The Critical Role of the QCU

Crystal MershExecutive Partner, QxP Inc.International GMP ConferenceMarch 11, 2014

• For the past ten (10) years the most cited FDA-483 observation involved the failure of the QCU.

• Data presented in 2013 at this conference1. Failure of QCU: 165 citations2. Improper failure investigations: 112 citations3. Inadequate procedures: 104 citations4. Inadequate lab controls: 98 citations5. Inadequate sampling: 76 citations6. Inadequate procedures: 69 citations7. Inadequate cleaning: 66 citations8. Inadequate training: 61 citations9. Inadequate calibration/inspection: 61 citations

The Facts

My role is best described as:

1. Quality Assurance2. Manufacturing3. Regulatory Affairs4. Quality Control5. Research & Development6. Executive Management7. Consultant8. Regulator9. Other

54%5%7%7%1%9%6%5%6%

IF You’re Looking for Love……

Regulatory Requirements

210.3 (b)(15)

Quality control unit means any person or organizational element designated by the firm to be responsible for the duties relating to quality control.

211.22Responsibilities of quality control unit• (a) There shall be a quality control unit that shall have the

responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have

occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured,

processed, packed, or held under contract by another company.

• (b) Adequate laboratory facilities for the testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in-process materials, and drug products shall be available to the quality control unit.

• (c) The quality control unit shall have the responsibility for

approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.

• (d) The responsibilities and procedures applicable to the quality

control unit shall be in writing; such written procedures shall be followed.

“The Commissioner intends to make the quality control unit responsible for ensuring that controls are implemented during manufacturing operations which ensuring drug product quality, not that the quality control unit actually perform each one of the duties. The Commissioner believes that, even under 211.22, management has the prerogative to organize its internal structure and assign responsibilities as it deems appropriate, as long as some identifiable person or unit has at least those responsibilities assigned by the regulations to the quality control unit.”

21 CRF 210/211 Preamble

Guidance for IndustryInvestigating OOS Test Results, 2006

“It is critical that the laboratory provide all individual results for evaluation and consideration by the QCU, which is responsible for approving or rejecting”

“This guidance uses the term quality unit (QU) to reflect modern practice while remaining consistent with the CGMP definition in 210.3(b)(15). The concept of the quality unit is also consistent with modern quality systems in ensuring that the various operations associated with all systems are appropriately planned, approved, conducted, and monitored.”

Guidance for IndustryQuality System Approach, 2006

Example Citations

“Your quality control unit (QCU) has allowed failing product to remain in distribution, released product to the market without adequate stability data to support the expiration dates, failed to conduct adequate investigations of discrepancies, failed to adequately review all analytical data prior to release, and failed to assure adequate analytical method validations were conducted for numerous finished product test procedures.”

WL Citation

“ We are particularly concerned with your firm’s failure to implement a robust Quality System. Repeat citations from prior inspections indicate that your quality control unit is not exercising its responsibilities, and may not have the appropriate authority to carry out its responsibilities.”

WL Citation

“Your response of October 28, 2011 is inadequate because you failed to describe the specific steps that you are taking to ensure adequate oversight by the quality unit over critical aseptic operations such as unidirectional airflow pattern studies.”

WL Citation

“The responsibilities and procedures applicable to the quality control unit are not fully followed.Specifically,Your Quality Unit has failed in the responsibility and authority to monitor Quality Systems designed to assure the quality of drug product manufactured and packaged at your firm. This failure is evidenced in the observations below (2-13), as well as continued NDA Field Alerts and recalls for similar problems over the last several years.”

483 Citations

History of QCU Citations

2006 2007 2008 2009 2010 2011 2012 20130

50

100

150

200

250

300

350

22b: Laboratory22: CMO22a: Materials22c: Documentation22a: Investigations22a: No QCU22d: Failure to Follow

Source: Summary of Inspectional Finding by Fiscal Year on FDA/gov

Practical Considerations

• An effective QCU must be fully independent • An effective QCU must be truly valued • Responsibility for “quality” is different than

responsibility for Quality Assurance• The criticality of the Quality System:– “You can’t oversee what you cannot SEE!”

• Device: “Failure of the management with executive responsibility to ensure that an adequate and effective quality system has been fully implemented and maintained at all levels of the organization, as required by 21 C.F.R. § 820.20”

• Drug: “Finally, the Agency is concerned about the response … to this matter. Corporate management has the responsibility to ensure the quality, safety, and integrity of its products. Neither upper management…nor…. ensured global, adequate, or timely resolution of the issues at these sites.”

WL CitationsResponsibilities of Management

10 Years later…

Why do we continue to see the QCU criticized?

Survey Says….

1. Strongly Agree2. Agree3. Disagree4. Strongly Disagree

The QCU reporting structure is isolated from other functions to preserve the

independence of the function.1. Strongly Agree2. Agree3. Disagree4. Strongly Disagree

39%40%14%

7%

The decisions of QCU is fully independent from all operations.

1. Strongly Agree2. Agree3. Disagree4. Strongly Disagree

19%39%34%

8%

The role of QCU is clearly defined and documented in a formal procedure.

1. Strongly Agree2. Agree3. Disagree4. Strongly Disagree

48%38%12%

1%

The QCU has the required skills – both technical and leadership – to

fulfill its responsibility.

1. Strongly Agree2. Agree3. Disagree4. Strongly Disagree

19%42%28%10%

The QCU is adequately resourced.

1. Strongly Agree2. Agree3. Disagree4. Strongly Disagree

8%27%41%24%

The QCU has oversight of the QC laboratory operations.

