quality risk management - rmc pharmarmcpharma.com/articles/quality risk...

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QUALITY RISK MANAGEMENT

Scott Rudge

1 of 36 RMC Pharmaceutical Solutions, Inc.

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OUTLINE

• What is the end product of QRM?• The Target Product Profile• Quality Attributes• Process Map• Cause and Effect Matrix• Failure Modes• Risk Register

12December16 www.rmcpharma.com 2 of 36 RMC Pharmaceutical Solutions, Inc.

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WHAT IS TO GAIN FROM QUALITY RISK MANAGEMENT?

1. Better products for patients2. A useable list of priorities that is visible to

management3. Increased focus on structure/function relationship4. A guideline for process/product development5. Information sharing from R&D to PD

• Start with the end in mind1

1Stephen Covey, Seven Habits of Highly Effective People


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WHAT ARE THE RISKS IN QUALITY RISK MANAGEMENT?

• Risk Assessment is not a substitute for good judgment

• Risks of Failure are not the only basis on which to make a decision• There is excellent research on decision making, and great

tools available that should be used more often• The details will swamp out the signal• Q9 is a set of tools, you must practice them to use

them well


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STRUCTURE OF QUALITY RISK MANAGEMENT

TPP (product design)

CQAs Risk MapCause Effect / Input

Output

Risk Analysis

Risk Register


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TARGET PRODUCT PROFILE

• Describes the biology of the product being developed

• Describes the clinical indication• Describes the typical patient use profile, and their

status (immune compromised, terminal, chronic)• The product packaging and stability requirements• The likely dose and the route of administration• Any additional characteristics of the product that

will make it useable or attractive to the patient


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TPP EMPHASIS

• The TPP, although rarely written, is the heart of process development and is what ties our activities to the care of the patient

• While we are all unlikely to be physicians, it is important for us to understand the character of the patients who will be using our products

• It’s also important for our compassion, to design products that the patient will use, where compliance will be easy and the drug will be effective


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TPP TEAM

• Here is the ideal TPP team:• Clinical• Marketing• Research/Discovery• Toxicology• Product development

• API representative• Drug product representative

• Senior management

• We are not always taught to work well with these groups, especially marketing, but they are critical to designing a great product that patients will use


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TPP GOAL

• Translate a molecule with interesting activity in Discovery studies into a product that will benefit patients and that they will use


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Output

Risk Analysis

Risk Register


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CRITICAL QUALITY ATTRIBUTES

• By definition: A physical, chemical, or biological property that should be within an appropriate limit, range, or distribution to ensure the desired product quality (ICH Q8(R2))

• Identification of potential CQAs

• CQAs are distinct from specifications

• Specifications may not include all CQAs, some may be captured in-process, for example, and some may be process related, like viral clearance and bioburden control, or may be part of product design, like compatibility with plastics in IV sets

• Specifications may include items that are NOT CQAs


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CQA IDENTIFICATION AND REVISION

• CQA’s should be identified from the TPP, toxicology studies and from known regulatory requirements• Product/dose related: Endotoxin, DNA, Host cell proteins,

residual solvents, elemental impurities, product concentration, bioactivity, stability and storage conditions

• Toxicology related: substance related impurities, substance related substances, host cell proteins, solvents and elemental impurities

• Regulatory/ industry standards related: viral clearance, bioburden, particulate matter

• When are CQAs revised?• New tox and clinical studies or dosage requirements• Recalls and complaints• PPQ data


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DISCUSSION SLIDE

• Here are two abbreviated product profiles. Discuss some of the attributes that this profile will confer on product Critical Quality Attributes:• Oncology product for late stage liver cancer• IV infusion, 5 grams/day, once weekly for 6 weeks• Patients are immune compromised• Prepared in the hospital pharmacy and delivered to infusion

center in an IV bag


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CQA FROM TTP1

• 5 grams per day means very low endotoxin and DNA specifications will be required

