising from the adverse [supplier]

assessment, either in terms of alternative material


sources, or [the suppliers] progress with remediation

plans.


Corrective actions were not effective to prevent f iti l d f t i i l Th freoccurrence of critical defects in vials ... The for-cause

audit of the glass vial manufacturer found significant evidence indicating that the vial lots were not manufactured with adequate controls to ensure consistent quality in the finished product. Vial


manufacturing was moved to another line which has improved inspection capabilities, but additional defective vials were received from the new line.

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You have not executed the new plan to audit

suppliers of active ingredients and raw materials as

committed in your response. Problem with excessive rejection of vials due to visible particles.

Contacted the contract sterilizer.

No steps were taken to audit and perform a complete evaluation of


No steps were taken to audit and perform a complete evaluation of

the contractors sterilizer process or to increase sampling and

monitoring of this API after finished lots were reported as above

limits for particles rejects.


The Rules


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820.100

Each manufacturer shall establish and maintain

procedures for implementing corrective and preventive

action. The procedures shall include requirements for:


action. The procedures shall include requirements for:


(2) Investigating the cause of non-conformities relating to

product, processes, and the quality system;

(3) Identifying the action(s) needed to correct and

prevent recurrence of non-conforming product and other

quality problems.

(4) V if i d lid ti [th ] t th t h


(4) Verifying and validating [them] to ensure that such

action is effective

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211.192

the failure of a batch or any of its components to

meet any of its specifications shall be thoroughly

investigated


investigated


A written record of the investigation shall be made and

shall include conclusions and follow-up.


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CAPA Defined

Title: Quality Management System Medical Devices

Guidance on the Control of Products and Services

Obtained from Suppliers

Authoring Group: GHTF Study Group 3

Endorsed by: The Global Harmonization Task Force


Date: December 11, 2008

CAPA Defined

If a Corrective Action or Preventive Action

(CAPA) is initiated additional feedback and

communication may be necessary. As part of

this action the manufacturer may need to re-

evaluate the continued suitability of the


evaluate the continued suitability of the

supplier.

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CAPA Defined

Depending on the nature of the procured

product/service, portions of the activities that are to be

performed under CAPA may be delegated by the

manufacturer to the supplier. The combined CAPA

related activities of both the manufacturer and the

supplier must satisfy the requirements of applicable



regulations and standards.

CAPA Defined

While some of the CAPA activities may be

delegated to a supplier, the overall

responsibility for these activities resides with

the manufacturer. CAPA related decisions

and effectiveness checks cannot be


and effectiveness checks cannot be

delegated and reside with the manufacturer.

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CAPA Defined


CAPA DefinedCAPA P A P

D

D

I

E

A

E

I Identify actions


V R V

I I

D F

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CAPA DefinedCAPA P A P

D

D

I

E

A

E

I Identify actions


V R V

I I

D F

CAPA Defined


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CAPA Defined

Each link of the chain must add value:

It only takes one weak link in the chain to put product at risk.

Verification and positive checks are required.


p q

CAPA Defined

The purpose of assessing the capabilities of

your suppliers is to provide a greater degree of

assurance, beyond that provided by in-coming

inspection and testing, that the raw materials

and components received meet the needs of


and components received meet the needs of

your product and process.

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CAPA Defined

The purpose of audit follow-up is to provide a

greater degree of assurance, beyond that

provided by review of an audit response, that the

actions planned and proposed have been

implemented and are effective


implemented and are effective.

CAPA Defined

One of the fundamental steps in any CAPA process is

completing an evaluation of the actions that were taken.

Verification and validation:

Were they completed?


Were they timely?

Were they appropriate and effective?

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CAPA Defined

Two important questions:

Can you follow up on every corrective action

commitment?

Is it necessary or required?


It depends

CAPA Defined

Effective decision making in a quality systems

environment is based on an informed understanding of

quality issues. Elements of risk should be considered

relative to intended use of a product, and in the case of

pharmaceuticals, patient safety


- Quality Systems Approach to Pharmaceutical cGMP

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CAPA Defined

It depends on

Criticality of supplier deficiency and its potential

to impact on the quality attributes of your

product, and ultimately, on patient safety.


