Api conference 2005 june dublin nk

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:


• 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


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”


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.


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.



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?


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)


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


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


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) .


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


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


”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)


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.


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


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


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).


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


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


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


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


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.


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


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°


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


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?)


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.


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.


Examples:

Training

• Using appropriate tools

• With professional techniques

• In the right place

• At the right time

All our samplers are qualified.


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


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.


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.


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”.


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

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Api conference 2005 june dublin nk