QbD for Sterile Products

Tim Lukas Pfizer

1. Introduction to the QbD framework/requirements 2. The Need, Value and Demand for QBD 3. QbD demands Expert Design & Detailed Assessment 4. QbD Product Development for Liquid Products A Chronological

staged progression (colour coded) Presentation interspersed with anecdotes

Presentation interspersed with questions

Presentation augmented with some product examples

5. Conclusion 6. Acknowledgements 7. Glossary of Terms

Content

2

The Framework of QbD

Process Analysers

Ena

bler

s: P

AT

Design of Experiments

Multivariate Analysis

Process Modelling

Science

Quality Risk Management Knowledge Management

Quality Quality Target Target Product Product

Profile Profile

Product Product & Process & Process Dev Dev

(CPP) (CPP) Design Design Space Space - -

Quality Target Product Profile (QTPP) CPPs

Design Space

Pharmaceutical Quality System

Control Strategy

Continuous Improve- ment

Product & process development

Und

erpi

nned

by

CQAs

3

Quality By Design for Parenterals With Reference to Other Liquid Products

QbD requires 1. Understand current standards and requirements for a quality product 2. Apply knowledge from design/development/manufacture of past

products, understanding susceptibilities and minimising sensitivity in prototype design

3. Understand the specific properties and challenges of your candidate 4. Select the best, robust development option 5. Conduct systematic evaluation of product attributes & sensitivity

resulting from change in components, composition, process/equipment, testing, storage, stability and use

6. Secure appropriate formulation, primary pack, process, storage and use

4

Quality By Design For Parenterals With Reference To Other Liquid Products

5

Approach similar when applied to Parenteral/liquid systems .

Opportunity to note specific considerations of liquids formulators (renaissance in liquids work associated with Paediatric guidance) .

Drawn extensively from industry (EFPIA) thinking about QBD .

Highlight some general and specific examples from industry .

A work in progress. QBD should and is evolving.

Development Issues - The Need for QbD

6

Muddling through with best guess formulations highlighted the need for Quality By Design

Flawed strategy with increasing analytical scrutiny and specifications shaped around batch data o Are three batches representative or unrepresentative!

o The less effort in control the broader the specification?

o The more diligent the team the tighter the controls (but the less to worry about)

Move away from reactive issues driven formulation fixes with the use of testing to check if quality is present

Embrace certainty through preparation of quality products Composition, formulation, process & controls integrate and dictate the only

outcome, the Quality Product o Confidence in product

o Freedom from pass/ fail testing worries

o Opportunity to eliminate release testing?

Regulator and Innovator demand. (Generics next?) 7

The Value Of QbD : Structured, Systematic And Professional Product Development

8

Quality By Design = Designing In Quality Then Confirming By Assessment

QBD - too often the focus is work confirming robustness. The implicit assumptions o Only possible if you designed the right formulation in the first place o You cant map an operating space if you are at the edge of failure

Late characterisation of product is a high risk strategy with major consequences. (Inheriting a licensed in product) If there is little operational space, options are limited o If possible - manage the product youve got and build in the best controls. Appreciate

there may be manufacture, stability, batch failure and recall issues. (costly in money, manufacture slots, opportunity, reputation, sales)

o If possible renegotiate the product profile (hit in differentiation & sales) o Start the formulation and design process again with improved knowledge o Get a better candidate!

Give yourself every chance of succeeding o Select the right molecule and properties to fit the known broad robust design space o Explore and understand product performance so you can define product robustness

and centre within design space as the most robust/forgiving product process and presentation

o Have time for iteration/response to knowledge/findings 9

Quality Design & Development

10

Design

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Define candidate properties that permit progression Facilitate fast low risk development and enable access And utilisation of institutional knowledge and capabilities

Access prior knowledge of candidate/series/moiety Conduct pre-formulation studies. Define formulation and process options offering robustness

Scope formulation and process options. Identify opportunities and flaws. Select the lead likely to be viable, robust and straightforward to develop.

