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Motto:
„Navigare
necesse est”
Katalin Nemák
Adapting to New Regulatory
Requirements:
Risk-Based Approach to
Compliance
IVT’s API Conference 21-24 June, 2005 Dublin
Katalin Nemák 2
FDA’s initiative and
how the industry can reflect to the invitation
with new concepts in quality management
API Conference Dublin 2005 Katalin Nemák 3
Invitation
New regulations
issued by FDA from 21 August 2002
show the intent of the agency
to encourage the industry:
API Conference Dublin 2005 Katalin Nemák 4
• to implement
modern technical
and science-based
tools to R&D and
manufacturing
• to be more
involved in
discussions
with FDA
experts in
collaborative
arrangements
API Conference Dublin 2005 Katalin Nemák 5
Aim of the initiative
The declared aim of the initiative
Pharmaceutical cGMPs for the 21st
Century: A Risk-Based Approach was:
”Merging Science-Based Risk Management
with an Integrated Quality System
Approach”
API Conference Dublin 2005 Katalin Nemák 6
Five guiding principles were
mentioned in FDA’s initiative
• Risk-based orientation
• Science-based standards
• Integrated quality system
•International cooperation
•Public Health Prevention
The introduction of the first three principles could cause
considerable changes in the life of the companies.
To give practical viewpoints to the implementation of the
principles state-of-the-art techniques and practices were
looked through.
API Conference Dublin 2005 Katalin Nemák 7
Ad point 1:
Basic elements of Risk Analysis • British Standard BS 5760: Reliability of Systems,
Equipment and Components published in 1982
• ISO/IEC 14971:1998, Application of risk management to
medical devices
It is accepted
R = P * S that the concept of risk (R) has two components:
P: the probability of the
occurrence of harm (how often the harm may occur);
S: the consequences of that harm (how severe it might be)
Risk acceptability is influenced by the perception of risk.
Description of the currently used methods is given in ICH Q9 guide.
API Conference Dublin 2005 Katalin Nemák 8
API Conference Dublin 2005 Katalin Nemák 9
Ad point 1:
Risk Management
Risk assessment Risk
Management
Ad point 1:
Comparison of FMEA, HAZOP and other techniques
Root Cause Failure Analysis:
indicates conducting a comprehensive analysis down to all of the root causes (physical, human and latent), but connotes analysis on mechanical
items only.
Failure Analysis : stops analysis at the Physical Root Causes.
We find that it has failed and we simply replace it.
HAZard OPerability: carried out by a team,
analyses the interactions between components.
FMEA: investigates the failures of the components, often
performed by an individual. API Conference Dublin 2005 Katalin Nemák 10
Ad point 2:
Built-in Quality Optimization of process steps to develop reliable and robust technology for scale-up
Answers:
Design of Experiment (DoE):
More factors can be varyed at
the same time :
- find the global maximum
- estimate the effects of
alterations
- predict overall yield
without further experiments
Questions:
• Which factors are critical? • How can we get an optimal factor setting? (maximum yield, + productibility). • How robust is our process? - effect of factors on the reaction around the optimum • Hazard?
API Conference Dublin 2005 Katalin Nemák 11
Ad point 2:
Experimental Design Calculation of global optimum for multiparametric systems
Two approaches of reaction optimization
”Changing one separate factor
at a time” (COST) method:
5 0
6 0
7 0
8 0
3 0 4 0 5 0 6 0 7 0
Yie
ld (
%)
Temperature (°C)
Interaction plot
pH (low)
pH (high)
pH (low)
pH (low)
pH (high)
pH (high)
DoE gives the surface of reaction space:
DoE tools: Computer controlled multiple reactor systems
Monoacyl
90 80 70 60
56 58 60 62 64 66 68 70 72 74 76 78 80
Reaction temperature (C)
0.9
1.0
1.1
1.2
1.3
1.4
1.5
1.6
Am
ou
nt
of
ac
id c
hlo
rid
e (
eq
.)
