SIMVASTATIN TABLETS: RISK ASSESSMENT OF POTENTIAL...

SIMVASTATIN TABLETS: RISK

ASSESSMENT OF POTENTIAL

ELEMENTAL IMPURITIES (v2)

ICH Q3D

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TABLE OF CONTENT

1. BASIC INFORMATION .................................................................................................. 3

2. SUMMARY OF THE ASSESSMENT PROCESS ........................................................... 6

3. OBJECTIVE AND ASSESSMENT STRATEGY ............................................................. 8

4. IDENTIFICATION OF THE POTENTIAL SOURCES OF ELEMENTAL IMPURITIES .... 9

5. ANALYSIS OF THE POTENTIAL ELEMENTAL IMPURITIES ..................................... 13

Water and services ..................................................................................................... 14

Manufacturing process ................................................................................................ 17

Container closure system ........................................................................................... 22

Drug substance ........................................................................................................... 24

Excipients ................................................................................................................... 28

6. EVALUATION OF THE LEVELS OF THE POTENTIAL ELEMENTAL IMPURITIES .... 39

7. CONTROL STRATEGY BASED ON THE ASSESSMENT .......................................... 44

8. CONCLUSIONS OF THE ASSESSMENT ................................................................... 46

9. REFERENCES ............................................................................................................ 47

ANNEX I. PDE VALUES .................................................................................................. 49

ANNEX II. ABBREVIATIONS .......................................................................................... 50








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1. BASIC INFORMATION

Written by:

Toxicology technician (Azierta)

Paulino Alonso ____________________

Date & signature

Reviewed by:

Toxicology department Manager (Azierta)

Beatriz Carrero ____________________

Date & signature

____________________ Date & signature

Approved by:

____________________ Date & signature

____________________ Date & signature

____________________ Date & signature








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Product details:

Company name:

Company address:

Drug product: Simvastatin 10, 20, 30, 40 and 60 mg film

coated tablets

Version number: 2

Expected revision date*: NA

* Only for updating analytical information. Not applicable for products that comply with

the specifications of the ICH Q3D guideline for elemental impurities. Changes in

suppliers of excipients and/or drug substances, as well as changes in the

manufacturing process, container closure system, or basic services may require an

additional revision of the potential elemental impurities.








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Reason(s) of the change(s): Updating the available information of elemental

impurities in raw materials and re-evaluation of the total level of elemental impurities.

Modifications included in version 2:

Section Change

5. Analysis (drug substance) Updated information from suppliers of simvastatin (Hisun and Jiangbei).

5. Analysis (excipients) List of excipients included at the beginning of the section.

Updated information from suppliers (magnesium stearate, anhydrous lactose, and titanium dioxide).

6. Evaluation The values were modified accordingly to the new data included in the analysis.

7. Control strategy Values updated according to the evaluated levels. The outcome was updated as well.

8. Conclusions The conclusions were re-written according to the outcome of the assessment.

2. Summary Updated according to the previous changes.








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2. SUMMARY OF THE ASSESSMENT PROCESS

Case presentation (drug product, dosage, indication):

Simvastatin film coated tablets: Tablets containing different strengths of simvastatin (10, 20, 30, 40 and 60 mg). The drug product is given orally once daily for the treatment of hypercholesterolemia. The maximum daily weight corresponds to the 60 mg tablet and it is 0.62238 g/day.

Identified sources of elemental impurities:

API (simvastatin), excipients, manufacturing equipment, water, and container closure system.

Elemental impurities included in the assessment:

Class 1: As, Hg, Pb, Cd

Class 2A: Co, Ni, V

Class 3: Li (intentionally added in API)

The actual/predicted levels are detailed for each source in section 5 (analysis).

Evaluation of the levels (option 1, 2a, 2b or 3):

The evaluation by option 2b showed acceptable levels for all the EIs included in the risk assessment.

Control strategy:

The total levels calculated for all the elemental impurities under assessment were below the control threshold, and therefore further controls are not necessary.