Define product attributes delivering safety efficacy quality and performance for this therapy. Build in realistic commercial differentiation and utility

Scope Product Options Select and define lead

Quality target product profile

Knowledge Gathering

Molecule properties Quality gate

Assess

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Evaluate the product experimentally based on Risk Analysis. Define fundamental performance indicators. Model predict & confirm quality & robustness experimentally. Establish robust product & process and any sensitivities requiring attention

Product and Process Risk Assessment

Experimentation and Predictive modelling

Control Strategy

Continuous improvement

Final Positioning and lock down

Accept product and position it in the design space based on deep product understanding

Successful Risk assessment. Successful Product. Now optimise manufacturing efficiency based on batch data. Establish flexibility to manage minor changes

Define control based on product/process knowledge and any sensitivities. Establish PARs, design space and response and any PAT approaches

Apply expert & organisational wisdom. Conduct Failure Mode Effects Analysis on the product & process. Identify high risks, potential cause & effects & likely critical process parameters & risk mitigation

The Quality Target Product Profile Requires Care And Understanding

Careful negotiation, defines the formulation challenge and the ease of delivery

Encompasses the needs of regulators, users, patients, marketeers and manufacturing

No requests that undermine quality or hamper development unnecessarily

Adapts to challenges in product development revising non-essential features of the product profile

Critical

Accurate

Realistic

Evolving

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Understand what is necessary to satisfy the regulators, patients

sufficient to provide differentiation possible to simplify development and manufacturing

The Quality Target Product Profile Requires Care And Understanding

Quality Target Product Profile

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Quality Target Product Profile

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Prioritising within the Product Profile

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The Quality Target Product Profile Dictates The Product Design Requirements

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Anecdote The Product Profile Dictates Design And Development Work

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Product Example : Dectomax

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Question/Calculation The Poiseuilles equation states

Q = r4P/8 L or more usefully P= 8 L Q / r4

o P is the pressure drop o L is the length of pipe o is the dynamic viscosity o Q is the flow rate o r is the radius

Also force x distance = work done = pressure x area

This relates the force of injection and the pressure exerted to get the injection to flow to the properties of the fluid and the pipe along which it flows.

J Pharm pharmaco 1979 v31 p497 500 Int J pharmaceutics v 36 (1987) p141 145

A prototype formulation can just be injected under field conditions. Unfortunately formulation requirements dictate that its viscosity is increased four fold. What can you do to the dosing system to offset the increased force of injection? Explain in quantitative terms design options for syringe and needle. 21

Candidate Selection Molecule + right properties = Development Candidate

Example molecule Symplain Weak base, pKa ~9.5

Key properties Solubility must support dose at

some useful pH (3 9) Stability must support a

solution presentation pH/stability sensitivity

manage from pH 3 4.5 Manageable Oxidation risk Manageable thermal lability

Benchmark vs prior knowledge and experience

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Understand Candidate Solubility

Define pKa

Predict solubility using Henderson Hasselbalch equation. Confirm exptlly

Measure intrinsic solubility using thermodynamic stable form of free acid/free base. wrong form=wrong solubility

Free acid/free base ppts when free unionised [D] exceeds saturated solubility in the [D+]/[D] equilibrium. This pptn event defines the maxm solubility at any pH. It defines the [D+] ceiling

Ionised form ppts in combination with a counterion.

Profile solubility of thermodynamically stable salt forms of interest.

Different salt counterions have different plateau solubilities --------

Dont create wrong salt form in situ

Amorphous forms may precipitate/salt out at extreme pH & high concentrations

Understand any counterion (Cl-) Ksp value sensitivity

Dont formulate buffer back at high pH where [D] can supersaturate

Cosolvents raise intrinsic solubility, prevent free base pptn so higher salt solubility is accessible.

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Question/Calculation

Calculate key points and sketch the pH solubility profile of candidates A to F using the equation provided for a free base pH = pK + log10 [S0]/([ST] [S0])

Candidate pKa Intrinsic Solubility(pH) Comments solubility(4C) 3 3.3 3.7 Viable?