(COST method)
API Conference Dublin 2005 Katalin Nemák 12
Ad point 2:
PAT: Process Analytical Technologies
Transition of emphasis from conventional quality control
(sampling and testing of the yielded product) to the
in-process control of the crystallization suspension or the
manufacturing mixture
Advantages: real-time measurements can be repeated
frequently, the samples from the ”matrix” can fully represent
the whole batch (less problem with homogeneity)
Challenges: setting specifications for in-process control,
handling OOS results
Limitations: costs, complex systems with sophisticated
techniques – can be hard to implement API Conference Dublin 2005 Katalin Nemák 13
Ad point 2:
Built-in Quality
Using PAT at API manufacturing For monitoring chemical
reactions:
•Process Mass Spectrometry
for the analysis of reaction
mixtures
•MS-Headspace analysis for
reactions with gassing
or adsorption of gases and
at operations under vacuum
can be used
For monitoring
crystallization and
finishing works:
•Turbidimetry for onset
•FT-IR/NIR or Raman
spectroscopy for the
whole process
•Acoustic methods for
powder operations
API Conference Dublin 2005 Katalin Nemák 14
Integrated Quality System
risk-based work planning
For the industry and for QA it means that we
have to use more complex and better integrated
quality systems, too.
Ad point 3:
From regulatory viewpoint:
submission
reviews
merging
and inspection
programs
API Conference Dublin 2005 Katalin Nemák 15
In the USA: - one legal system exists, - there is a single market in pharmaceuticals, - FDA handles all authorizations in a centralized form.
The EU is an extending community of countries with different cultural, legal and economical backgrounds - harmonization is more difficult and time-demanding.
In EU:- multicentral authorization exists, - MRA-s facilitate trade and ensure public health
protection - emphasis was taken to the harmonization of the release
procedures (QP responsibilities, parametric release) .
API Conference Dublin 2005 Katalin Nemák 16
Comparison of US and EU regulations
In Hungary – milestones in the activities of the health authorities
• 1927 – Introduction of manufacturing inspection by health authorities
• 1962 – Foundation of the National Institute of Pharmacy (quality control of bought medicines)
• 1970 – Organization of the Inspectorate within the NIP – control over manufacturing processes
• 1976 – Joining Pharmaceutical Inspections Convention (PIC) of EFTA, GMP became compulsory (GMP regulations issued as NIP guide)
• 1995 – Joining Pharmaceutical Inspections Cooperation Scheme (PIC/S)
• 2004 – Joining EU
API Conference Dublin 2005 Katalin Nemák 17
In Hungary – regulations of today
GMP is incorporated into the national laws as an attachment
• XXV. law in year 1998 ”the medicines intended for human use” declared to allow put medicines for human use into the market only with marketing authorization from NIP
• 37/2000. (III. 23.) council decree ”about the personnel and facility requirements of manufacturing medicines intended for human use”- GMP in attachment (translation of the whole EU GMP 13 chapters including API manufacturing)
• 84/2001(V.30.) Mutual Recognition Agreement with EU
• 86/2004. (IV. 20.) council decree extended the above item (according to the modifications in EU GMP)
• 39/2004. (IV. 26.) decree of the Ministry of Health about the QP responsibilities
API Conference Dublin 2005 Katalin Nemák 18
”Quality by Design”
Development of new Master Batch Record
Sheets for products under scale-up:
– critical control points / control methods
– set up of critical technical parameters
are discussed based on the results of
risk analysis.
(Technology Review Team meeting:
Chem. Pilot, Anal. Sci., QA)
API Conference Dublin 2005 Katalin Nemák 19
Complex Quality Management for regulatory compliance
After having compiled the final report on manufacturing of a new API batch we
prepare a SPECTRAL evaluation table and organise a
Batch Manufacturing Evaluation Team meeting
to discuss the data and the observations. This tool is useful to explore the roots and to prevent the reoccurrence of
the problems.
API Conference Dublin 2005 Katalin Nemák 20
System
Process
Equipment
Control methods
Training
Recording
Auditing
Logistics
Overview of a typical
process-flow: Starting material #1
bromination
alkylation
protection
ester hydrolysis
removal of prot. group
Starting material #2
oxime formation
ring-closure
catalytic hydrogenation
oxidation
acylation
salt formation
purification, recrystallization
API Conference Dublin 2005 Katalin Nemák 21
M
M
L
L
L
L
L
L L
L
S
M
M
L
M
M S
S
S
M
M
M
L
M
S
M
L
S
S
M
L
S
S
S
S
Where to measure which quality feature? Example for risk analysis
Sol React pH Extr Distil Cryst Filtr Wash Dry Mill Clean reactant adjust
Priority number
Appearance:
(homogeneity) 8
(particul. mat.) 9
colour 11
particle size d. 10
crystallinity 7
Solubility 6
colour of sol. 12
Identity 1
Assay 2
Purity:
residual solv. 5
related subst. 3
unspec. imp. 4
API Conference Dublin 2005 Katalin Nemák 22
S
Effect of process steps on the quality:
S - Small M - Medium L - Large
Science-based setting of technical
parameters, critical process values There are a lot of special chemical reactions for which critical
parameters were determined experimentally:
• Photo-bromination: wavelength, energy of UV light and time of irradiation are critical.