• Also, host cell proteins must be low due to the high dose. • Because the patient is immune compromised, risk of infection

is extreme. Bioburden specifications should be tight, viral clearance tight

• Formulation should be compatible with plastic, and preferably with light exposure

• Exposure is acute, so product related impurities are not as critical as they may otherwise be

• Since the patient doesn’t handle the product directly, storage and dosage form may require a pharmacist, vials are OK, frozen storage OK

• Since the product will be diluted, the product concentration in the vial is not critical, must be small enough as to not change the infusion drastically, but this is not a large constraint


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SECOND TPP

• Here is the second hypothetical TPP• Product is for Type 1 diabetes for enhanced control of

blood sugar• Requires patient to mediate dose depending on blood

sugar, up to three times a day• Needs to fit into an insulin pen• Needs to be carried throughout the day by the patient• Dose is approximately 20 mg/dose, three times a day• Administered subcutaneously• Patients are generally lean


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CQA FROM TTP2

• Self administered by patient, so:• In use stability at body temperature for a week is critical• Dosage form must be easy to manipulate• Concentration must be at least 20 mg/mL so that dose will be <

1 mL, prefer 200 mg/mL. Tolerance on concentration should be low

• Dose relatively low, so DNA, Endotoxin, HCP can be proportionally higher. Lean patients means the levels maybe should be based on a 50 kg patient, rather than 70 kg

• Neutralizing antibodies are an issue, so the similarity to a native molecule must be very high, product related impurities and aggregate must be very low


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Output

Risk Analysis

Risk Register


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TRANSLATING CQAS TO CPPS

12December16 www.rmcpharma.com

Unit Operations (1 – 10)

Quality Attributes (1 – 5)

Glycosylation, Man 6P (5)

High Molecular Weight

Aggregates (5)

Low Molecular Weight

Fragments (3)

Charge Isoforms (3)

Bioactivity (5)

Viral Safety

(5)

UF DF 5 5 12 3 5 5Chromatography

Step 1 5 5 3 18 10 30

Chromatography Step 2 5 30 3 6 10 30

Viral Inactivation 5 10 3 3 30 40

Chromatography Step 3 30 5 18 18 10 5

Viral Filtration 5 15 3 3 5 40


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EXPANDING THE RISK SPACE

• This is the first step where the scope of the project can grow exponentially

• For QRM to be usable, efforts must be made to identify not only the highest risks, but also the lowest risks.

• There are risks everywhere, so you have to use common sense and judgment in identifying the right areas for focus


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BIAS ERROR IN CQAS AND PROCESS MAPPING


Identifying attributes and parameters as critical when they are not:

Expenditure of additional resources may be consumed to monitor and control these factors without any benefit to product quality.

Identifying attributes and parameters as noncritical when they are critical:

Lack of adequate control over important quality attributes and process parameters

Misidentification of an attribute or parameter as critical or noncritical


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PROCESS FLOW AND CAUSE AND EFFECT


Further break a process down to sub-steps, for example the cell bank life cycle, shown above. Then risk map again based on the sub-processes


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RISKS IN CELL BANK CREATION

• Lack of clonality (or proof)• Lack of genetic stability• Lack of sterility• Unknown viruses or phages• Rushed clone selection without good

characterization (cell line or product)• Lack of materials control or knowledge


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CELL BANK SUB-PROCESS RISK MAP


Unit Operations (1 – 10)

Quality Attributes (1 – 5)

Glycosylation, Man 6P (5)

High Molecular Weight

Aggregates (5)

Low Molecular Weight

Fragments (3)

Charge Isoforms (3)

Bioactivity (5)

Viral Safety

(5)

Bank Creation 25 5 3 3 50 50Cell Bank

Manufacture 5 5 3 3 5 50

Cell Bank Storage 5 5 3 3 5 5

Cell Bank Maintenance 5 5 3 3 30 50

Risks are identified only for clone selection and viral contamination. No other risks need to be analyzed at this time


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Output

Risk Analysis

Risk Register


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CAUSE/EFFECT –INPUT/PROCESS/OUTPUT

• Now the focus is on sorting through details• This can be done ad-hoc, but there are tools for

performing this in a systematic fashion• In Cause/Effect, each aspect of a process or sub-

process is listed, and an effect of failure for each aspect is analyzed according to the CQAs

• In Input/Process/Output analysis each input and output is listed, and the process that works on the I’s is described. Then a huge matrix of I’s, P’s and O’s can be constructed and evaluated.