The table, with the results of the evaluation and its comparison with the established

PDE values, is presented below:








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Source As Hg Pb Cd Co Ni V Li

Man. Proc. - - - - - 0 - -

Simvastatin 1.2 1.2 1.2 1.2 1.2 1.2 1.2 58.5

Preg. Starch 0.003 0.006 0.0042 0.012 0.012 0.012 0.012 -

MCC VIVAPUR®

0.0015 0.0015 0.003 0.0003 0.003 0.018 0.006 -

Mg Stearate - - - - - 0.057 - -

Anhydrous lactose

- - - - - - - -

Talc 0.0078 7.8·10-6

0.00156 0.00078 0.0234 0.2418 0.0351 -

BHA 0.00036 0.00012 0.00024 0.0012 0.0012 0.0012 0.0012 -

TiO2 0.0045 0.00045 0.045 0.00045 0.00045 0.0225 0.045 -

HPC KLUCEL®

0.0024 0.0024 0.0024 0.0024 0.012 0.012 0.012 -

HPMC VIVAPHARM®

0.002 0.0002 0.0015 0.0001 0.0004 0.01 0.0005 -

Total level (µg/day)

1.22 1.21 1.26 1.22 1.26 1.52 1.31 58.5

PDE (oral) (µg/day)

15 30 5 5 50 200 100 550

Acceptance*** YES YES YES YES YES YES YES YES

CT (30% of PDE)

4.5 9 1.5 1.5 15 30 60 165

Value < CT? YES YES YES YES YES YES YES YES

Outcome No control

No control

No control

No control

No control

No control

No control

No control








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3. OBJECTIVE AND ASSESSMENT STRATEGY

The objective of this document is to provide a detailed risk assessment of potential

elemental impurities in a drug product in accordance with the ICH guideline Q3D on

elemental impurities (25 August 2015, EMA/CHMP/ICH/353369/2013, Committee for

Human Medicinal Products, European Medicines Agency). Elemental impurities do not

provide any therapeutic benefit to the patient and should be controlled within

acceptable limits. The determination of health based exposure limits for elemental

impurities are based on their Permitted Daily Exposure (PDE) values. These values

have been already calculated for each element for the oral, inhalation and parenteral

routes of administration, and are provided in the ICH Q3D guideline (see annex I).

The assessment strategy involves four steps: i) Identification of the potential sources

that may introduce elements in the finished product, ii) Analysis of the elements that

can be introduced by each source, iii) Evaluation of the actual or predicted levels of

elemental impurities and comparison against the established PDE values, and iv)

Definition of the control strategy based on the results of the risk assessment.

It is of key relevance for the elemental impurities risk assessment to describe the raw

materials and manufacturing processes used to produce the finished drug product. This

document provides all the relevant information for each material and process, and the

source of the information is provided in the references section. Further modification of

the data after the assessment review date (e.g. updated results from elemental

analysis from an excipient supplier) should be considered and this document should be

updated.








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4. IDENTIFICATION OF THE POTENTIAL SOURCES OF ELEMENTAL IMPURITIES

In this step, the potential sources of elemental impurities in the drug product are

identified. For this, the manufacturing process should be thoroughly followed in order to

identify all the components, materials, and processes that could include elemental

impurities in the final drug product. The ICH Q3D guideline suggests 5 potential

sources of impurities in a finished drug product: i) water, ii) manufacturing equipment,

iii) container closure, iv) drug substance, and v) excipients [Scheme 1]. If other(s)

potential source(s) of contamination is(are) identified, it(they) should be included in the

risk assessment.

[Scheme 1]. Potential sources of elemental impurities in a drug product.

Each of these sources should be considered to determine the overall contribution of

elemental impurities to the drug product. According to the manufacturing instructions of

simvastatin tablets, a brief explanation of the components, materials and processes is

given below (the detailed analysis of each identified source is performed in the next

section):

Excipients and API are mixed, sieved and compressed. Then, the tablets are film-

coated (this process requires water) and packed in aluminum blisters. As result, the

potential sources of contamination are summarized in Table 1.








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Table 1. Potential sources of elemental impurities contamination identified for

simvastatin tablets.

