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Today’s SpeakersDr. Mike Long, MBBDirector, ValSource LLC / Group Leader, PDA Quality Risk Management Interest Group

Jeffrey Hartman, Validation Manager, MMD Validation Quality Assurance, MERCK/ Group Leader, PDA Quality Risk Management Interest Group

Kimberly K. Ray, LSS Black Belt, Sr. Manager Project Management/Customer Service, OSO Biopharmaceuticals, Secretary of ISPE Containment Steering Committee

Per-Ake Ohlsson, Global Manager, Market Unit Pharma & Personal Care, Alfa Laval

Participating on the Q&A Panel: Tara Gooen, Team Leader for New and Generic Drug Manufacturing Team, Division of Manufacturing and Product Quality

Pharmaceutical Technology Webinar January 27, 2011

Dr. Mike Long, MBB

Director, Valsource

[email protected]

Intro

• Where are we going as an industry with Risk Management

• Risk Management – words of wisdom

• Brief note on Risk MaPP

Five Risk Guidance/Standards you should be familiar with…

• ICH Q9 – Quality Risk Management (2005)

• ISO 14971 -Medical devices — Application of risk management to medical devices (2007)

• ISO 31000 - Risk management—Principles and guidelines (2009)

• PDA PDA Technical Report 44, (TR 44) Quality Risk Management for Aseptic Processes (2008)

• ISPE – Risk-MaPP : Risk-Based Manufacture of Pharmaceutical Products (2010)

Pharma Risk Management Maturity Level

Source: The Chartered Quality Institute, A guide to Supply Chain Risk Management for the Pharmaceutical and Medical Device Industries and their Suppliers. 2010.

Source: CH Q9 Quality Risk Management

Gaining Proficiency

Area of improvement

Expectations

• You have Risk Assessments performed on your processes.

• MHRA has laid out an expectation that sites have a formal risk register:– High Level Document , Think “Risk Master Plan”

– Summarizes significant risks and their mitigation

– All formal risk assessments need to be linked to Register

– Explanation of your risk review process

http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodManufacturingPractice/FAQ/QualityRiskManagement/index.htm

Words of Wisdom

• A “Risk Based Approach” is not a gift card to reduce testing.

• Risk Management Requires a Balance of identifying and mitigating threats and taking advantage of opportunities

RM Implementation

• Care must be taken to ensure the RM does not become a “Hammer” in search of a “Nail”

– I have the solution, now find me a problem!

A note on Risk MaPP

• Risk-MaPP : Risk-Based Manufacture of Pharmaceutical Products

• .. “provides a scientific risk-based approach based on ICH Q9 to manage the risk of cross-contamination to maintain an appropriate balance between product quality and operator safety”

A note on Risk MaPP

• Addresses the controls to comply with 21 CFR 211.42(c)

…There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mixups…

Not Plausible ≠ “I do not think”

Risk MaPP and Plausibility

Not Plausible ≠ Can’t Happen

Not Plausible = Not Probable

Risk is defined as……the combination of the probability of occurrence of harm and the severity of that harm

Risk = S x O

High likelihood (10)

Med /moderate likelihood(5)

Low Likelihood (1)

Occurrence

Not Plausible

16

Risk Management Opportunities in

the Validation Lifecycle

Pharmaceutical Technology Webinar

11 AM – 12 PM EST

27 January 2011

Jeffrey L. Hartman, MERCK

17

AGENDA

Applications of Risk Management in Validation

Equipment / Facilities Qualification & Computerized Systems Validation

Process Validation

Cleaning Validation

18

Equipment / Facilities Qualification

ASTM 2500 – Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment, August 2007 New Principles

Risk-based approach to commissioning & qualification activities, designated as verification

Risks to product quality and patient safety should govern the scope and extent of verification activities for manufacturing systems

Subject Matter Experts have the responsibility for verification activities, ownership not defined organizationally

Life Cycle approach to verification activities, not once & done Risk Assessment for defining initial activities, updated

throughout system lifecycle to assure robust manufacturing systems

19

Equipment / Facilities QualificationSTM ASTM 2500 – Standard Guide for Specification, Design, and Verification of Pharmaceutical and

