improving post-approval change processes as a way to ......improving post-approval change processes...
TRANSCRIPT
Improving Post-Approval Change Processes as a Way to Ensure Technical Innovation and Drug Product Availability
CMC Strategy Forum, Washington D.C., January 25th, 2016
Anders Vinther, Ph.D.Chief Quality Officer, Sanofi PasteurChair, PDA PAC Task Force
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The Apparent Dilemmas
• Regulatory capacity demands a balance between:– the degree of regulatory oversight to ensure safe and effective health products– the barriers to timely access to those products
• As global regulatory capacity increases so does oversight, but at a potential risk to timely access to medicines
• Pharmaceutical companies must balance between:– necessary changes as well as voluntary changes to innovate, remain CGMP
compliant and ensuring drug product availability– satisfying stakeholders/owners expectations to financial performance
• As regulatory complexity for post approval changes and cost pressure continue to increase, so does the logistics challenge at a potential risk to drug product availability
• Together our objective is to improve public health
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EU GMPs, Part I, Chapter 1
“Continual improvement is facilitated through the
implementation of quality improvements appropriate to
the current level of process and product knowledge”
ICH Q10Pharmaceutical Quality System
Objectives
Product realizationState of control
Continual Improvement
Existing Regulatory Expectations to Innovation
Process Analytical Technology (PAT) was supposed to facilitate innovation,
but it hasn’t been successful. Why?And why are we struggling with
innovation as an industry?
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Product Realization:Drug Shortages Happen Often
Source: EAHP, European Association of Hospital Pharmacists. EMA Workshop on Shortages due to manufacturing and quality problems, London, UK, 09-Oct-2015
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Our Industry is Working on solutions to Drug Shortages Caused by Quality and Mfg Problems
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w.pda.org/DrugShortage
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The Heterogenous Regulatory PAC LandscapeMakes it a Challenge Being a Global Supplier
Example: One pediatric vaccine protecting against several diseases
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Pentavalent Vaccine: a Pediatric CombinationImmunizing Against 5 Diseases
Hib
Diphteria
Pertussis
Tetanus
Polio
Each vaccine consists of not 1 but 8 antigens (drug substances). Formulation is critically important to efficacy
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The Pentavalent Vaccine in Numbers. Yes – It’s a Patchwork Picture
Individual tests1265
222 Analytical methods
Raw materials141
49 Manufacturing steps
Buildings10
8 Antigens
1 Vaccine
C O M
P L E X I T Y
MULTIVALENT FINISHED BATCHES Lot
CCR 200193
4
CCR 200208
0
CCR 200006
3
CCR 201308
7
CCR 200460
8
CCR 200746
9
CCR 204246
7
CCR 205395
7
CCR 2001117
CCR 207215
3
CCR 204865
6
CCR 200585
1
CCR 207349
8
CCR 206339
3
CCR 208169
7
CCR 201357
0
CCR 209758
5
CCR 206302
3
CCR 200903
2
CCR 206253
3
CCR 200416
4
CCR 204878
3
CCR 210316
8
CCR 201268
5
CCR 206304
4
CCR 203397
0
CCR 203933
3
CCR 210372
9
CCR 2101625
CCR 209483
0
CCR 209875
7
CCR 209098
8
CCR 207685
7
CCR 203202
6
CCR 204376
3
CCR 206159
8
LOT 1 H2221-1LOT 2 H4131-1LOT 3 H4131-2LOT 4 H4132-1LOT 5 J2035-1LOT 6 J2209-1LOT 7 J2210-1LOT 8 J2214-1LOT 9 J2215-1