POTENTIAL SOURCES OF CONTAMINATION IN THE DRUG PRODUCTSIMVASTATIN TABLETS

Water

Manufacturing equipment

Container closure system

API

Excipient(s)

According to the clinical indications and recommended posology (AEMPS, 2015),

simvastatin can be used in the treatment of hypercholesterolemia (recommended dose

range 10-40 mg, taken in one dose); homozygous familial hypercholesterolemia

(recommended doses are 40 mg once daily or 80 mg/day taken as two 20 mg and a 40

mg tablet); and cardiovascular prevention (20-40 mg taken in one dose). The product

characteristics are presented in Table 2.

Table 2. Product characteristics based on the recommended posology for the

products covered by this review.

Parameter Product Characteristics

Dosage form Film-coated tablets (oral route)

Tablet strength 10 mg 20 mg 30 mg 40 mg 60 mg

Weight (mg) 103.51 207.44 311.16 414.09 622.38

Dosing schedule (max tabs/day)

1 1 1 1 1

Max daily product weight (mg)

103.51 207.44 311.16 414.09 622.38

Clinical indication Hypercholesterolemia








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Production facility Multipurpose production facility

Equipment material

ss316L

API Generic purchased API

Water Purified water (Ph.Eur. grade)

Maximum daily product weight calculation: The dosage range is 5-80mg/day given orally

as a single dose in the evening. Adjustments of dosage, if required, should be made at

intervals of not less than 4 weeks, to a maximum of 80mg/day given as a single dose in

the evening. The 80mg dose is only recommended in patients with severe

hypercholesterolemia and at high risk for cardiovascular complications who have not

achieved their treatment goals on lower doses and when the benefits are expected to

outweigh the potential risks. To date, Atreiza manufactures simvastatin at strengths up to

60 mg. In the worst-case scenario, the patients receiving the simvastatin 60 mg tablets

would be the most exposed population, since the dosing schedule and tablet total weight

result in the highest daily product intake. For this, the maximum daily product weight is

taken as the most conservative approach for the elemental impurities risk assessment. It

is considered that the conclusions from the assessment would cover the other scenarios.

The quali-quantitative composition of the finished product to be assessed is presented in

Table 3.








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Table 3. Quali-quantitative composition of simvastatin 60 mg tablets

Component Total weight (mg)

Simvastatin 60.00

Pregelatinized starch 60.00

Microcrystalline cellulose 30.00

Magnesium stearate 3.00

Anhydrous lactose 447.06

Talc 7.80

Butylated hydroxyanisole 0.12

Titanium dioxide 4.50

Hydroxypropyl cellulose 4.95

Hydroxypropyl methylcellulose 4.95

Total product weight 622.38








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5. ANALYSIS OF THE POTENTIAL ELEMENTAL IMPURITIES

In this step, a risk assessment is performed for each of the potential sources of

elemental impurities, including all the relevant information as detailed as possible. It is

considered that the pre-defined potential sources of contamination can be divided into

two groups: a) General sources, which include water, manufacturing process and

container closure system; and b) product specific sources, which include API (drug

substance) and excipients.

According to the ICH Q3D guideline (EMA, 2015), the following table provides

recommendations for inclusion of elemental impurities in the risk assessment.

Table 4. Elements to be considered in the Risk Assessment.

Element Class

If intentionally added (all

routes) If not intentionally added

Oral Parenteral Inhalation

Cd 1 yes yes yes yes

Pb 1 yes yes yes yes

As 1 yes yes yes yes

Hg 1 yes yes yes yes

Co 2A yes yes yes yes

V 2A yes yes yes yes

Ni 2A yes yes yes yes

Tl 2B yes no no no

Au 2B yes no no no

Pd 2B yes no no no

Ir 2B yes no no no

Os 2B yes no no no








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Rh 2B yes no no no

Ru 2B yes no no no

Se 2B yes no no no

Ag 2B yes no no no

Pt 2B yes no no no

Li 3 yes no yes yes

Sb 3 yes no yes yes

Ba 3 yes no no yes

Mo 3 yes no no yes

Cu 3 yes no yes yes

Sn 3 yes no no yes

Cr 3 yes no no yes

Water and services

Contains only non-intentionally added elements. The risk of inclusion of elemental

impurities from water can be reduced by complying with compendial (e.g., European

Pharmacopoeia, Japanese Pharmacopoeia, US Pharmacopeial Convention) water

quality requirements, if purified water or water for injection is used in the manufacturing

process(es).

