Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009
Give an aid by providing some points of discussions on the understanding of the quality risk management concept Illustrations of how Risk Mamangement can be applied in sterile product manufacture
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
2|
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
5|
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Guidelines on
Quality Chemical and pharmaceutical QA Safety In vitro and in-vivo pre-clinical studies Efficacy Clinical studies in human subject
Multidisciplinary
6|
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
General topics
Q1 Stability Q2 Analytical Validation Q3 Impurities Q4 Pharmacopoeias Q5 Quality of Biotechnological Products Q6 Specifications Q7 Good Manufacturing Practice Q8 Pharmaceutical Development Q9 Quality Risk Management Q10 Pharmaceutical Quality Systems
8|
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Design
9|
GLP GCP
Safety Efficacy
ICH Q9
GMP/GDP
10 |
Quality
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Product Defects
Efficacy
Preventable Adverse Events
ICH Q9
Quality
Safety
Unexpected Consequences
Injury or Death
Public Health
11 |
Manufacture of sterile medicines Advanced for SFDA GMP Source: basic model adaptedfrom FDA workshop (1999). Managing the inspectors Risks from Medical Product Use. Nanjing, November 2009
ICH Regulators: FDA: New paradigm with the 21st Century GMP initiative EMEA: Revised EU directives MHLW: Revised Japanese law (rPAL) EU & Japan became involved at ICH GMP Workshop in July 2003: 5 year vision agreed: Develop a harmonised pharmaceutical quality system applicable across the life cycle of the product emphasizing an integrated approach to quality risk management and science Consequent ICH Expert Working Groups (EWG):
ICH Q8, on Pharmaceutical Development, doc. approved 2005 ICH Q9, on Quality Risk Management, doc. approved 2005 ICH Q10, on Quality Systems, topic accepted 2005
12 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
risk-based
concepts and principles
13 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Changed Paradigm
Q9
Past:
Future:
GMP checklist
Quality Systems across product life cycle
14 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
High
co nt in ua l
im
pr ov e
en t
Low
Q8 Pharmaceutical Development
Low
High
15 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Manufacturing Distribution
Q8
16 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Q10
Patient
Old Approach
Quality decisions divorced from science and risk evaluation. Adherence to filing commitments. Post-factum sampling and quality testing. Process Validation .
New Approach
Remarks
Design Space concept introduced to integrate process knowledge with regulatory evaluation. Quality by design definition applied. Measure critical process parameters to control output product quality. Regulators and industry place higher reliance / trust / understanding on systems. Multidisciplinary evaluation and decision making. Requires mechanisms to communicate Process Understanding data ("inspectable rather than reviewable") .
Broad Concept
Quality
Systems
Quality decisions and filing committments based on Process Understanding and Risk Management. Quality by Design. Management of variability Process control focused on critical attributes. Continuous Quality Verification. Systems designed to inhibit Changes managed within changes & minimize business company's quality system. risks. Discourages Real time batch release improvement & innovation . feasible. Compliance focus. Changes require prior approval. Regulatory scrutiny adjusted to level of Process Understanding. Continuous improvement allowed within Design Space.
Regulatory
17 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Process Understanding
Process Understanding
CMC CMC regulatory regulatory Oversight (Submission) oversight cGMP cGMP regulatory regulatory oversight (Inspection) oversight
Q8 & Q9
Companys Quality system PAC PAC to to Continuous Continuous Improvement Improvement Risk
Q10 & Q9
Risk
18 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
19 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
20 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Understand and influence the factors (hazards) which impact regulators and industry business Create awareness and a culture
The hurdles
Increasing external requirements
for best practice, transparency and compliance
Public / Community Governments Regulators Patients Investors / Creditors
Growing complexity
and scope of risks
?
Increasing Documentation efforts and costs Projects
for sustainability
Systems Interfaces
Globalisation Multinational Multi-factor approaches Regulatory expectations Acceptance of risk and uncertainty
22 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Improve communication
through sharing best practice and science based knowledge
Organizations might use many different meanings of risk Depending on the type of risk management program
In general, "probability" and "severity" must be considered In a given program definitions will fine-tune the concepts so that a risk management program can be created and applied Make the detail in the definition fit the objective of the program
Accept the different "realities" among the stakeholders Harmonized guidance needs to focus concepts into useful terms for the purpose (e.g. protection of patient [Q9])
25 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
26 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors G. Claycamp, FDA, September 2005 Nanjing, November 2009
probability
severity
27 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
past
28 |
today
future
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
(Mission, Policy)
Where to be in future?