LOT 10 J2216-1LOT 11 J2251-1LOT 12 J4001-1LOT 13 J4002-1LOT 14 J4032-1LOT 15 J4033-1LOT 16 J4034-1LOT 17 J4035-1LOT 18 J4087-1LOT 19 J4090-1LOT 20 J4098-1LOT 21 J4104-1LOT 22 J4109-1LOT 23 J4118-1LOT 24 J4122-1LOT 25 J4133-1LOT 26 J4156-1LOT 27 K2038-1LOT 28 K2039-1LOT 29 K2042-1LOT 30 K2043-1LOT 31 K2044-1LOT 32 K2045-1LOT 33 K2086-1LOT 34 K2108-1LOT 35 K2113-2LOT 36 K2121-1LOT 37 K2122-1LOT 38 K2124-1LOT 39 K2125-1LOT 40 K2146-1LOT 41 K2148-1LOT 42 K2152-1LOT 43 K2155-1LOT 44 K2160-1LOT 45 K2160-1LOT 46 K2161-1LOT 47 K2162-1LOT 48 K2163-1LOT 49 K2164-1LOT 50 K2165-1LOT 51 K2166-1LOT 52 K2167-1LOT 53 K2168-1LOT 54 K2169-1LOT 55 K2170-1LOT 56 K2172-1LOT 57 K2172-1LOT 58 K4006-1.LOT 59 K4007-1.LOT 60 K4007-1..LOT 61 K4039-1LOT 62 K4047-1LOT 63 K4073-1LOT 64 K4093-1LOT 65 K4098-1LOT 66 K4106-1LOT 67 K4122-1LOT 68 K4153-1LOT 69 K4157-1LOT 70 K4158-1LOT 71 K4159-1LOT 72 K4163-1LOT 73 K4164-1LOT 74 K4165-1LOT 75 K4170-1LOT 76 K4174-1LOT 77 K4175-1LOT 78 K4176-1LOT 79 K4177-1LOT 80 K4178-1LOT 81 K4179-1LOT 82 K4180-1LOT 83 K4181-1
Change is natural, and necessary to innovate, but variances in regulatory approval processes lead to multiple version of same product and a logistics challenge
Approved in 105 countries
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Example, Continued….
9
• 83 batches produced in one year• 1/3rd of the Changes impacting more than 50% of the batches• No more than 7 batches ‘version’ identical • 55 batches totally different from one to another• 81 batches impacted by new autoclave• 78 batches impacted by new reference standard• 43 batches impacted by updating analytical method to new pharmacopoeia
version• 36 batches impacted by change from pyrogen to LAL endotoxin testing• 26 batches impacted by new raw material supplier
XNumber of possible changes in Established Conditions
Number of different regulatory processes
= a lot !
Sustainable ? Does this kill innovation?
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We are here !
The current situation leads to drug shortages & inadequate innovation. And what about the state of control?
Together we must do a better job to ensure the Q10 objectives of• Product Realization,• State of Control• Continual Improvement
& to improve public health
But how ?
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Common Objectives
Industry
• Globalization• Improved efficiency• Reduced process
variability• Improve public
health globally
Regulators
• Nationalization• Safeguard public
health locally• Sustainable supply• Enforcing cGMPs• Safe, efficacious quality products
• Availability of drug products - sustainably• Innovation• Improved controls
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PAC Processes Need to be Improved to Ensure Technical Innovation and Drug Product Availability
• Some elements of regulatory oversight can be shared – Evaluation of quality, efficacy and safety
• Other elements of regulatory oversight must be local– The licensing decision– Local manufacturing oversight– Pharmacovigilance– Appropriate distribution controls (stability and cold chain)– Product security (protection against counterfeiting and adulteration)
ScienceSpecific
CountrySpecific
X
X
• Shift the dialog to be scientific and evidence based, case studies• Emphasize that our industry is global – changes should be assessed globally• Set expectations for PAC global approval time limits & publish data
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Improving PAC Processes - Thoughts
• Enhance Regulatory Agency reliance on each other• Reduce regulatory submission burden
– Shift the dialog upstream to protocols instead of reports (PACMPs)– Shift many more changes to be covered only in an effective
Pharmaceutical Quality System (PQS) (no regulatory submission)
• Articulate the need for innovation based on scientific facts• Plan together through Lifecycle Management Plans (LCM)• Standardized global Change Protocols
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Articulate the Need for Technology Innovation
• Articulate expedited & harmonized PAC approvals when– Enhanced redundancy– Improved process & product controls– Improved cost-efficiency, reduced lead times– New technologies bring added value
• Recommend specific validation/comparability studies for new technologies*– Single Use Systems– Continuous manufacturing– Modernization of aging facilities– Technologies to manufacture products for new therapies– Etc..