The water used in the manufacturing process of simvastatin tablets is purified water

(PW) obtained through reverse osmosis (RO) and filtering in a PW distribution loop

manufactured by LETZNER. The system is in accordance with the regulations of

Ph.Eur. and guarantees the quality of purified water at all points of use. The equipment,

tanks and piping are made in jointless stainless steel type 316L (ss316L) which is

passivated yearly. The PW loop contains sanitary connections and orbital welds, and

the system only allows PW into the tank for distribution. The sanitization is performed

by increasing the temperature and LETZNER performs maintenance at least two times

per year. The system is re-qualified each year. The Piping and Instrumentation

Diagrams (P&ID) of the PW loop are presented in Figures 1 and 2.








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Figure 1. P&ID of the water purification by LETZNER.








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Figure 2. P&ID of the PW loop installation by LETZNER.

In addition to the qualification, the PW is guaranteed by preventive physicochemical

and microbiological analyses. The quality of PW is analyzed weekly (water is taken

from two points of use for analysis each week so that all the points of use have been

analyzed in 4 months). The weekly analyses guarantee that the PW complies with the

Ph.Eur. specifications. Moreover, the system is continuously measuring the

conductivity, which is intrinsically related with the presence of ions in the water. The

value observed during the visual inspection of the PW loop was remarkably low (0.07

µS/cm at 18.5 ºC) which could be indicative of the quality of the purified water. Finally,

it should be mentioned that in case of corrosion the conductivity would increase, and

therefore it could be easily detected.

As conclusion, the purified water used complies with the specifications required by the








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European Pharmacopoeia, the water loop is qualified and appropriately maintained,

and the quality is continuously guaranteed at all points of use by frequent analysis. For

this, according to the ICH Q3D guideline for elemental impurities, the risk of inclusion of

elemental impurities in water is sufficiently reduced.

In addition, air has been taken into account since it is another service used in the

manufacturing process of simvastatin tablets. The compressed air is free of particles;

water (presents a very low dew point, -20 ºC); and oil. The installation is a HVAC,

manufactured by Atlas Copco, and it is qualified as a preventive action to minimize the

risk. In addition, the system contains a pre-filter installed in the piping that conducts the

air to the manufacturing place, and filters are installed in all the points of use. These

filters are qualified when installed. With the available information, it is considered that

the risk of inclusion of elemental impurities in a finished drug product by the

compressed air is negligible.

The conclusion from this risk assessment is the following: Although water and air were

considered as potential sources of elemental impurities, the qualification of the

materials and processes involved, quality assurance, controls, analyses, compliance

and specifications described above permit to consider that the predicted levels of

elemental impurities from these sources in the final drug product would be minimal.

Consequently, the mentioned services are not taken into account further in the risk

assessment.

Manufacturing process

The risk of inclusion of elemental impurities can be reduced through process

understanding, equipment selection, equipment qualification and Good Manufacturing

Practice (GMP) processes.

The manufacturing process starts with the pulverization of butylated hydroxyanisole

(BHA) in a mortar. It is then sieved (through 0.5 mm mesh) and mixed together with a

portion of microcrystalline cellulose. Then, the previous mixture, anhydrous lactose,

simvastatin, microcrystalline cellulose and pregelatinized starch are placed in a MCG

600 container and mixed in a Bohle PM 1000 blender at 6 rpm for 5 minutes and

sieved (2 mm mesh size) in a BTS 200 at the minimum speed (approx. 155 rpm). The

product is mixed again at 6 rpm for 30 minutes. This mixture is compressed in either a

Bonals compressing machine equipped with rollers. In the Bonals BC150, the following

parameters are set: Pressure 75 KN, granulator angular speed 170 rpm, screw speed








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11 rpm, distance between rollers 1.0 mm, and angular speed of the rollers 30 rpm. The

tablet cores prepared with the Bonals are sieved in a Frewitt granulator with mesh size

of 1.25 mm and 5 mm. This pool sieving machine exerts pressure on the compacted

sheet against the mesh, yielding small compacted pellet-like particles, which are then

mixed with magnesium stearate and talc and compressed in Fette 2090i, Fette 2100 or

Fette 1200 compressing machines, resulting in the formation of the simvastatin tablets.

The certificates of analysis of the punches are available in the production department.

