The Role of the QP: before & after Annex 16

Presented by: Karen Ginsbury

For IFF, Denmark

November 2015

PCI Pharmaceutical Consulting

What’s bothering me…

• Getting geared up to do cleaning validation using the PDE / HBEL toxicological limits

• Getting a handle on the CMO supply chain –managing outsourced operations

Responsibility Authority

• (Duty and that Is to release the batches)

• (Gives you a right to decide on the status of the batch including to reject the batch)

Responsibility Authority

• Having the duty to perform a task

• Being accountable for performing that task

• Having control over the performance of the task

• Without “additional” authorization

• The power or right to give orders, make decisions, and enforce obedience

• Within the framework of a company or organization

Responsibility Authority

• YOUR duty to:

– Keep management informed

– Request and insist on appropriate resources

– Take action if authority is not granted

• must be granted by:

– Owner

– Board of directors

– General manager / CEO…

– Your boss if other than the above

• AND they must allow you to perform your responsibilities without interference and with appropriate resources

Responsibility vs Authority

• The behaviors, beliefs and values characteristic of a particular group

• Culture is:– Transmitted actively by defining:

• Mission

• Goals

• Metrics

– Transmitted passively and often subconsciously by behavior, body language, facial expressions and other actions

Delegated QP with Head QP

• What happens if you disagree with the Head QP who overturns your decision?

• The final responsibility is with the Head QP and they could overturn and sign

• Document all the information that is the basis for your decision and the Head QP then must document their reason for overturning your recommendation

• This should be in the SOP itself. Some companies put in that batch rejection must run by or be performed by the Head QP

Better do it now…

• Qualitycustomer requirements expectationsfulfilling specificationsconsistently producing the same product which is the one you intend to produce

• Quality is meeting all the requirements all the time

• Quality Systemensures or is intended to ensure that we achieve qualityawarenessSOPs documents explaining how to do activities and implement regulatory requirements and guidelines

• Is the sum total of the organized arrangements (facility, utility, systems, equipment design, activities, procedures, personnel…) made with the intention of preventing things from going wrong and ensuring that the process and the product meet all the requirements all the time

What sort of Organization do you work in / with? – active and visible support

Grumpy Cat

• What has changed?

• What is your most challenging issue?

What’s Troubling Me…

Certification by a QP and Batch Release: Annex 16

• Issued October 2015

• Effective 15 APRIL, 2016

• Reason for update: SUPPLY CHAIN

Let’s look at Annex 16What jumps out ?

• 8 has grown to 21• Control of entire supply chain including excipients and API

and need to know the whole chain – if not in full control need agreements with QPs preceding you before release of the final productis a major oversight

• Need confidence in the whole system – can only get the oversight if you have set up a working system which makes the information available – will need a lot of ongoing effort:RESOURCES for setting up the system to get the data / information and then for maintaining the system and handling changes - education

Let’s look at Annex 16What jumps out ?

• Prepare end to end process maps – block diagrams showing every link in the supply chain back to earliest starting materials and through to the other end i.e. distribution

• Make a risk assessment on the whole supply chain and justify what you have or don’t have – can we have “white list” suppliers

• Put your resources at the high risk items

Let’s look at Annex 16What jumps out ?

• Manufacturing steps at different sites – quality agreement and CLEAR definition as to which QP is responsible for what operations

• Handling of unexpected deviationsQP discretion? Yes or no

Annex 16

• Potential product quality defects are included and chapter 8 gets a mention – if PV QP doesn’t share information about post-marketing events…how will the batch release QP know if there are potential quality defects

• Monthly meetings between PV QP and release QP to share adverse events defined in SOPoutsourced PV so have SOP and quality agreement to share everything that is received post market from the market twice a year and if a signal is identified

• We apparently need a contract or SOP between QP release and QP PV regarding who takes action when product hold / recall is warranted – who makes that decision – either one could make the decision but must notify the other

Annex 16Batch release – pre-requisites

• Supplier qualification and falsified medicines directive

• API and excipients:– Audits

– quality agreements

• CMOs:– Production

– Packaging

– Other service providers…

Annex 16Batch release – pre-requisites

• Validation and qualification (annex 15)in – or out of scope?