CAPA Defined

It depends on

Criticality of supplier deficiency and its potential

to impact on the quality attributes of your

product, and ultimately, on patient safety.


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CAPA Defined

How much is enough?


CAPA Defined

Risk

Management


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CAPA Defined

First, we are seeking better controls at the point of productionpoint of production.

A second key element of our strategy is to hold importing companies responsible for their supply chain.

Third, we are going to deploy our agencysresources strategically. This is essential as our

d t k di i th


mandate keeps expanding, even in these economically challenging times.

CAPA Defined

Model for industry

better controls at the point of production

hold suppliers responsible

deploy resources strategically


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CAPA Defined

Developing a risk-based approach

Understand the needs of your product and process

Rate audit deficiencies according to severity/criticality

to your product and process needs.

Use risk management to prioritize work.


g p

Level how soon, how often, to what extent

Formality

CAPA Defined

Required work, including follow-up, can be

prioritized but cannot be eliminated using risk

management principles.

Manufacturers cannot risk-manage away

l t i t


regulatory requirements.

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CAPA Defined

Identify risk factors important to your operationD fi it i / i k f h f t Define criteria/risk scores for each factor

Create risk assessment tools Define action levels for each risk level Mechanism to feed forward information for the

next rating in supplier quality management


g pp q y gsystem periodic supplier risk review, done at least yearly by

many companies

CAPA Defined

Risk factors

CQAs of finished product directly dependent on the

relevant quality attributes of components.

Purity

Content, strength, concentration


Sterility

Impurities

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CAPA Defined

Define action levels

Level A: evaluation of effectiveness before receipt of next lot.

Level B: evaluation of effectiveness within 6 months

Level C: evaluation of effectiveness at next scheduled dit


audit

CAPA Defined

Benefits

Rationalized approach to manage follow-up

Prioritization

Manages risk effectively

Uses resources efficiently


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CAPA Defined

If CAPA activities are delegated to suppliers, the manufacturer needs to ensure that:

1. CAPA related activities performed by suppliers are defined in the manufacturers QMS.

2. Based on the products provided by a supplier, all CAPA specific activities to be performed and data/information to be provided by that supplier are identified (e.g. related to the extent of control necessary at the supplier).

3. The suppliers obligations related to CAPA activities are communicated to the supplier and clearly defined and documented.


4. The supplier fulfils his obligations in relation to the CAPA activities (e.g. timely processing of corrections).

5. Documentation and records related to a suppliers CAPA activities are controlled and readily available.

Case Study for Managing CAPA

Excipient Supplier


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Case Studies for Managing CAPA

Two consecutive out-of-specification (OOS) results that

occurred with bulk product endotoxin testing:

The first OOS occurred with the batch manufactured in the week

of Jan 7, 2008.

The second OOS occurred with the batch manufactured in the

k f J 14 2008


week of Jan 14, 2008.


Batch 1

Sample Endotoxin (EU/mL) Bacteria (CFU/mL)Sample Endotoxin (EU/mL) Bacteria (CFU/mL)

Pooled plasma

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Batch 2Sample Endotoxin (EU/mL) Bacteria

Pooled plasma

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Container Batch Endotoxin (EU/mL)A 0.1

B 0.0421

B 0.042C 0.1D 0.185E 0.169

2

F 0.2G 0.3H 0 6


2 H 0.6I 2.3 [OOS]J 2.4 [OOS]


Interim conclusions

Maltose was the source of the endotoxin

Either we contaminated the maltose during storage

and handling, or

The maltose was contaminated by the supplier


Contamination was variable, non-uniform

Next step??

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Contacted the supplier

Discussed the incident being investigated

Reviewed their process

Deviations?



Deviations

Discovered that this batch had been reprocessed.


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11 audit observations

Observation rating Risk Response Level

2 critical Level A

4 j L l B


4 major Level B

5 minor Level C

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Define action levels

Level A: evaluation of effectiveness before receipt of next lot.