Biopharmaceutical Manufacturing Systems and Equipment, August 2007

Resembles ICH Q9 Flowchart End game - Qualification / Verification resources focused on critical

attributes and functionality Eliminates redundant verification activities that have minimal impact or

risk to patient safety and product quality

20

Process Validation

FDA Draft Guidance – Process Validation: General Principles and Practices Principles

Life Cycle approach to Process Validation, 3 Stages with Process Design, Process Performance Qualification, Continued Process Verification

More emphasis on process development & defining boundaries

Better use of statistical tools to monitor and assess process performance

Gain process knowledge & understanding throughout manufacturing until decommissioning / divesture

Risk Management provides the tool to focus resources and define what really is critical to both patient and product.

21

Process Validation – Life Cycle

Stage 1- Process Design Product Profile Early Risk

Assessment Prelim CPPs / CQAs Development (DEV)

Plan Execute Studies (e.g.

DOE) DEV Report Update Risk

Assessment Finalize CPPs / CQAs,

process boundaries Develop Control

Strategy

Stage 2 - Process Performance Qualification Systems Commissioning /Qualification Process Performance Execution Risk Assessment Review / Update

Control Strategy

•Stage 3 – Continued Process Verification

Q8, Q9, & Q10 in Synergy

Develop Monitoring Reports

Assessing the data

on a frequent basis

Make any

changes to

assure process

remains in a state

of control. Update

Control Strategy/Risk Assessment

Develop Monitoring

Plan from ControlStrategy (CS)/

Risk Assessment (RA);monitor critical areas of the

process

22

Cleaning Validation – Risk Based

Cleaning Specifications

ISPE Risk-MaPP (Risk-Based Manufacture of Pharmaceutical Products, September 2010) Baseline guide that provides a scientific risk-based

approach, based on ICH Q9, to manage the risk of cross contamination

Guidance on assessing how health based limits are established for cleaning validation – Acceptable Daily Exposure Limits (ADE) Justification

Disease management at the molecular level, dosages typically less

Targeted mode of action where API may or may not have systemic impact

ADE greater precision and specificity with assessing risk to patient health when compared to alternative approaches, e.g. NMT 1/1000 min or LD50

23



Acceptable Daily Exposure (ADE) or equivalent Daily dose of a substance below which no adverse

effects are anticipated, even if exposure occurs for a lifetime

ADE (mg/day) = NOAEL (mg/kg/day) x BW (kg)

UFC x MF

where:

ADE = Acceptable Daily Exposure

NOAEL = No-Observed-Adverse-Effect Level

BW = Body Weight

UFC = Uncertainty Factor(s)

MF = Modifying Factor

24



Impact Regulatory – ICH Q7/ EudraLex Volume 4 Part II (Scope API)

Residue limits should be practical, achievable, verifiable and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component.

Cleaning specifications – With ADE, Maximum Allowable Carryover (MACO) based on risks to patient

Some cases, calculated limits too high Visual Inspection

VRL - 95% of formulations tested detected @ levels ≤ 4 ug/cm2*

Baseline / Process Capability Limit

Historical experience - 0.4 – 4.0 ug/cm2

*Forsyth, Richard J. and Hartman, Jeffrey L., “A Risk Based Approach to Cleaning Validation using Visible Residue Limits”, Pharmaceutical Engineering, Vol. 28, No. 3, 2008, pp. 8-22

25

Cleaning Validation – Selecting Swab

Location and Number

Can include Severity based on ADE of the API, e.g. the lower the ADE, more Medium / Medium-Low locations tested.

2626

Cleaning Validation – Clean Hold

Time Validation (Fault – tree)

Risk based sampling considering risks to product quality

Harm – Bioburden

Proliferation

Wet Processing

EquipmentStorage Conditions

Transport of

Equipment

Evidence of pooled

water, product

Uncovered,

Environmental

Conditions

Site to Site

Transfers, Outside

Controlled

Environment

27

Conclusion

Risk Management is a tool to efficiently and effectively design, create and maintain robust manufacturing processes. This is achieved by prioritization and focusing resources where it brings the most value to both the patient and product.