A 5.7 5 g/ml B 6.3 1 g/ml C 5.7 1 g/ml D 6.3 5 g/ml E 6.7 5 g/ml F 6.7 1 g/ml

Discuss their relative merits as injectables providing a dose of 2mg/ml. What specification needs to be set to maintain solubility at 4C?

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Anecdote: Desperate Measures To Achieve Objectives. A Price Worth Paying?

In formulation design

*GRAS = Generally Recognised As Safe

Development speed and certainty if you stick with precedent. Novel excipients bring many challenges. Developing design and understanding space from scratch.

Examples - the Cyclodextrins, Hydroxypropyl beta cyclodextrin(HPBCD) and

Sulphobutylether beta cyclodextrin, sodium salt (SBECD)

Pharmacopoeial Precedented Unprecedented

GRAS* & qualified

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Check degradation mechanism and specific sensitivity o pH and H+/OH- catalysed o Metal ion catalysed o Oxidation/light o Thermal lability

Measure small degradation change & [D]f ~[D]i. [D] constant, degradation rate then D independentpseudo zero order. Typically small change during shelf life.

Arrhenius predictions to aid with shelf life prediction. ASAP evaluation providing degradation profile is representative.

Confidence that 4C or lyophile options will support candidate

Exploration of a pH range to support a specification and match with solubility requirement

Understand Candidate Stability

Arrhenius ln k = ln A Ea/RT ln k = ln A Ea/RT + B(%RH)

ASAP (Accelerated Stability Assessment Programme)

K. Waterman

Pharm Res 24 780 (2007) 26

Question/Calculation

Stability calculation using ASAP.

Implications of a shift in equilibrium moisture content by applying ASAP

Exploit short term, high temperature, high moisture, stress stability conditions in which small amounts of degradation occur

Application valid if degradation is mirrored qualitatively across the temperature range (iso-conversion conditions).

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Question The Stokes Einstein (Smoluchowski relation) applies to the diffusion of

spherical particles through liquid with low Reynold number

D = k T/6r

An intermolecular diffusion controlled reaction between drug and excipient is threatening shelf life. If the viscosity () of the product shifts during storage it could threaten product shelf-life. A polymer in the formulation also degrades by hydrolysis during sterilisation. Excipient polymer viscosity depends on excipient quality control and is molecular weight dependent.

What are the implications for the definition of polymer quantities in the formulation and polymer quality assurance?

Consider how much would viscosity have to vary as a result of sterilisation to compromise stability?

What are the implications for excipient quality, molecular weight and formulation concentration/overage in the formulation?

How much of a viscosity increase is needed to improve stability in initial design?

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Anecdote Ensure You Have Adequate Stability For The Proposed Use And Pack

Candidate instability in alcohols/water Most formulation/solubilisation options excluded Move to GRAS listed aprotic solvents could achieve satisfactory stability

and performance Allowed development of topical prototype formulations, stable in glass

vials. Topicals needed to be cheap and packaged at low cost in plastic tubes Moisture transmission through plastic tubes undermined stability Packaging and moisture control costs undermine viability of a cheap

frequently used product

Packaging needs to be an integral part of the product profile Costs are a key concern in generic and Animal Health markets

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Pet endectocide Topical Spot on Monthly dosing Single use tube Easy dosing to pets Polypropylene plastic tube?

Product Idea: Spot On

! Learning

Packaging challenge costs preclude development

Alternative candidate and formulation work required

Product profile, pack requirements and deliverables shape product viability and development

Triglyceride Formulation

Free from water and alcohols

Solution Isopropyl acetate solvent Volatile loss & moisture

ingress modelling Moisture activity/Chemical

stability predict shelf life. Special tube and Al blister

costs prohibitive Identify alternative series with improved stability

Challenge Low cost Limited solubilisers Avoid volatile alcohols Stabilisation against hydrolysis Satisfactory stability in glass

vials Stop moisture ingress through

plastic tubes and Al blisters

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Scope Product Options

What formulation options have a track record of success? Which formulation excipient options are understood and compatible with

my candidate?

What are the chemical stability risks real or apparent, significant or manageable?