In these certificates, the composition of the punches shows that the material is tool

steel and that there are no class 1 elements present, and the concentration of nickel

and vanadium (class 2a elements) is specified as maximum 0.75 and 1 wt%,

respectively. The actual analyzed levels were reported to be 0.20 for nickel and 0.23

for vanadium. At the end of the process, a de-dusting machine (GRATEX or KRAMER)

and a metal detector (SAFELINE or CEIA) are placed to remove any un-compacted

material and to detect potential metal leaching in the tablets. The metal detector is

calibrated with the following standards: stainless steel 0.4-0.5 mm, ferric standard, non-

ferric standard and blank. The system will reject the tablets in which metals are

detected. The tablets are collected in PEB containers and stored for further coating.

The metal detector is calibrated with a sphere of 0.4 mm of diameter in the case of

stainless steel. In this sphere, the volume is 0.0335 mm3 and considering a density of

8000 kg/m3 (equivalent to 8 µg/mm3) (Atlas Specialty Metals, 2004), the total quantity

of stainless steel is 0.268 µg. In ss316L, Nickel is present between 10 and 14%. From

this margin, 14% is taken as the most conservative approach for the risk assessment

purpose: 14% of 0.268 µg is 0.0375 µg. In conclusion, any tablet containing ≥0.0375 µg

of Nickel would be rejected by the metal detector.

The next step consists in the film-coating of the as-prepared tablets. For this, water,

hydroxypropyl cellulose and hydroxypropyl methylcellulose are stirred for 30 minutes in

a 100 L reactor vessel connected at 40 ºC with a reflux condenser. In a 50 L reactor,

talc, titanium dioxide and water are stirred for 30 minutes to form a suspension. This

suspension is filtered through a 0.3 mm mesh and added, under stirring, to the

previous one. The film coating process is performed in a Pellegrini coating pan with the

following parameters: Pan speed 3 rpm, income temperature 60-85 ºC, sample

temperature 45-50 ºC, pulverization pressure 2 bar, pulverization flow 150-225 mL/min.

This process is sustained for several hours, until the weight of the tablets increases 2-

3% (mean weight 622.4 mg). The film-coated simvastatin tablets are stored in

polyethylene bags and silica gel is placed between the bags.








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Taking into account the manufacturing process, identified the equipment used and

having understood each step, the risk assessment is performed by the RPN (risk

priority number) method to identify the critical steps in which elemental impurities could

be introduced in the drug product. The risk assessment is based in three points:

severity, probability and detection. Each point is evaluated with a risk level (1 for low

risk, 2 for medium risk and 3 for high risk).

Severity (S): Takes into account the relative quantity of drug product that can receive

EIs and the equipment involved.

Probability (P): Considers the energy and conditions of the process in relation with the

equipment.

Detection (D): Accounts for the possibility of detection of equipment malfunctions that

could increase the risk of inclusion of elemental impurities.

Tables 5 and 5a show the values assigned for the risk assessment:

Probability

1 Low 2 Mild 3 High

Severity

3 High 3 6 9

2 Mild 2 4 6

1 Low 1 2 3

Low risk Medium risk High risk

1 2 3 4 6 9

Detection

1 High 1

Low 2 Low 3 Low 4 Low 6 Medium 9 Medium

2 Mild 2

Low 4 Low 6 Medium 8 Medium 12 Medium 18 High

3 Low 3

Low 6 Medium 9 Medium 12 Medium 18 High 27 High

The following table summarizes the risk assessment of the manufacturing process,

including the RPN results (pre-risk assessment and final risk-assessment taking into

account equipment qualification and GMPs), equipment involved, process, conditions

and specifications of the equipment (including routine GMP controls and remarks).








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Table 6. Risk assessment of the manufacturing process of simvastatin film coated

tablets.

Equipment Process Kinetic energy

Conditions

Pre Risk assessment Material Remarks GMP controls

Final Risk assessment

S P D RPN S P D RPN

Mortar Grinding Low

(manual) Not

aggressive 1 1 3 3 Ceramic

Small mortar for manual grinding. Not

mechanical, no qualification required. The potential leaching of EIs to the sample is negligible considering the small quantity of

product involved in this process

Covered by routine GMP

(maintenance, cleaning, etc.)