• Computerized systems (annex 11)especially for batch release and inventoryin – or out of scope?

• Batch record review and data integrity…

Annex 16Batch release – pre-requisites

• QP discretion

• CAPA, investigations…

• And before any of that process mapping and risk assessment!

Risk Assessment for Excipients

What’s Troubling the Inspector 2015

• #1 Data integrity

• #2 Quality Culture (???)(attitude of most senior management??)leadership?

• #3 Quality Metrics

• #4 Drug Shortages

• #5 Supply chain and falsified medicines(although ties in with #1…closely)

GMP / GDP Inspectors Working Group

FDA Guidance Agenda 2015

What changes in last 12 monthsEU GMPs

Part 1• Cap 2: Personnel• Cap 3: Premises and Equipt• Cap 5: Production• Cap 6: Quality Control• Cap 8: Complaints, Recalls

Part 2 APIsAnnex 1Annex 15 Annex 16Annex 17

Effective:• 16 Feb 2014• 01 Mar 2015• 01 Mar 2015• 01 Oct 2014• 01 Mar 2015

• 01 Sep 2014• Concept paper on revision• 01 Oct 2015• 01 April 2016• Draft out

2 - Personnel

• Effective Feb 2014

• Changes:

– Integrate principles of quality system i.e. ICH Q10

– Leadership and quality culture /metrics(come to it a little later on)

3 – Premises and Equipment

3.6 as part of improved guidance on prevention of cross-contamination involving Cap 5

5 - Production

6 – Quality Control

8 – Complaints, Quality Defects and Product Recalls

Annex 15 Validation

Annex 17: Real TimeRelease Testing RTRT

32

Part 2 – Active Substance / API

Other

• US GMPs: 21CFR parts 210, 211, part 11 and part 820

• FDA guidances:

– Draft guidance on quality metrics

– Quality system guidance vs ICH Q8, 9, 10

– Process validation guidance

– Contract Manufacture

Other

• MHRA Compliance Report program and FDA on quality metrics

• WHO Guidances

• PIC/s Guidances

• USP, European Pharmacopoeia

• Pulling together the threads and staying updated

Hot Topics – Data Integrity

Data Integrity – does your company have a data governance policy?

What is Quality

• Meeting requirements – all of them all the time and that means defining the requirements

• Annex 16 defines requirements for batch certification and release

Waivers

• the act of intentionally [and voluntarily] relinquishing or abandoning a known right, claim, or privilege

• So a “planned” deviation or “temporary” change or “special” release is a waiver of “quality” which is meeting requirements (all of them all the time)

Have you Heard About…ISO 9001:2015?

What is the differenceProduct control Process control

Product vs Process Control

Product

• Is controlled at the end of the process and you can do nothing about it – you have already made the quality –so you test and if it is ok –release and if it is not ok –you SHOULD reject but you probably get into an OOS fight

Process

• Is controlled through understanding where the variability is and controlling critical process parameters such that all three cakes come out the same even when baked by three different students in three different ovens

“My bread is fresh and tasty”

Quality control: the process of

producing the product (or service) with

the intent of eliminating problems that

might result in defects

The use of techniques and activities to

achieve, sustain and improve the

quality of a product

Where does QP Responsibility Fit…?Certification and Release

44

CPPs and CQAs

(Critical) Quality Attribute (CQA):• A physical, chemical, biological or microbiological property or

characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality

[= safety, efficacy, performance](Critical) Process Parameter (CPP):• A process parameter whose variability has an impact on a

critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality

45

46

People

Equipment

Measurement

Process

Materials

Environment

I

N

P

U

T

S

(X)

y = ƒ(x)