What are the physical stability risks and constraints? Disproportionation, sedimentation, viscosity, particulates, pack interactions, leachables/extractives?

Avoid the issues and pick a viable option. Give yourself a hope of a sensible fishbone diagram analysis later

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Composition of Symplain Citrate Injection

(1) Equivalent to 0.5 mg/ml or 2.5 mg/vial of symplain, based on a theoretical potency factor of 73.5% for the citrate salt. Actual weight may vary according to the potency of lot used.

(2) Reflects nominal fill weight. An appropriate overfill is included to ensure labeled extractable volume. (3) If needed, added as a ~ 0.1 M solution in WFI.

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Selecting The Appropriate Composition

Component Comments API Company standard. Appropriate quality controls special care with final

crystallisation solvent, endotoxins, impurities & particulates

Sodium Citrate Buffer precedent at satisfactory pH. Avoid buffer at extreme pH. Ensure no pack interaction. No disproportionation risk with API. Buffer pKa position.

Sodium Chloride Tonicity appropriate. No issues/challenges with sterilisation. Beware common ion effect if appropriate.

HCl Risk/challenge of pH drift during manufacture or in the product. pH adjustment in manufacture aided by buffer if present

NaOH Risk/challenge of pH drift during manufacture or in the product. Worry about introduction of ash if used in large quantities. (Salt purification aid)

Anti-oxidants Precedent, chemical compatability, Control at end of shelf-life

Preservatives Precedent at level, appropriate performance at required pH, chemical stability/compatability. AET criteria met.

Polymers Source, synthesis, peroxides and impact on stability. Robustness to sterilisation. Viscosity and ease of filling

Packaging Available, proven, stability established, already in use, stock item, already validated in use, compatible with formulation. Leachables, ab/adsorption.

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Question/Calculation A drug, di sodium salt of Molecular Wt 446 Dalton is crystallised. It has solubility of 4.46 mg/ml. Calculate its solubility product. What solubility suppression is observed in isotonic saline? How does dissolution rate change under sink conditions moving from water to isotonic saline? Consider the implications for formulation design and manufacturing.

When calculating Ksp, make sure you have the right equation

D 2- + 2 Na+ Na 2 D Ksp = [Na]2 [D]

Even if the drug has good solubility the effect of the solubility product will be marked because of the square relationship for Na+.

A drug salt of molecular weight 446 has a solubility of 4.46 mg/ml. Solubility is 0.01M

Ksp = 0.01 x 0.01 x 0.01 = 1.0 x 10-6 M.

Isotonic saline contains 150mM Na So Ksp = 1.0 x 10-6 = 150 x 10-3 x 150 x 10-3 x [D]

Drug solubility = 4.44 x 10 5 M = 17.8 gA /ml. A 250 fold drop which will impact dissolution

Saline is not a good choice of tonicity adjuster 34

Buffer Question How effective is my formulation buffer? How much do I need in my system? (IUPAC approach)

We normally consider pH change after a change in H +. So how much acid or base generating degradation will prompt a change in pH in my system?

A 100mM buffer system is formulated optimally around its pKa of 5. During formulation storage the pH shifts from pH 6 to pH 4. (Best case and broad pH specification enabled) What acid concentration is generated during the experiment?

If 100mM buffer shifts from pH 6 to pH 4

A-/HA ratio changes from 90.9/9.09 to 9.09/90.9 an 81.8% change.

81.8% acid is associated to form HA and 81.8 mM H+ is consumed.

(fractionally 0.41 = buffer capacity out 1 pH unit from the pK)

This approach, calculating across a significant pH shift as occurs experimentally, is consistent with the IUPAC definition of buffer capacity. J. Chem. Ed 74 937 (1997)

How much buffer will you need at which pH condition? 35

Buffer Calculation A compound (MWt 250 Da) formulated at 10 mg/ml has good solubility in the pH range 3 to 7 & good pH stability in the range 4.0 5.8. During degradation H+ ions are generated. After 2 years shelf life H+ generated is 1% of drug load.