This dialog needs to extend from Quality & Regulatory Affairs professionals to Operations leaders and experts
* PDA: global Change Protocols
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Reduced Regulatory Submission Burden. What if we….
• Used the Pharmaceutical Quality System (PQS) and Post Approval Change Management Protocols (PACMPs) to downgrade PACs using a risk-based approach, while maintaining a state of control.
• Changes to non-Established Conditions (non-ECs)– Manage in the PQS
• Changes to Established Conditions (ECs). Risk and science based approach– PACs having no potential impact to quality, safety and/or efficacy of the drug product handle
and manage in the PQS only (“Do & Record”)– PACs requiring prior approval by national legislation consider submitting the planned
change(s) in a PACMP for evaluation by Regulators. Based on assessment implement either a) only in the PQS (“Do & Tell”) provided all acceptance criteria of the approved PACMP are met or b) after written report summarizing the completed PACMP activities approved by the Regulators (“Tell & Do”). An approved report should be required for any PAC described in the box here
*1. Addition/elimination of a CQA2. Addition/elimination of a method on the control
system3. Widening of specifications4. Changes to CPPs 5. Changes to shelf life6. Changes to novel excipients
*
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LCM - What it is
• A Lifecycle Management Plan (LCM Plan) is part of the company’s product lifecycle strategy; it is optional and may be submitted with a new application or for an existing product
• Opportunity for company to – prospectively and transparently provide information for managing the post approval phase of the product
lifecycle globally – enhance transparency of planned changes and globally harmonized approaches– summarize globally agreed upon Established Conditions (ECs) and the company’s Control Strategy– summarize plans to ensure product supply and availability– explain and link planned post approval changes to the development summary and the PQS– describe how the company ensures an effective PQS is developed and maintained
• Describes planned changes at high level including product quality impact assessment comparability approach, and suggested reporting category
• A summary of all planned major changes, their interdependency and suggested reduced burden of post approval changes reporting
• Optional structured approach to engaging in a dialog between company and the Health Authorities about planned changes
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LCM Plan – Potential Benefits
• Facilitates ICH Q8 - Q10 objectives• Harmonizes ECs across several countries for the drug product. Summarizes the Control
Strategy and how it is linked to the ECs.• Summarizes in one place how the product is planned to be managed in the commercial stage
of the product lifecycle.• Opportunity to link planned post-approval changes needed to ensure continued product
availability.• Mutual understanding of post approval commitments and planned changes between the
company and the Health Authorities (Assessor and Inspector).• Expedites reviews and implementation of planned post approval changes.• Enhances predictability, certainty and transparency of studies to implement a change.• Provides an opportunity to reduce the reporting category• Ability for company to communicate to assessors the company’s approach to ensuring an
effective PQS, how post-approval changes are managed in the PQS, and how product knowledge is managed during the commercial stage of the product life cycle.
• Where considered necessary, summarizes the company’s plans for supply and drug product availability including identified risks in one place.
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Conclusion
• Industry & regulators have many objectives in common, but we are coming from different positions; active dialog is critical to success
• Current regulatory process complexity is not sustainable, it is causing drug shortages & it hampers technology innovation
• Some elements of regulatory oversight can be shared; others must be local
• As an industry we can advance technology if we – speak up and work together to drastically improve innovation pace– shift the dialog to be more scientific– articulate the need for technology innovation, & have more Operations leaders
involvement– articulate the need for reduced regulatory burden
• PDA is actively supporting the ICH Q12 work connecting people, science and regulation in the areas of LCM Plan template, global Change Protocols, defining an effective PQS, and specific examples of potential reduced regulatory burden
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Back to the Vaccines: hexavalent vaccine on market, i.e. penta + one…
Hib
Diphteria
Pertussis
Hepatitis B
Tetanus
Polio
Public health convenience, but also added complexity from a manufacturing perspective. All stakeholders must work together to encourage innovation
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