QbD for Sterile Products Tim Lukas Pfizer
Content 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 Acknowledgements
7.
Glossary of Terms Terms 2
Content 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 Acknowledgements
7.
Glossary of Terms Terms 2
The Framework of QbD d e n n i y p r b e d n U
Quality Quality Target Target Product Product Profile (QTPP) Profile T A P : s r e l b a n E
Science Pharmaceutical Quality System Quality Risk Management Knowledge Management Product &Product process Design & Process Design development Space Space Dev CQAs CPPs (CPP)
Control Strategy
Continuous Improve- ment
Process Analysers Design of Experiments Multivariate Analysis Process Modelling 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
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.
5
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
o
o
Are three batches representative or unrepresentative! The less effort in control the broader the specification? 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? 7
•
Regulator and Innovator demand. (Generics next?)
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
o
•
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
o
o
o
•
Only possible if you designed the right formulation in the first place You can’t map an operating space if you are at the edge of failure
If possible - manage the product you’ve 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) If possible renegotiate the product profile – (hit in differentiation & sales) Start the formulation and design process again with improved knowledge Get a better candidate!
Give yourself every chance of succeeding o
o
o
Select the right molecule and properties to fit the known broad robust design space 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 Have time for iteration/response to knowledge/findings
9
Quality Design & Development
10
Design Quality target product profile Molecule properties Quality gate
Knowledge Gathering
Scope Product Options Select and define lead
Define product attributes delivering safety efficacy quality and performance for this therapy. Build in realistic commercial differentiation and utility 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.
11
Assess Product and Process Risk Assessment
Experimentation and Predictive modelling
Final Positioning and lock down
Control Strategy
Continuous improvement
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
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
Accept product and position it in the design space based on deep product understanding
Define control based on product/process knowledge and any sensitivities. Establish PARs, design space and response and any PAT approaches
Successful Risk assessment. Successful Product. Now optimise manufacturing efficiency based on batch data. Establish flexibility to manage minor changes
12
The Quality Target Product Profile Requires Care And Understanding
Critical
–
Careful negotiation, defines the formulation challenge and the ease of delivery
Accurate –
Encompasses the needs of regulators, users, patients, marketeers and manufacturing
Realistic –
No requests that undermine quality or hamper development unnecessarily
Evolving –
Adapts to challenges in product development revising non-essential features of the product profile
13
The Quality Target Product Profile Requires Care And Understanding
Understand what is necessary to satisfy the regulators, patients sufficient to provide differentiation possible to simplify development and manufacturing
14
Quality Target Product Profile
15
Quality Target Product Profile
16
Prioritising within the Product Profile
17
The Quality Target Product Profile Dictates The Product Design Requirements
18
Anecdote – The Product Profile Dictates Design And Development Work
19
Product Example : Dectomax
20
Question/Calculation The Poiseuille’s equation states Q = ! r 4"P/8 µL or more usefully o
o
o
o
o
"P=
8µLQ/
! r 4
!P is the pressure drop L is the length of pipe µ is the dynamic viscosity Q is the flow rate 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 22
Understand Candidate Solubility Amorphous forms may precipitate/salt out at extreme pH & high concentrations
Predict solubility using Henderson Hasselbalch equation. Confirm exptlly
Understand any counterion (Cl-) Ksp value sensitivity
Free acid/free base ppts when free unionised [D] exceeds saturated solubility in the [D +]/ [D] equilibrium. This ppt’n event defines the max’m 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 -------Don’t create wrong salt form in situ
Measure intrinsic solubility using thermodynamic stable form of free acid/free base. wrong form=wrong solubility Cosolvents raise intrinsic solubility, prevent free base pptn so higher salt solubility is accessible.
Don’t formulate buffer back at high pH where [D] can supersaturate Define pKa
23
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 [S 0]/([ST] – [S0]) Candidate
A B C D E F
pKa
Intrinsic solubility(4°C)
5.7 6.3 5.7 6.3 6.7 6.7
5 1 1 5 5 1
Solubility(pH) 3 3.3 3.7
Comments Viable?
µg/ml µg/ml µg/ml µg/ml µg/ml µg/ml
Discuss their relative merits as injectables providing a dose of 2mg/ml. What specification needs to be set to maintain solubility at 4°C?