Proposed regulatory pH specification is 4.0 5.7. Internal specification is set at pH 4.3 to 5.5 This ensures supplies in the field always have robust stability.

Manufacturing and pH testing variation means we make the supplies at pH 5.2 (worst case 0.2 unit variation in manufacture/testing)

After manufacture supplies start life at pH 4.9. At end of shelf life, the final pH in the sample on stability should not drop below 4.5 (allows for expt error).

How much (what is the minimum) buffer that will manage a pH drift from 4.9 to 4.5 on stability? If possible pick acetate buffer pK 4.75. (optimal buffer) Calculate the molarity required for this buffer system?

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Question/Calculation Drug molarity in solution is 10/250 = 0.04 M H+ generated on stability = 0.04/100 = 4 x 10 -4 M

pH = pK + log10 [A-] / [HA]

At the starting pH 4.9 = 4.75 + log10 [z] / [B - z]

where Buffer Molarity is unknown B

0.15 = log10 [z] / [B - z] 1.4125 = z/(B-z) B = 1.708 z

At the final pH 4.5 = 4.75 + log10 [y] / [B - y]

-0.25 = log10 [y] / [B - y] 0.5623 = y/(B - y) B = 2.7782 y

H+ generated on stability = 0.04/100 = 4 x 10 -4 M

However the acetate concentration decreases during the stability pH drift from x to y moles/litre, therefore y = z 4 x 10 -4 moles/litre.

So B = 2.7782 ( z - 4 x 10 -4 ) B = 2.7782 [( B/1.708) - 4 x 10 -4 ]

2.7782 x 4 x 10 -4 = ((2.7782/1.708) - 1) B 1.11 x 10 -3 = 0.6266B

So minimum buffer molarity M = 1.77 m M In this case a low level of buffer would be appropriate minimum if this was the only acid generating mechanism.

Getting the buffer quantity low is particularly important if working at extreme pH. 37

Anecdote: Preservatives/AET and CDs

Cyclodextrins (CDs) are useful solubility enhancers. The beta cyclodextrins used pharmaceutically consist of seven 1,4 linked gluco-D-pyranose units in a ring creating a torus shape. Moieties of similar size to substituted phenyl groups bind into the central cavity. This enhances solubility.

Each of the seven sugars has three potential sites of chemical substitution in the 2, 3 and 6 positions making a maximum theoretical degree of substitution (DS) of 21.

Two beta CDs have been used parenterally.

Encapsin Hydroxypropyl cyclodextrin (HPBCD)

Captisol Sulphobutylether cyclodextrin as its sodium salt (SBECD)

These can be used to aid solubility. Useful reference on Cyclodextrins (CD) Mark E Davis, Marcus E Brewster in Nature Reviews Drug Discovery 3 1023 -1035

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Unfortunately the CDs also include most of the preferred preservatives which have a favourable structure for inclusion.

There is competition in solution which means less CD is available to dissolve drug. Preservative is associated with CD increasing the formulation requirement. This makes multi-dose products containing CD difficult to preserve.

When formulating find preservatives with minimal inclusion

find conditions where sufficient preservative is free to pass the Anti-microbial Effectiveness Test (AET)

ensure sufficient drug is included to achieve necessary solubility

These are complex challenging systems with a complex design space. (eg.Cerenia)

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Anecdote: Preservatives/AET and CDs

Question/Calculation A Pharma Co. is considering developing a single dose CD formulation using HPBCD (Encapsin) as an alternative to its current SBECD (Captisol) formulation which contains 5mg/ml drug P(M Wt 500 Da) in a 4.326% SBECD solution. If the association constant for the free base drug is K= 2000 dm3 mol-1 in SBECDNa (DS=6.3, Av. MWt 2163 Da) and K= 670 dm3 mol-1 for free base drug associating in HPBCD (DS= 4.5, Av M.Wt 1396) then.