• Catalytic hydrogenation: the reaction mixture must be stirred and mixed very efficiently to ensure good contact of the phases since the reacting agents are in heterogeneous phases. Temperature and pressure are prescribed.
• Acylation - through acid-chloride: the water content of the reaction mixture and the humidity of air have to be maintained because acid-chlorides are instable chemical substances, usually sensitive to water (inertisation is needed).
API Conference Dublin 2005 Katalin Nemák 23
Known functions describing process efficacy
In each production step there are a lot of physico-chemical processes, which are well described with equations.
•Flow rate: (Reynolds) Re = d•v•ρ/μ — inertia/friction over 2300 the flow become turbulent ( Kármán’s cycles) •Mixing: (Euler) N = f(D,d,H,b,h, ρ,μ) affected mainly by geometrical parameters (if Re>300, Froude=ac/[2
2g] Vo) •Heat-exchange: q = k•F•(t1-t2) affected mainly by the contact surface (for distillation Nusselt number = •d/ is used) •Filtration: (Darcy) 1/F•dV/dt = K•p/L pressure difference and surface are critical •Extraction: yn = (x0-xn )•VA/VB — solvent ratio is critical
API Conference Dublin 2005 Katalin Nemák 24
Examples (Pál Fekete) : scale-up: V2 > V1 (similar geometry of equipment)
• Flow rate: time of addition can be the same
(linear speed v 1< v2) W1 W2
• Mixing: time of mixing can be the same
• Heat-exchange: time of heating increases (non-linear)
• Filtration: time of filtration increases (non-linear)
• Extraction: volume of solvent increases (linear); extraction requires more time
Predicting the effect of scale-up
API Conference Dublin 2005 Katalin Nemák 25
d12 v1 d2
2 v2 V1 V2
F1 F2 > V1 V2
F1 F2 > V1 V2
n1 d12 H1 n2 d2
2 H2 V1 V2
VB1 VB2 = VA1 VA2
API Conference Dublin 2005 Katalin Nemák 26
SPECTRAL evaluation
of observations
and data
coming from
production
– a useful tool for
risk communication
and risk review
Process Material Equipm Control Device Staff Env
Weigh out interm, reagent - 2*check balance 2 op U Solving 1 solvent #1 react. 1 visual feeder 2 op U Reaction 2 solvent # 1 react. 2 T / t, IPC HPLC 2op+lead+lab U Adj. pH acid / base sol react. 3 pH check pHmeter 2 op+lead U Extraction water extract. visual mobil 2 op U Distillation - distill. temp reg thermom 2 op U Solving solvent #2 react. 4 visual feeder 2 op U Crystall. seed react. 5 temp reg thermom 2 op U Filtration centrif. visual bag 2 op C Washing solvent #3 centrif. visual feeder 2 op C Drying - vac. dryer loss on d lab plate 2 op C Milling - mill - scoop 2 op C Packaging PEbag,fieber-d - sampling printer 2 op C
Cleaning solvent, water all above visual,lab lab equip 2 op+lab U,C
API Conference Dublin 2005 Katalin Nemák 27
Table of production elements (example)
Examples: System
On a Batch Manufacturing Evaluation Team meeting we asked for the training records of the operators. We realised that one new employee hadn’t received the general training.
As part of reorganization project at our site general trainings previously organised by the central HR had been stopped.
It is of crucial importance to follow the Change Control procedure for tracking changes in the course
of general process flows.