What to do?
(e.g. Directives)
How to do?
(e.g. Guidelines)
Detailed instructions
(e.g. Standard Operating Procedures)
Records
29 |
Numbers
Does the Risk Priority Number tell the truth?
What amount of data is enough? e.g. start with the existing data set
30 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Potential threat
- chemical reaction - manufacturing issues - facilities and equipment
Anything that has the potential to harm patients, product quality or the business (loss, interruption, image)
hazard
Failure
- technical breakdown - human breakdown - extrinsic effect
System defect
- not detected - insufficiently prevented - emerges by degree
31 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Uncertainty
today Time RISK: For a given severity of risk event, what are the chances (probability) of exceeding the USL in the next period of time?
32 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Process Parameter
Tomorrow ?
Upper Specification Limit (USL)
Uncertainty
Time
today
RISK: Control options are scenarios for risk management. Note that this scenario shows the best estimate is below the USL.
33 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Uncertainty
Time
34 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
uncertainty
Manage risks
in relation to probability & severity
Quality
Degree to which a set of inherent properties of a product, system or process fulfills requirements combination of the probability of occurrence of harm and the severity of that harm
Risk
Management
QRM
36 |
Systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle
ICH Q9
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Develop scope by using different viewpoints e.g. from management, internal and external customers
37 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
ISO/IEC Guide 73: 2002 - Risk Management Vocabulary - Guidelines for use in Standards ISO/IEC Guide 51:1999 - Safety Aspects Guideline for their inclusion in standards WHO Technical Report Series No 908, 2003 Annex 7 Application of Hazard Analysis and Critical Control Point (HACCP) methodology to pharmaceuticals GAMP Good Practice Guide ISPE, 2005 A risk-based approach to compliant electronic records and signatures
38 |
Risk Identification
Risk Analysis Risk Evaluation Risk Communication
unacceptable
Risk Acceptance
Output / Result of the Quality Risk Management Process Risk Review Review Events
39 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
ICH Q9 document
Main body explains the What? Annex I give ideas on the How? Annex II give ideas on the Where?
It can be implemented by industry and regulators Pharmaceutical development (ICH Q8) and Quality Systems (ICH Q10) will facilitate the What?, How? and Where? It helps prevent overly restrictive and unnecessary requirements being imposed by either industry or regulators (ICH Q9)
40 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
To show how it can be applied by regulators and industry to quality of pharmaceuticals (including API)
We already do a lot of quality risk management activities without identifying them as such
41 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Consequences
43 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
QRM
Using QRM
Continuous improvement
Improve it
Update documentation
(Risk of) Failure ? Manufacture Quality for market Risk Managem ent Do, what you say (QRM)
Approval
45 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Definitions of Compliance: Conformity in fulfilling official requirements The act or process of complying to a desire, demand, or proposal or to coercion A disposition to yield to others The ability of an object to yield elastically when a force is applied: flexibility Definition of Flexibility: characterised by a ready capability to adapt to new, different, or changing requirements
Source: www.webster.com, 01. Nov.04 46 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Not every single detail can nor should be covered by Specifications (product quality) Documents (quality systems)
Set priorities and allocate resources according to the potential for protection of patients
47 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Facilitates common approaches to quality risk management in our every day jobs Supports science-based decision making Focus resources based on risks to patients Avoids restrictive and unnecessary requirements
49 |
Facilitates communication Matrix team approach An aid to convince the stakeholders with trust
Encourages a preventive approach Proactive control of risks and uncertainty Benefit of knowledge transfer by team approach Changes behavior Better understanding of risk-based decisions Acceptance of residual risks
51 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
The use of Quality Risk Management is mandatory is an expectation of EU & PICs GMP but ICH Q9 is not
However, if you dont use it, you will not gain the benefits
52 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Change in behaviour
Sharing information
53 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Change in behaviour
Change in behaviour
Integration of QRM into existing systems and regulatory processes will take time, trust and communication
56 |
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009