P + CD PCD K = [PCD]/[P] [CD]

1. Calculate for the 5mg/ml formulation how much drug is included in SBECD in percentage terms.

2. What quantity of drug is free in solution? 3. If you swap to HPBCD how much is needed? 4. What is the particle number in solution for the formulations and how much

NaCl should be added to achieve appropriate tonicity? 40

Question/Calculation 1. [P] = 5g/L /500 Da = 0.01M [SCDNa] = 43.26g/L / 2163 = 0.02M P + CD PCD K = [PCD]/[P] [CD] 0.01-x 0.02 x x K = x/ (0.01 x)(0.02-x)=2000

x2 61x + 0.4 = 0 X = [61 (612 1.6)0.5 ]/2 = 0.006558 M 0.006558 x100%/0.01 = 65.58%

2. 0.01 0.006558 = 0.003442M or 0.3442 x 5mg/ml = 1.721mg/ml

4a. Particle number = [P] + [CD] + [PCD] + [Na] = 0.003442 + 0.013442 + 0.006558 + (0.02 x 6.3) complete dissociation = 0.1494M, approximately half the 300mM requirement

Suggests that 0.45% NaCl would be a useful additive to adjust tonicity

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Question/Calculation 3. P + CD PCD K = [PCD]/[P] [CD] 0.003442 R 0.006558 670 = 6558/(3442 . R)

R = 0.0028437 = free CD

T (Total CD) = R + [PCD] = 0.0028437 + 0.006558 = 0.0094017M 0.0094017 x 1396 Da = 13.1248g/L 1.312%

4a. Particle number = [P] + [CD] + [PCD] = 0.003442 + 0.0094017 = 0. 012844M,

very little of the 300mM requirement has been used. (300 12.8) / 300 x 0.9% ~ 0.9% NaCl Standard adjustment is reasonable

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Product And Process Risk Assessment

Weve done our best to design the product What are the implications for future development? Are there any things we have overlooked? Have we designed something sensible we can work with and manufacture

as standard?

Where should we focus our efforts in ensuring success and a problem free product throughout its commercial life?

Have we a clear dispassionate rationale for what we are and are not going to do?

Avoid being dismissive based on false presumptions of a track record of success with a particular process

Collate organisational knowledge and exploit individual expertise (science based decisions, not a democracy avoid non expert decision skew )

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Typical Manufacturing Process

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Derivation Of Quality Attributes From The Quality Target Product Profile

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Initial Risk Assessment: Based On Prior Knowledge Applied To Qas

DP Quality Attributes derived

from TPP

Drug Product Manufacturing Unit Operations/Variables Components

Mixing, holding Filtration (in-line) Filling Stop-pering Capping Steam Sterilization API attributes Stopper / glass attributes

Appearance Identity Assay Impurity Sterility Endotoxins pH Particulate Matter Extractable volume O2 in headspace C/C Integrity Osmolality

Low risk or no impact on quality attributes Potentially high risk to quality attributes 46

Initial Risk Assessment: Documenting Rationale For High/Low Risk Areas

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Recognising Potential Contributors To Chemical Instability

Prioritise experiments, investigate significance, address &/or control 48

Anecdote : Packaging And Leachables And Control Of Excipients

It is easy to view the formulation as a separate entity to the excipients and packaging supplies that are integral to its performance Dont

These components and their interaction with the product need to be considered.

Changes can have disastrous consequences. (our knowledge base is not that broad, supplier understanding is also limited)

The fishbone diagram makes you think actively about your system and not drift into problems

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Product : Phosphate Prodrugs

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Experimental and Predictive Modelling

Many questions are raised by the risk assessment process. Experience helps you focus effort on the big risks If there is a concern only data will reassure colleagues and regulators that

the product is robust

Develop experimental designs that capture interdependence through the manufacturing process

Modelling helps avoid the completion of obvious experiments. Modelling helps you investigate and design experiments and avoid the

unnecessary process work.

Modelling helps you harness knowledge from multiple previous products rather than focus on 1 or 2 batches of this product.