API Conference Dublin 2005 Katalin Nemák 28
Examples: Process optimization
with DoE method amine acylation
Parameters temperature „acyl”agent addition time Optimum 1(minimal Bisacyl yield): 74.5 C 1 eq. 41.3 min Optimum 2(maximal Monoacyl yield): 71.9 C 1.5 eq. 39.5 min
Bisacyl Monoacyl
The reaction is robust,
10% parameter alteration
can be allowed
1 2
API Conference Dublin 2005 Katalin Nemák 29
Yields Monoacyl Bisacyl Amine
Optimum 1 96.8 0.8 2.4
Optimum 2 97.6 1.8 0.6
The Delta filter-dryer had a
relatively large dead volume as it
has a lateral bottom valve.
We contacted the supplier and
they offerred to install a machine
to turn the equipment with an
angle about 20 degrees.
Examples: Equipment
20°
API Conference Dublin 2005 Katalin Nemák 30
Examples: Control methods •Visual controls are important
for controlling process flows right in time.
(see the clarity of filtrate, end of filtration, level of solutions in
the feeder during addition into tank)
•According to new safety
rules glassware has to be removed
from the facilities. •What should we use
instead of glass? Plastic?
Visual controls
API Conference Dublin 2005 Katalin Nemák 31
Examples: Control methods
Assay vs. Purity (dispute of
Sándor Görög, János Répási et al.): Assay methods (named as ”sacred cow”) in several cases measure related impurities, as well. Specific methods for impurities can sometimes lead to more precise results.
Setting specifications and expressing results
New problems have arisen with the detection of potential genotoxic impurities after the issue of new EMEA guide. (Possibilities for detection of impurities at 1 ppm level?)
API Conference Dublin 2005 Katalin Nemák 32
Examples: Control methods
Core Monograph vs.
Complementary tests
In R&D we have to prepare the Control Monograph
based on a few data. During scale up we can get altered
results for physical tests as these features are impacted
by enlarged geometric and time parameters.
Example: After having an OOS for the ”colour of
solution” test it was agreed to put this test to the
Complementary part of the Monograph.
API Conference Dublin 2005 Katalin Nemák 33
Examples: Training
Critical personal responsibility: sampling • Avoid contamination (chemical and biological) of the test
material during sampling
• Representative sampling (more than one or two sampling points)
• Avoid contamination (chemical and biological) of samples
We need to have qualified samplers.
API Conference Dublin 2005 Katalin Nemák 34
Examples:
Training
• Using appropriate tools
• With professional techniques
• In the right place
• At the right time
All our samplers are qualified.
API Conference Dublin 2005 Katalin Nemák 35
Process control systems have to run
under strict requirements on:
Example: after changing Windows 95 to Windows 2000
a number of documents cannot be printed in the same format (each line was some pixels higher).
• record retention and traceability
• retrievable archiving system
• change control system
• access recording, audit trails
• printable and reprintable data files
API Conference Dublin 2005 Katalin Nemák 36
Examples: Recording and documentation
• In R&D our Batch Record Sheets have to be kept for
over 15-20 years. The storage has to be organized under
maintained conditions, ensuring easy retrieval.
• Printouts on heat-sensitive papers have to be copied.
• The quality of the recycled paper is not guaranteed for
such a long period of time, consequently, this type of
paper is not acceptable for printing Batch Record Sheets.
Compliance to ANSI/NISO Z39.48-1992 (Permanence of Paper) would suffice.
API Conference Dublin 2005 Katalin Nemák 37
Examples: Recording and documentation Archiving
Examples: Auditing
We had a fermentation product as our starting material for which we did not have an appropriate method to determine acceptability.
We had to perform use tests. About 3 from 6 batches were acceptable.
To be on the safe side we initiated discussions with the supplier and we conducted several audits at their manufacturing site.
API Conference Dublin 2005 Katalin Nemák 38
Examples: Logistics
~ 50 % of our complaints are ”shipping complaints”
• For heat-sensitive products a delay of delivery can do harm to the quality of the product. The use of temperature registers in the packages is essential in that case. (Temperature excursion can be compared with stability data.)
• To avoid unauthorized access we use numbered tamper proof seals inside (on the PE-bag) and outside on the drums.
• We decided to employ only our qualified courier company and all packs will be sent ”from hand to hand”.
API Conference Dublin 2005 Katalin Nemák 39
Avoid real and present dangers!
IVT’s API Conference 21-24 June, 2005 Dublin Katalin Nemák 40
Have experienced, good
partners and friends! IVT’s API Conference 21-24 June, 2005 Dublin Katalin Nemák 41