Level B: evaluation of effectiveness within 6 months

Level C: evaluation of effectiveness at next scheduled dit


audit


Audit observations:

No evaluation of starting material quality before

reprocessing

Lack of adequate validation (process and cleaning)

Limited in-process testing/ heavy reliance on testing


p g y g

of final product

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Audit response

Finished product testing met specifications

No previous failures

Limited corrective action commitments



Notes

We had used this supplier for 12 years with no

previous issues.

Ironically, we had switched to the suppliers low

endotoxin grade of maltose just over a year previous


to the incident. Basically, it was the same process,

same material, just certified to meet endotoxin

specifications [through additional testing].

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Assessment

Looking for better controls at the point of production

Could not verify or validate effectiveness



Depending on the nature of the procured

product/service, portions of the activities that are to be

performed under CAPA may be delegated by the

manufacturer to the supplier. The combined CAPA

related activities of both the manufacturer and the




regulations and standards.

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Combined CAPA related activities

Critical observations

related to high risk of endotoxin contamination during

manufacturing of subsequent lots

Critical observation = Level A evaluation

l ti f ff ti b f i t f t l t


evaluation of effectiveness before receipt of next lot

Response adequate?

Implemented additional quality control testing.


Responses to other significant (major)

observations

Evaluated during subsequent discussions with

supplier

Provision of evidence of completion


Provision of evidence of completion

Additional follow-up during subsequent on-site audit

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Interactive Exercise


Interactive Exercise

1. Observation

2. Your expected response

3. Suppliers actual response

4. Your evaluation of the suppliers response

5. Audit Team evaluation of the response


p

6. Action plan/ follow-up

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Observation #1

The firm lacks a documented quality management

system.

Auditors were informed that the set of standard operating

procedures (SOPs) that exist are outdated are not used by the

organization. These SOPs were created in the 1990s as part of

an unsuccessful attempt to achieve ISO registration. There are


g

multiple uncontrolled forms in use (i.e. for QC testing and

Assembly). The organization does not have a Quality Manual.

Observation #1

What would be an adequate or appropriate response

from the supplier?


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Supplier Response

The lack of a documented quality management system

will be addressed by registering to the most current

ISO9001 standard. (target completion date: 7 months)


Your Evaluation

Is the suppliers response adequate?

Does it address the observation?

What, if any, other factors would you consider in your

evaluation?


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Audit Team Evaluation

Provide Supplier with Cangene expectations and

industry guidelines surrounding quality management

systems and manufacturing process controls.

Cangene to source alternate supplier(s) for these raw

materials.

C t f i k t t d t i if


Cangene to perform a risk assessment to determine if

any other immediate actions are required.


Lead Auditor deemed [other] corrective actions within

their response to be unacceptable and concerns were

elevated to Supplier Quality Team. CAPA was initiated

to discontinue use of this supplier.


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Additional information

Supplier repackaged raw materials

No line clearance procedures

No documented/validated cleaning procedures for

common utensils/equipment

Repackaging in unclassified/uncontrolled conditions


p g g

Action plan/ follow-up

Interim steps/controls?


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Observation #2

Quality Control procedures are deficient in that investigation of Out

f S ifi ti lt did t f ll di ti tli d i th FDAof Specification results did not follow directives outlined in the FDA

Guidance for Industry Investigating Out of Specification Test

Results for Pharmaceutical Production. Suppliers procedure for

Non Conforming Material is focused on detailed instructions

regarding disposition of nonconforming product without providing

ffi i t i f ti i ti ti f OOS lt d ti


sufficient information on investigation of OOS results and reporting

of re-test results.

Expected Response

What would you expect the supplier to address in their

response?