1 batch providing success versus an accurate estimation of the boundary of failure

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Formulation Design Of Experiments

Use DOE to characterize inter-dependent and synergistic effects of Temperature, pH, Oxygen and Light on product stability to the point of use

pH > temp > O2 > light

Formulation design & controls

(Manage through manufacture packaging and administration set)

Sterilization process (Storage and use)

Manage with Manufacturing controls

Terminal Sterilisation Feasibility: Cumulative Contributions To Degradation

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Terminal Sterilization Feasibility

Parameters: o Set-point temperature o Dwell time

Key requirements (CQAs): o Sterility Assurance Level (Log Reduction 8) o Degradation 2%

Limits can be defined based on first principles:

o Sterilization theory:

o Arrhenius kinetics:

Less experimentation required Allows non-empirical Design Space development 54

Balancing opposing effects: sterility assurance vs chemical stability

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Terminal Sterilization Feasibility: Identify A Mutually Compliant Operating Solution Space For

Sal And Purity

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Terminal Sterilisation Design Space

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Question/Calculation

If there was an interruption to a sterilisation cyclecould your product go through it all over again?

What would the implications be for stability?

Is there a process that is most energy efficient and shift efficient for manufacturing, can these conditions be underwritten so flexibility exists in operations

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ANECDOTE: Link Between Formulation Choice And Design Space Complexity Formulating with Cyclodextrins. SBECD DS=6.5 CD is a heterogeneous population of cyclodextrins with different substitution

patterns (21 potential centres for substitution) K the association constant (binding stability constant) is a population mean K may and does vary with Degree of substitution(DS) on the CD As DS varies moles of CD varies since CD is used as a % w/v in the

formulation K varies with Temperature K varies with pH Stability depends on pH Solubility depends on K Chemical Stability may depend on K (steric effects) Chemical stability depends on viscosity Careful mapping of design space boundaries so formulation is always

robust 59

Control Strategy

If the control is needed for product quality make sure it is developed and applied.

Develop based on previous experience in collaboration with the manufacturing site and capabilities.

o Cant impose your aspirations.

o Build in time for introduction of new approaches

The simpler the better. Avoid complications and ambiguity. Integrate controls with design space & specification

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Parametric Release For

Sterility

Risk assessment (FMEA)

Detailed decision tree for batch release

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ProcessControls

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Process Controls Controls on O2 exposure:

oEliminates the need for an antioxidant oReduces degradation extending the terminal sterilisn design

space

PAT Applications: oN2 sparge of compounded solution (feedback control to limit

dissolved O2 content) oFill weight monitoring with feedback control oN2 purge rate during filling (feedback control to limit O2

headspace) oBut temperature & duration design space needed for

sterilisation

Real Time Release (RTR) oFill weight data in lieu of extractable volume 63

Visualization Of Control Strategy

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Revised Risk Assessment

Failure Mode Effects Analysis quantifies risk and prioritizes work Risk is manageable/acceptable after implementing the control strategy

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Revised Risk Assessment Stopper / glass attributes API attributes Steam Sterilization Capping Stop- pering Filling Filtration Mixing, holding

Components Drug Product Manufacturing Unit Operations/Variables DP Quality Attributes derived from TPP

Osmolality C/C Integrity O2 in headspace Extractable volume Particulate matter pH Endotoxins Sterility Impurity Assay Identity Appearance

Low risk (Originally red - Potentially Critical to Quality) Risk mitigated and/or Control Strategy implemented

Acceptable risk following implementation of control strategy 66

Continuous Improvement Opportunities Successful Risk assessment, Successful Product. Now optimise

since development provided Design space flexibility to manage minor changes

Manufacturing understanding and efficiency based on batch data. Identify and act on trends & knowledge to improve product and supply for customers and efficiency for manufacturer.

Simple data review and tracking allows spot change and avoid problems.