1. Strongly Agree2. Agree3. Disagree4. Strongly Disagree

42%41%12%

5%

The QCU is given the authority and support from Executive Management to

fulfill its role.1. Strongly Agree2. Agree3. Disagree4. Strongly Disagree

20%54%20%

6%

Executive Management is integrally involved and aware of quality issues.

1. Strongly Agree2. Agree3. Disagree4. Strongly Disagree

28%46%23%

3%

Executive management does not inappropriately influence (or attempt to

influence) the decisions of the QCU.

1. Strongly Agree2. Agree3. Disagree4. Strongly Disagree

17%46%27%11%

Data

Information

What do we do differently to get a different result?

Thank you!

Contact Information:cmersh@qualityexecutivepartners.comwww.qualityexecutivepartners.com

Survey Says!

Data Analysis by:bduncan@qualityexecutivepartners.comwww.qualityexecutivepartners.com

54%

5%7%

7%1%

9%

6%5%

6%

Demographic Comparison

Quality AssuranceManufacturingRegulatory AffairsQuality ControlResearch & DevelopmentExecutive ManagementConsultantRegulatorOther

The Audience

Question % Agreement

2) The QCU reporting structure is isolated from other functions to preserve the independence of the function

79%

3) The decisions of the QCU are fully independent from all operations 58%

4) The role of QCU is clearly defined and documented in a formal procedure

86%

5) The QCU has the required skills – both technical and leadership – to fulfill its responsibility

62%

6) The QCU is adequately resourced 35%

7) The QCU has oversight of QC laboratory operations 83%

8) The QCU is given the authority and support from Executive Management to fulfill its role

74%

9) Executive Management is integrally involved and aware of quality issues

74%

10) Executive management does not inappropriately influence (or attempt to influence) the decisions of the QCU

63%

General Results

9 Questions: Common Themes

Question% Agreement

QA Mfg Exec. Mgmt Regulators

2) The QCU reporting structure is isolated from other functions to preserve the independence of the function

3) The decisions of the QCU are fully independent from all operations

4) The role of QCU is clearly defined and documented in a formal procedure

5) The QCU has the required skills – both technical and leadership – to fulfill its responsibility

6) The QCU is adequately resourced

7) The QCU has oversight of QC laboratory operations

8) The QCU is given the authority and support from Executive Management to fulfill its role

9) Executive Management is integrally involved and aware of quality issues

10) Executive management does not inappropriately influence (or attempt to influence) the decisions of the QCU

<50% Agree 50% - 75% Agree

>75% Agree

Quality Assu

rance

Manufacturin

g

Regulatory Affairs

Quality Contro

l

Research &

Development

Execu

tive Management

Consulta

nt

RegulatorOther

0%

20%

40%

60%

80%

100%

120%

2) The QCU reporting structure is isolated from other functions to preserve the independence of the function

>80%

<50%

Demographic Perceptions

Quality Assu

rance

Manufacturin

g

Regulatory Affairs

Quality Contro

l

Research &

Development

Execu

tive Management

Consulta

nt

RegulatorOther

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

3) The decisions of the QCU are fully independent from all opera-tions

>80%

Demographic Perceptions

Quality Assu

rance

Manufacturin

g

Regulatory Affairs

Quality Contro

l

Research &

Development

Execu

tive Management

Consulta

nt

RegulatorOther

0.00%

20.00%

40.00%

60.00%

80.00%

100.00%

120.00%

4) The role of the QCU is clearly defined and documented in a formal procedure

>80%

Demographic Perceptions

Quality Assu

rance

Manufacturin

g

Regulatory Affairs

Quality Contro

l

Research &

Development

Execu

tive Management

Consulta

nt

RegulatorOther

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

5) The QCU has the required skills – both technical and leadership – to fulfill its responsibility

<60%

Demographic Perceptions

Quality Assu

rance

Manufacturin

g

Regulatory Affairs

Quality Contro

l

Research &

Development

Execu

tive Management

Consulta

nt

RegulatorOther

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

6) The QCU is adequately resourced

>50%

Demographic Perceptions

Quality Assu

rance

Manufacturin

g

Regulatory Affairs

Quality Contro

l

Research &

Development

Execu

tive Management

Consulta

nt

RegulatorOther

0.00%

20.00%

40.00%

60.00%

80.00%

100.00%

120.00%

7) The QCU has oversight of QC laboratory operations.

>90%

Demographic Perceptions

Quality Assu

rance

Manufacturin

g

Regulatory Affairs

Quality Contro

l

Research &

Development

Execu

tive Management

Consulta

nt

RegulatorOther

0.00%

20.00%

40.00%

60.00%

80.00%

100.00%

120.00%

8) The QCU is given the authority and support from Executive Management to fulfill its role.

>80%

Demographic Perceptions

Quality Assu

rance

Manufacturin

g

Regulatory Affairs

Quality Contro

l

Research &

Development

Execu

tive Management

Consulta

nt

RegulatorOther

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

100.00%

9) Executive Management is integrally involved and aware of qual-ity issues

>80%

Demographic Perceptions

Quality Assu

rance

Manufacturin

g

Regulatory Affairs

Quality Contro

l

Research &

Development

Execu

tive Management

Consulta

nt

RegulatorOther

0.00%

20.00%

40.00%

60.00%

80.00%

100.00%

120.00%

10) Executive management does not inappropriately influence (or attempt to influence) the decisions of the QCU

>80%

Demographic Perceptions