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CAUSE AND EFFECT MATRIX


Key Attribute N/A Y Y Y YRating N/A 9 9 9 9

Process Step Process Parameters

Ass

ay

In-p

roce

ss

purit

yIn

-pro

cess

ch

eck

for

resid

ual

step

-2

Yiel

d

Scor

e

Step 3 Reactor type : QVF reactor 0 0 0 0 0Step 3 Quality of TFA 9 9 9 0 324Step 3 Inert atmosphere (flow of nitrogen rate) 9 9 9 0 324Step 3 Volume of n-heptane (9 vol) 9 9 0 9 324

Cause and effect matrix performed only for the combinations from the process map that are identified as critical, then major.


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FAILURE MODES


CategoryCause of Process/

Parameter Failure

Risk Impact (on Process or

Product)Severity Detection Occurrence

Probability

Primary Risk Control or Mitigation Strategy

Risk Ranking After

Mitigation*

Personnel Parameter entry issue/error

Process Medium High Medium Trained personnel

Low

Sampling contamination

Process and product

High Medium Medium Extensive aseptic training

prior to manufacturing; SIP validation

Low

Off-line read-out Process Low Low Low Personnel training

Low

Equipment Pumps Process Low High Low Calibration/qualification of

pump

Low

Agitation Process High High Low Calibration of system

Low

SIP failure Process High Medium Low Validation of SIP process

Low

CIP failure Process Low Medium Low Validation of CIP process

Low

Steam Process High High Low Validation of utilities

Low

Oxygen Process High Medium Low Received as raw material

with QA release

Low

Air Process High Medium Low Use as clean compressed sterile air with QA release

Low

Carbon dioxide Process High Medium Low Received as raw material

with QA release

Low


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FAILURE MODES -> RISK MITIGATION

• This is where we use some of the other tools in Q9 can come in, Ishikawa

• DOE, Feasibility Studies and Engineering Batches• Equipment modifications, new technologies• Better procedures, maintenance of equipment and

validation• All manner of methods to mitigate risk


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FAILURE MODES -> RISK REGISTER

• Failure modes analyses populate the risk register• The risk register is a global picture of the risks for a

particular product.• Should encompass risks in all aspects of the

development and deliver of a therapy to patients.• How to manage this without overload is a current

topic in the industry.• Some software is available, I don’t think there is a

consensus product.


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RISK REGISTER, BIG AND SMALL


Category Parameter Risk Occ

urre

nce

Det

ectio

n Seve

rity

RPNMitigation Strategy Owner Status

Source document

storagePrepare

column for next batch

temperature, time,

storage solution

10 10 10 1000

sampling for bioburden and

binding capacity , proper storage

conditions

Smith Open FMEA-Capture Column

contamination

DS: Remove and replace

equipment/materials for difficult to

clean shared product contact

equipment/materials (pH

probes, vent filters, column

frits, non-stainless product contact

parts/materials etc.)

Equipment/ material/parts not replaced

10 10 10 1000

Determine extent of shared equipment is there - bioreactors,

columns, filter holdes. Column frits are

shared (DS). Non stainless parts are not

swabbed or replaced.

Jones Open FMEA Changeover


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CONCLUSION

• Quality Risk Management from source to operation was diagramed.

• The key is keeping an eye on the output, making it manageable, and keeping it patient and quality focused

• QRM is a great tool for use throughout your development and product lifecycle


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quality risk management - rmc pharmarmcpharma.com/articles/quality risk...

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