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Actual Response

[Supplier] is committed to provide product which meets specifications. We do not investigate out of specifications results according to the "Control of Nonconforming Product" Procedure. As

i d b thi d h t f ifi ti lt i i t d t th Ch i trequired by this procedure , each out of specification result is communicated to the Chemistry Technical Support designate & authorized personnel. These personnel provide technical scrunity for each questionable result. The Technical Support along with QC Management makes decisions regarding retesting or resampling & retesting. The decisions are documented in the QC records. All results are reported as required by QC procedure. This approach renders a very good protection of product quality and good efficiency of the operations. We take into account out of specification results very seriously. We monitor performance using a variety of metrics such as 1st pass quality. Metrics are presented & evaluated by Senior Management during Management review As a result of the audit observation the current system for OOS results was reviewed by


review. As a result of the audit observation, the current system for OOS results was reviewed by Management, and it was concluded that the current system is adequate for our operations and no changes are required.

Your Evaluation


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Your commitments to resolution of OOS results through your NCR procedure are appreciated. I would need only to confirm that your procedure p pp y y pmeets industry standards. Could you please summarize your approach to handling OOS results:

rules for re-testing and re-sampling

rules for reporting the re-test results

approach to investigation of OOS root cause

timelines for closing the investigation


Alternatively please comment if your NCR procedure meets expectations regarding handling OOS results as outlined in the FDA guidance document Investigation of Out of Specification Test Results for Pharmaceutical Production .

Suppliers response

Our Quality Management System has been established according to ISO 9001 requirements We ensure & monitor theaccording to ISO 9001 requirements. We ensure & monitor the compliance of our systems & processes through Surveillance & Recertification ISO Audits, Internal Audits, and Management Reviews. [Supplier] does not manufacture finished Pharmaceutical products and is therefore not subject to the FDA guidance. [Supplier] is solely a manufacturer of raw

t i l Th t i l d t h ifi i t d d


materials. These materials do not have a specific intended use and are used in a variety of industries. Our Quality Management Systems has established controls that govern our operations and assures the quality or our products.

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Action plan/ follow-up

Next steps?

How would you close-out this observation?


Observation #3

Routine surveillance audit scope included investigation of a significant quality issue.q y

White tacky substance on vial exterior

1 major, 3 minor observations

Organization and maintenance of the warehouse for Raw Materials and Finished Goods appeared deficient in that:

housekeeping practices appeared insufficient. Procedure and logs for warehouse cleaning and sanitization were not implemented


g p

packing trays in warehouse area were not stored as per written procedure. The trays were not stored in an orderly fashion, a number of trays were not wrapped in plastic foil, dust/dirt was collected on a number of trays, wiping of trays pre-and post-use in clean area was not documented in the Batch Record.

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Expected response


Actual response


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Your evaluation/action plan


Action Plan

Lead auditor escalated to Supply Quality Team.

Supply Quality Team

Reviewed current relevant information

History of quality defects

Supplier responsiveness to quality issues/audit observations

Recent quality issues (cracked vials/overlaps) resulting in batch


Recent quality issues (cracked vials/overlaps) resulting in batch

rejection.

Scheduled a for cause audit

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Action Plan

Audit observations

1 critical - directly related to audit cause

6 major contributing factors leading to vial quality issues

1 minor


Critical Observation

Vial lot was not manufactured in a state of control to ensure product quality and conformity. Review of the manufacturing batch record revealed the following deficiencies:

repeated observations of overlaps and minimum lip thickness defects. No apparent investigation and/or corrective action for these issues.

QA Auditors gave at least six verbal warnings to Production of the defects (and borderline passing vials) that they were seeing during consecutive QA Audits. No documented investigation/corrective action.

The [electronic] inspection system which identifies such defects was not verified


[ ] p yprior to use as per [supplier] procedure.

The repeated overlaps defects noted in the Packing Production Report did not trigger any re-work (re-inspection). Only the failure of the first QA Audit Lot, for minimum lip thickness, resulted in re-inspection of the first six trays of the manufactured lot.

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Your Evaluation/ action plan


Supply Quality Team action plan

Escalated to Senior Management

Senior Management discussions with supplier

Recommended sourcing of new vial supplier

Action on remaining inventory from supplier


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Thank you!

Jeff Broadfoot

Director Quality Assurance


Director, Quality Assurance

Cangene Corporation

jeff broadfoot session 6

Documents

fda cangene corporation

current regulatory climate2

regulatory burden

loose supply chain oversight

q y fda

day audits

contaminated products

capa defined3