Per Q9, The level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk.

THANK YOU!

Polling Question #1

Which of these is your highest contamination concern:

• Cross-contamination

• Microbiological contamination

• Equipment cleanliness

Quality Risk Management Plan (QRMP)

for OSO BioPharmaceuticals

Manufacturing, LLC. (OsoBio)

Outline

Global Regulatory Bodies Reactions

QRMP Evolution

Quantitative Studies

Qualitative Assessment (FMEA)

Development of Site Wide QRMP Document

Intro to OSO BioPharmaceuticals Manufacturing, LLC

Page 30

OSO BioPharmaceuticals Manufacturing, LLC

(OsoBio)

OsoBio is CMO located in Albuquerque,

New Mexico focusing on biologic and

pharmaceutical injectable finished drug

products – (sterile liquid, liquid

suspension and lyophilized

formulations).

The site has demonstrated the ability to

handle virtually any category* of

biological or pharmaceutical product,

from clinical to commercial scale,

specializing in difficult and complex

products, including potent compounds,

proteins, and monoclonal antibodies.

*does not include beta-lactams

Page 31

OsoBio Quality Risk Management Plan

Evolution (timeline)

.OsoBio hired the consulting services of

Julian Wilkins, co-author of ISPE's New

Baseline Guide®, Risk-MaPP to do an

assessment of the facility with regard to

the handling of potent compounds.

Further assessments were

performed which consisted of a

more thorough look at

procedures and practices as well

as in depth interviews with

manufacturing personnel.

Initial containment plans began

development

Initial Failure Modes Effects

Analysis (FMEA) of entire

process began.

FMEA finalized.

Mannitol studies conducted to

provide data to support assumptions

set forth in the FMEA.

Governing QRMP for handling of

potent compounds is approved.

2006

2007

2008

2009

Page 32

Category OEL (mcg/m3/8hrs)

1 >1,000

2 1,000 – 100

3 100 – 10

4 10 – 1

5 <1

OsoBio has developed a categorization system (based on the Merck

Performance Based Exposure Control Limit Categorization System) for

compounds to ensure efficient risk communication to employees and clients

and to ensure selection of the correct exposure control methodologies.

OsoBio Categorization

Page 33

ADE Concepts

The concept of the Acceptable Daily Exposure (ADE) is introduced to indicate a daily dosage that any population can receive for forty years without any observable adverse effect.

This number is derived from the No Observable Effect Level (NOEL) information in the NDAs on the toxicity of the product to the patient. The ADE for the API handled by OsoBio is needed in order to assess the risk of cross-contamination from one product to another product.

ADE values are required for all Category 4 and 5 compounds.

OsoBio will use ADE values using an independent toxicologist, the Threshold of Toxicological Concern or the MAC calculation.

Monographs and other toxicological and clinical information on the toxicology of the compounds will be used in setting the ADE. The ADEs are either provided by the client to OsoBio or developed from industry data.

Page 34

Process Mapping

Process Mapping was performed on each of the following areas:

Material Receipt

Sampling

Compounding/Formulation

Filling

Equipment Cleaning/Decontamination

Capping/Exterior Vial Wash

Lyophilization

Lyophilization Unload

Packaging/Inspection

Page 35

FMEA

OsoBio has adopted the FMEA format for risk assessment. This

technique is well proven since its introduction in 1947 and is based on

assessing:

Severity – the impact on the patient and caregivers

Occurrence – how often this effect takes place

Detection – how easily the failure can be detected.

Each factor is multiplied by the others for a resulting risk priority number

(RPN)

S x O x D = RPN

Page 36

Scoring

The severity, occurrence and detection levels used in the FMEA are as

follows:

#Severity Occurrence Detection

Max.