24
Anecdote: Desperate Measures To Achieve Objectives. A Price Worth Paying? In formulation design Pharmacopoeial
Precedented
Unprecedented GRAS* & qualified *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) 25
Understand Candidate Stability •
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 independent–pseudo 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 4°C or lyophile options will support candidate Exploration of a pH range to support a specification and match with solubility requirement
Arrhenius ln k = ln A – E a/RT ln k = ln A – E a/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).
27
Question •
The Stokes Einstein (Smoluchowski relation) applies to the diffusion of spherical particles through liquid with low Reynold number D = k T/6"#r 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? 28
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 29
Product Idea: Spot On Pet endectocide Topical Spot on Monthly dosing Single use tube Easy dosing to pets Polypropylene plastic tube?
Triglyceride Formulation Free from water and alcohols
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
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
! Learning • Packaging challenge costs preclude development • Alternative candidate and formulation work required • Product profile, pack requirements and deliverables shape product viability and development
30
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
31
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. 32
Selecting The Appropriate Composition Component API
Comments 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. 33
Question/Calculation A drug, di sodium salt 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 µgA /ml. A 250 fold 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 buffer system is is formulated optimally around around its pK a 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 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) Da) formulated at 10 mg/ml mg/ml has good solubility in the pH range 3 to 7 & good pH stability stability in the range 4.0 – 5.8. During degradation H+ ions are are generated. After 2 years shelf life H+ generated is 1% of drug load. Proposed regulatory 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. stability. Manufacturing and pH testing variation means we make the supplies at pH 5.2 (worst case 0.2 unit variation in manufacture/testing) manufacture/testing) After manufacture supplies supplies start life at pH 4.9. 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? stability? If possible pick acetate acetate buffer pK 4.75. (optimal buffer) Calculate the molarity required for for this buffer buffer system? 36
Question/Calculation +
Drug molarity in solution is 10/250 = 0.04 M H generated on stability = 0.04/100 = 4 x 10 -4 M
At the starting pH
pH = pK
+
log10
[A-] / [HA]
4.9 = 4.75
+
log 10
[z] / [B - z]
where Buffer Molarity is unknown B
At the final pH
0.15 = log10 [z] / [B - z]
1.4125 = z/(B-z)
4.5 = 4.75
[y] / [B - y]
+
log 10
-0.25 = log10 [y] / [B - y] +
B = 1.708 z
0.5623 = y/(B - y)
B = 2.7782 y
-4
H generated on stability = 0.04/100 = 4 x 10 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 2.7782 x 4 x 10
-4
-4
)
B = 2.7782 [( B/1.708) - 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. 37
Getting the buffer quantity low is particularly important if working at extreme pH.
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 38
Anecdote: Preservatives/AET and CDs 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) 39
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 dm 3 mol-1 in SBECDNa (DS=6.3, Av. MWt 2163 Da) and K= 670 dm 3 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 P 0.01-x
+
CD 0.02 –x
x2 – 61x + 0.4 = 0
!
[SCDNa] = 43.26g/L / 2163 = 0.02M PCD x
K = [PCD]/[P] [CD] K = x/ (0.01 –x)(0.02-x)=2000
X = [61 – (61 2 – 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
41
Question/Calculation 3.
P
+
0.003442
CD R
PCD
!
0.006558
K = [PCD]/[P] [CD] 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 4a.