OUTPUT

y

Inputs to the process

control variabilityof the Output

Observation

Ind

ivid

ua

l V

alu

e

4038363432302826242220

120

115

110

105

100

95

90

_X=102.37

UCL=116.68

LCL=88.05

I Chart

Observation

Ind

ivid

ua

l V

alu

e

6058565452504846444240

115

110

105

100

95

90

85

80

_X=97.94

UCL=112.65

LCL=83.23

I Chart

Observation

Ind

ivid

ua

l V

alu

e

8078767472706866646260

115

110

105

100

95

90

_X=99.63

UCL=111.55

LCL=87.71

I Chart

Observation

Ind

ivid

ua

l V

alu

e

10098969492908886848280

110

105

100

95

90

85

_X=98.76

UCL=111.17

LCL=86.35

I Chart

Observation

Ind

ivid

ua

l V

alu

e

6058565452504846444240

115

110

105

100

95

90

85

80

_X=97.94

UCL=112.65

LCL=83.23

I Chart

Observation

Ind

ivid

ua

l V

alu

e

8078767472706866646260

115

110

105

100

95

90

_X=99.63

UCL=111.55

LCL=87.71

I Chart

Observation

Ind

ivid

ua

l V

alu

e

9181716151413121111

115

110

105

100

95

90

85

_X=99.95

UCL=114.17

LCL=85.72

I Chart

Adapted from slide by Moheb Naser, When at FDA

CPPs affect CQAs: Reliable / PredictableKnown variation / Reduce Variation

46

George Bernard Shaw

The only man I know who behaves sensibly is my

tailor - he takes my measurements anew each time

he sees me.

The rest go on with their old measurements and

expect me to fit them

FDA Metrics

FDA Optional Metrics Related to Quality Culture and Process Capability/Performance

Optional metric #2

Optional metric #2

Optional metric #3

What Quality Data Would Be Reported

What Quality Data Would Be Reported

Measurement is the basis of the Quality Process

• What do we measure

• What could we measure

• What should we measure

• What can we measure

Data Collection Plans (Protocols)

What data NEEDS to be collected(if all data is important then none is important)

HOW should it be collected?

HOW should it be analyzed?

HOW should it be presented? And by who and to whom?

56

How many metrics

• BE CAREFUL – if everything is important then nothing is important

About Measurement

• “Measurement is the first step that leads to control and eventually to improvement

• If you can’t measure something, you can’t understand it

• If you can’t understand it, you can’t control it

• If you can’t control it, you can’t improve it.”

H. James Harrington

Measureable…But Meaningful

• If a measurement matters at all, it is because it must have some conceivable effect on decisions and behavior

• If we can't identify a decision that could be affected by a proposed measurement and how it could change those decisions, then the measurement simply has no value

Douglas W. Hubbard, How to Measure Anything: Finding the Value of Intangibles in Business

Data Collection Plans

• Who decides what data to collect?

• How do they make that decision?

• How do they COMMUNICATE the decision?(what are the tools)

• How do they educate for compliance with the data collection plan?

The toolbox – Fabulous 14 Tools

• Process flow diagram• Cause and effect (fishbone)• Pareto chart• Check sheets• Location diagrams• Tally count• Time plot• Scatter diagram• Histogram• Stem and Leaf• Box and Whisper plot• Regression analysis• Control Chart• Conformance chart

Dashboards

• Dashboards are reporting tools that consolidate and arrange numbers, metrics and sometimes scorecards on a single screen

• Usually tailored for a specific role

• Display metrics targeted for a single point of view or department

Dashboards

The Power of Walking the Floor

• Thoughts?

The Power of Walking the Floor

• “You see but you do not observe”

• Just stand and watch a production operation and ask questions about what you see

• Talk to operators and LISTEN to their comments

• You must understand the processes you are certifying

In Conclusion

• GMP isn’t enough even if “c”

• Keep it Simple:

– Define requirements

– Use Risk Management to identify risks and prevent them from happening

– Monitor and improve in a PDCA cycle

In Conclusion

• Stay up to date…

• Stay cool, calm and collected

• Ask for and make sure you get data and information in order to make informed decisions

• Have process maps and regularly audit or have links in the chain audited by people you trust

• Investigate and participate in significant deviations, changes and quality defects / complaints

• Refuse to be brushed aside with an “it’s ok”

• Use RISK MANAGEMENT not just “take risks”

THANK YOU FOR PARTICIPATING

FIND ME AT: karen@pcipharma.com