RPN

1Be unnoticed and not

affect performance

Once every 6-100

yearsObvious 1

3Minor nuisance

resulting in no loss

Once every 1-3

years100% inspection 27

5Likely to result in a

complaint

Once per 6

months

Statistical

sampling125

7Extreme customer

dissatisfactionOnce per batch

All manually

inspected343

10Injury to patient or end

user

More than once

per batch.

Not detectable by

current methods1000

Page 37

FMEA---Scoring Severity, Occurrence

and Detection

The following Risk Priority Number (RPN) limits have been set:

Scores from 1 – 100 are acceptable, the lower the score the lower the

risk.

Scores between 101 and 200 should be investigated and remedied.

Scores over 200 require immediate attention.

During the evaluation, the severity was set at 10 for potent products as

a worst case.

The basis for setting the severity at the highest level was concern over

the impact which carry-over from this drug could have on

immunosuppressed patients taking another drug manufactured by

OsoBio.

Page 38

Potential Routes of

Cross-Contamination

Mix-Up

The ability for accidental human

error to cause the use of

contaminated equipment,

incorrect API, excipients, or

product contact materials.

Retention

Retention of material on product

contact parts from previously

processed materials due to failure

or inadequate cleaning.

Mechanical Transfer or Carry-Over

The transfer by mechanical means of

contaminants from non-product contact

parts, transfer systems, etc.

Airborne Precipitation

The risk of one product in airborne

suspension contaminating another

product.

Page 39

Containment Controls Utilized for FMEA

Containment Controls

Manual Redundant Verification

Electronic Redundant Verification

End Product Testing

SOPs

Master Batch Records

Validated Cleaning Procedures

Sanitization/Decontamination Procedures

Closed Processes

Closed Transfer Processes

Closed Bag (e.g. glove bag)

Visual Inspection

Dedicated/Disposable Equipment

Engineering Controls (AHU, HEPA, Pressure Differentials, etc.)

Separation by Time (Campaign)

Page 40

Page 41

FMEA

Assessment Results

Formulation/Compounding For category 4 and 5 compounds the formulation vessel and

product contact parts are dedicated, indelibly labeled and tagged or are single use disposable.

If the API is a powder, the API is placed in a negative pressure glove bag, sealed and the weight of API is dispensed into a secondary container.

The exterior of the secondary container is wiped out using WFI and transported out via the equipment sleeve.

The secondary container is attached to the formulation vessel and the powder or slurry is discharged.

If required per the batch record, the residual API is bagged out using a double crimp technique, wiped down and returned to the raw material storage room.

Page 42

Assessment Results (con’t)

The room in which this operation takes place is Grade C.

The Formulation rooms are protected by air locks from the general corridor.

The compounding suites have a negative pressure differential to the compounding airlocks.

Each formulation step is subject to redundant manual verification at set up, operation, disassembly and cleaning.

All items are labeled and verified through the Ross Enterprise Resource Planning (ERP) system.

The Batch Record is also reviewed for proper cleaning and use of the clean tags, therefore there is a low risk of cross contamination.

Page 43

Quantitative Study

The purpose of the study was to establish baseline quantitative limit data, based on the ADE, for the manufacture of potent compounds

The study was conducted in three (3) phases

Phase I included a mannitol run (surrogate used because of its ease of detection, free-flowing properties, and solubility). During the run, the equipment train was soiled in strategic locations to simulate worst-case conditions with regard to adverse production events.

Phase II included a water-run, immediately following the mannitol fill, without cleaning or sanitization procedures being implemented to simulate a complete system failure.

Phase III included a water-run after cleaning and sanitization procedures were executed to simulate routine manufacturing procedures.

Samples were collected from the Phase II and III manufacturing runs and assayed for mannitol content.

Page 44

Quantitative Study Results

Parameter

Phase II Run Phase III Run

Percentage of samples above Limit of Detection (0.5 ng)

12 out of 176 = 6.8% 3 out of 176 = 1.7%

Maximum amount of mannitol detected in a vial

42 nanograms 2.7 nanograms

Mannitol level at which there is 99% confidence that 95% of the vials are below **

7.7 nanograms 1.3 nanograms

Page 45

Two additional Phase I and III studies have been performed with all

below limit of detection of 1.0 ng.