1.312%
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 42
Product And Process Risk Assessment •
We’ve 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 ) 43
Typical Manufacturing Process
44
Derivation Of Quality Attributes From The Quality Target Product Profile
45
Initial Risk Assessment: Based On “Prior Knowledge” Applied To Qa’s DP Quality Attributes derived from TPP
Drug Product Manufacturing Unit Operations/ Variables Mixing, Filtration holding (in-line)
Filling
Stoppering
Capping
Components
Steam API Stopper / glass Sterilization attributes 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
47
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 – Don’t
•
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
49
Product : Phosphate Prodrugs
50
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 51
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 Sterilization process (Storage and use)
Formulation design & controls
Manage with Manufacturing controls
(Manage through manufacture packaging and administration set) 52
Terminal Sterilisation Feasibility: Cumulative Contributions To Degradation
53
Terminal Sterilization Feasibility •
Parameters: o
o
•
Key requirements (CQA’s): o
o
•
Sterility Assurance Level (Log Reduction $ 8) Degradation % 2%
Limits can be defined based on first principles:
o
o
•
Set-point temperature Dwell time
Sterilization theory:
Arrhenius kinetics:
Less experimentation required
• Allows non-empirical Design Space development
54
Balancing opposing effects: sterility assurance vs chemical stability
55
Terminal Sterilization Feasibility: Identify A Mutually Compliant Operating Solution Space For Sal And Purity
56
Terminal Sterilisation Design Space
57
Question/Calculation •
If there was an interruption to a sterilisation cycle…could 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
58
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
Can’t 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
60
Parametric Release For Sterility •
Risk assessment (FMEA)
•
Detailed decision tree for batch release
61
!"#$%&& (#)*"#+&
62
Process Controls • Controls on O2 exposure: o
o
Eliminates the need for an antioxidant Reduces degradation extending the terminal sterilis’n design space
• PAT Applications: N2 sparge of compounded solution (feedback control to limit dissolved O2 content) Fill weight monitoring with feedback control N2 purge rate during filling (feedback control to limit O 2 headspace) But temperature & duration design space needed for sterilisation o
o
o
o
• Real Time Release (RTR) Fill weight data in lieu of extractable volume o
63
Visualization Of Control Strategy
64
Revised Risk Assessment
• •
Failure Mode Effects Analysis quantifies risk and prioritizes work Risk is manageable/acceptable after implementing the control strategy
65
Revised Risk Assessment DP Quality Attributes derived from TPP
Drug Product Manufacturing Unit Operations/Variables
Components
Mixing, holding
API attributes
Filtration
Filling
Stoppering
Capping
Steam Sterilization
Stopper / glass attributes
Appearance Identity Assay Impurity Sterility Endotoxins pH Particulate matter Extractable volume O2 in headspace C/C Integrity Osmolality
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 67
Product Example: Stronghold Selamectin formulated in Glycol ether (DPGMME) and Propan-2-ol Challenge • IPA used – promotes spread - supersaturation
Pet endectocide Spot on dosing monthly single use easy dosing to pets flexible plastic tube
Resolution • Tube seal integrity & dose delivery Tube thickness & diffusion modelling and vapour steady state
- transdermal delivery • Al blister design - Systemic efficacy (endos) - Limit head space • IPA varies provides easy dose - Controlled land width & glue volume - Land width seal quality/alignment • IPA diffuses through PP tube - Control Al thickness and quality • IPA hold up in Al blister • IPA diffusion through blister • Moisture ingress • Significant leachables
• Hold strategy for tubes prior to blistering • Pin hole He leak check, microscopy
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
• Qualify formulation storage change 68
Product Example: Slentrol Solution in Medium Chain Triglyceride oil Polypropylene bottle LDPE insert and liner Rubber free dosing device
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
Weight loss in dogs Dose on food/in mouth Taste Acceptance Titrating escalating dose Daily dose regime Easy measurement Convenient dosing
Solution • Oily solution to meet dose titration & bioavailability need • Non rancid oil – no oxidation
• Formulation avoids antioxidant, preservation requirements & pack impact
• Preservation achieved as is no migration effects
• In use studies on device performance and stability
• 3 PP bottles designed to fit manufacturing line set up
• Bottle insert fitting strategy at manufacturing site
• stock item child resistant cap
• Consistent bioavailability
• purpose designed bottle insert
• Oil compatible packaging
• Bottle insert cap compatible and fits dosing devices
• No confusion with syringes • preservation for in use (months)
Learning
• Dosing devices for oil use (swelling free)
• Extractives leachables with representative material in other standard bottles •
Extractives/leachables on device/insert (known polymer resins)
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Conclusion •
Highlighted examples of application of QbD principles in a science-and risk-based approach to Drug Product development
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Upfront planning around a QTPP is key to success
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Sensible design is essential it makes the assessment process meaningful
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Key assessment components are: o
o
o
o
o
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Comprehensive risk assessment on product, components, process Demonstration of risk minimization approaches How to document risk acceptance rationale DoE and modeling to develop product/process understanding 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 70
Acknowledgements •
Nancy Harper (Pfizer)
• Others from EFPIA’s QbD Small Molecule Team: Thomas Backensfeld (Bayer Schering) Christian DeMuynck (Nycomed) Ritva Haikala (Orion Pharma) Heinz Wiederkehr (Roche) Brian Withers (Abbott)
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Pfizer colleagues too numerous to single out working on Human and Veterinary Medicines over the last 25 years
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Glossary of Terms 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 72
Thank You