Benefits in throughput, reduced waste, downtime and lost manufacturing capacity, eliminate systemic errors, position optimally in specification

Understand variability in API, excipients and process Manage change in manufacturing sites/facilities

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Product Example: Stronghold Selamectin formulated in Glycol ether (DPGMME)

and Propan-2-ol

Learning Fundamental diffusion

science modelling

Primary pack controls include the Al blister

Attention to seal quality & control/thickness of pack

Understand IPA and water flux

Non critical formulation variation underwritten in the clinic

Pet endectocide Spot on dosing monthly single use easy dosing to pets flexible plastic tube

Challenge

IPA used promotes spread - supersaturation

- transdermal delivery - Systemic efficacy (endos)

IPA varies provides easy dose volume

IPA diffuses through PP tube IPA hold up in Al blister IPA diffusion through blister Moisture ingress Significant leachables

Resolution Tube seal integrity & dose delivery

Tube thickness & diffusion modelling and vapour steady state

Al blister design -Limit head space -Controlled land width & glue -Land width seal quality/alignment -Control Al thickness and quality

Hold strategy for tubes prior to blistering

Pin hole He leak check, microscopy Qualify formulation storage change

68

Product Example: Slentrol Solution in Medium

Chain Triglyceride oil Polypropylene bottle LDPE insert and liner

Rubber free dosing device

Weight loss in dogs Dose on food/in mouth Taste Acceptance Titrating escalating dose Daily dose regime Easy measurement Convenient dosing

Challenge Oil leachables dose titration 20 fold

(0.05 1 mg/kg) dose target 2 100kg

Tamper evident child resistant cap Formulation taste acceptability

through life

Consistent bioavailability Oil compatible packaging No confusion with syringes preservation for in use (months)

Solution Oily solution to meet dose titration &

bioavailability need Non rancid oil no oxidation Preservation achieved as is no

migration effects 3 PP bottles designed to fit

manufacturing line set up stock item child resistant cap purpose designed bottle insert Bottle insert cap compatible and fits

dosing devices Dosing devices for oil use (swelling

free)

Learning Formulation avoids anti-

oxidant, preservation requirements & pack impact

In use studies on device performance and stability

Bottle insert fitting strategy at manufacturing site

Extractives leachables with representative material in other standard bottles

Extractives/leachables on device/insert (known polymer resins) 69

Conclusion Highlighted examples of application of QbD principles in a

science-and risk-based approach to Drug Product development

Upfront planning around a QTPP is key to success Sensible design is essential it makes the assessment process

meaningful

Key assessment components are: o Comprehensive risk assessment on product, components, process o Demonstration of risk minimization approaches o How to document risk acceptance rationale o DoE and modeling to develop product/process understanding o Application of DoE, Design Space, PAT, RTR, etc. for robust control

QBD is in its infancy but it is here to stay for parenteral and liquid products

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Acknowledgements Nancy Harper (Pfizer)

Others from EFPIAs QbD Small Molecule Team: Thomas Backensfeld (Bayer Schering) Christian DeMuynck (Nycomed) Ritva Haikala (Orion Pharma) Heinz Wiederkehr (Roche) Brian Withers (Abbott)

Pfizer colleagues too numerous to single out working on Human and Veterinary Medicines over the last 25 years

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AET Anti-microbial effectiveness testing ASAP Accelerated Stability Assessment Programme CD Cyclodextrin GRAS Generally Recognised As Safe HPBCD Encapsin Hydroxypropyl cyclodextrin IM Intramuscular IV Intravenous LA Long acting MD Multi-dose RTR Real Time Release SAL Sterility assurance limit SBECD Captisol Sulphobutylether cyclodextrin, Sodium salt SC Subcutaneous VM Veterinary Medicine

Glossary of Terms

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Thank You

About the Lecturer Dr Tim Lukas is a Physical Chemist by training who has worked on

human and veterinary medicine development for more than twenty years, based at Pfizers Global Research and Development laboratories in Sandwich, Kent. His work has spanned discovery support through to full development on oral, parenteral and inhaled new chemical entities and biologicals.

Specific formulation experience includes Dectomax, Cerenia, Vfend and Phosfluconazole injectables, and Stronghold spot on, for which he holds the formulation patent.

Tim led the Pharmaceutical development of Slentrol oral solution, coordinated the Pharmaceutical sciences development of the Pfizers Veterinary Medicines Portfolio including Advastat premix, Palladia and Trocoxil and set up Pfizers Veterinary Medicines Formulation group in Mumbai, India.

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