Conclusion of the Quantitative StudyOsoBio is capable of safely handling any pharmaceutical compounds

with a safety factor of at least 10 as defined by the ADE of the compound

/ Expected Carryover Level with 99% Confidence that 95% of Vials are

below 1.3 ng. "Table for Distribution-Free Tolerance Limits (One-Sided)”

from "Annals of Mathematical Statistics“**

Reaction of Global Regulatory Bodies to the QRMP

FDA (CDER/CBER)

The Site and Product Specific Quality Risk Management Plan was presented to FDA at district office with FDA representatives from CDER and CBER (some via teleconference) – December 2009

FDA reviewed the document on site as part of a General Inspection – March 2010

Although the FDA does not provide formal approval for this type of plan, the agency does permit the handling of these products in a multi-product facility as long as there is ample evidence to show there is no risk to cross contamination from the product.

Received FDA’s verbal indication that the agency was pleased with the transparency of the presentation prior to manufacture and that they had no major concern.

Page 46

Reaction of Global Regulatory Bodies to the QRMP

EMA was sent a copy of the Site and Product Specific Quality Risk Management Plan and also reviewed the document on site at the company's request– December 2009

EMA/MHRA Type 5 Post Inspection Letter provided by Ian Thrussell, GMP Inspector:

“On the basis of the inspection, and subsequent correspondence, I confirm that your proposed operations concerning the filling of H1N1 attenuated bulk vaccine are in general compliance with the principles and guidelines of GMP.”

No negative observations were noted from either agency regarding the manufacture of potent products in the multi-product facility.

Minor edits made to document and clarified inactivation for biological products versus decontamination for chemical products

Page 47

Thank You

Polling Question #1 Results

Polling Question #2

Is your company currently applying Risk-MaPP principles· Yes· No

Equipment Safety

Quality by Design based on contamination risks

January 27th 2011

Per-Åke OhlssonGlobal Manager

MU Pharma & Personal Care

Alfa Laval

www.alfalaval.comA healthy injection for your business

Equipment Safety

1. A Risk Based Approach on drug contamination

2. Quality by Design on equipment


Sterilisation/sanitisation

Cleaning, rinsing, flushing

Equipment design

Drug ContaminationA Risk Based Approach

• Micro-organisms

• Pharmaceutical products

• Cleaning agents

• Material extraction/reaction from

process equipment

• Air-borne particles and dust

• Substances for operation


EquipmentQuality by Design based on contamination risks

Equipment considerations:

1. Cleanable (flushable)

2. Equipment material

3. Aseptic Design

4. Mix-proof Design

5. Consistent performance

6. Documentation


1. Cleanable (flushable) Basic rules

• You can’t clean what you can’t contact

• High shear forces enhance cleaning


1. Cleanable (flushable) Cleaning Impact

Increased Action, Chemistry & Temperature can speed up the process

Time

Action

Chemistry

Temperature

TACT


1. Cleanable (flushable) Equipment design

• Dead legs

• Air pockets

• Pockets & Crevices

• Velocity

• Surfaces

• Drainability


• Must be selected based on processed media

• Should not add any substances or wear particles

Material used during manufacturing of equipment (polishing

paste, slipping agents, lubrications, etc)

Equal spare parts (same recipe, dimensions, manufacturing

technique, etc.)

100 m100 m

2. Equipment material


Equipment should seal of the environment from the

medicinal product

• The surrounding air contains contaminants

3. Aseptic design


Cleaning liquids and substances for operations must not come

into contact with the medicine.

• Cleaning liquids

• Substances for operation

4. Mix-proof design


5. Consistent performance

• A safe system is only safe as long as it performs consistently

• All equipment needs maintenance and cleaning

• Change control procedure must be performed


6. Documentation

Why is equipment documentation needed?

• Confirm correct equipment

• Secure correct installation, operation and maintenance

• Secure equal spare parts

• Keep track of installed equipment

Polling Question #2 Results

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