1 1 2 2

0.5 mm mesh

Sieving Low

(manual)

Not aggressive (manual)

1 1 3 3 ss316L Material certification. Covered by routine

GMPs 1 1 1 2

BOHLE PM 1000

Mixing (dry) Low Not in

contact with drug product

- - - NA ss316L

Installed in 2005. The equipment is qualified. The equipment is not

in contact with the product: not

considered as relevant for the risk assessment

of EIs

NA - - - NA

MCG 600 Container / mixing (dry)

None / Low

Not aggressive

(dry) 1 1 2 2 ss316L

The overall risk of inclusion of EIs during the storage of a dried product is considered negligible. The same applies to a mixing

process at low speed and short time.

Covered by routine GMPs

(maintenance, cleaning, etc.)

1 1 1 1

BOHLE BTS 200

Sieving High Not

aggressive (dry)

1 2 3 6

ss316L Installed in 2005. The equipment is qualified.


1 1 2 2

2 mm mesh

ss316L Consumable. Certified

and guaranteed by supplier.

Mesh is always checked after

sieving

BONALS BC150

Compacting High Not

aggressive 1 2 3 6

ss (not specified)

No information available

Periodic visual inspection for abrasion and corrosion and routine GMPs

1 2 2 4








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Plastic bags

Storage None Not

aggressive (dry storage)

1 1 2 2 PE

The overall risk of inclusion of EIs during the storage of a dried product is considered

negligible


1 1 1 1

FREWITT MG-633 Oscillating

granulator High

(shear) Not

aggressive

1 2 3 6 ss316L Installed in 2001. The equipment is qualified.

Periodic visual inspection for

abrasion and/or corrosion and routine GMPs

1 1 2 2

FREWITT MF-3

1 2 3 6 ss316L Installed in 2010. The equipment is qualified.

1 1 2 2

FETTE P2100

Compressing machines

High (pressure)

Not aggressive

2 2 2 8

ss316L Installed in 1999 and 2002. Two machines.

Both are qualified. Periodic visual inspection for

abrasion and/or corrosion and routine GMPs

2 1 1 2 FETTE 2090i

ss316L Installed in 1998 and 2003. Two machines.

Both are qualified.

FETTE 1200

ss316L Installed in 2007. The equipment is qualified.

KRAMER or

GRATEX de-dusting

system

de-dusting by aspiration

Low Not

aggressive 1 1 2 2 ss316L

Three machines. Installed in 2007. The equipment is qualified


1 1 1 1

Safeline or CEIA metal

detector

metal detection

Low Not

aggressive - - - NA NA

The presence of the metal detector at the end of the process

reduces the probability of acceptance of

tablets with certain concentration of

metals: Increases detection in risk

assessment

Calibration before and during use. Routine GMPs

- - - NA

Reactor tanks 50

and 100 L

Solution of components

High (shear)

Not aggressive (Aqueous solution under

stirring)

1 1 3 3 ss316L The tanks for solution are associated to the

coating pan.


1 1 2 2

0.3 mm mesh

Filtering of a suspension

Low Not

aggressive (manual)

1 1 3 3 ss316L Material certification. Covered by routine

GMPs 1 1 1 2








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GS Pellegrini, HT-HP or HP-F300 coating

pan

Film-coating Low

Barely aggressive

(mild temperature)

1 2 3 6 ss316L

Three machines. Installed 1999, 2000

and 2004. All the equipment is qualified.


1 1 2 2

As it is shown in the previous table, the processes that were identified as the most

critical were: sieving (in Bohle BTS200 or Quadro Comil U20), compacting (in Bonals

BC150), regularizing (in Frewitt Mg-633 and MF-3), compressing (in Fette 1200, 2090i

and 2100), and film-coating (in GS coating pan, Pellegrini, HT and HP). In these

processes, the equipment qualification and GMPs reduced significantly the risk of

inclusion of elemental impurities. The outcome of the assessment is that the risk of

inclusion of elemental impurities is low in all the processes involved in the

manufacturing of simvastatin film coated tablets. According to the ICH Q3D guideline

on elemental impurities, it is considered that the contribution of the manufacturing

process to the overall level of elemental impurities is negligible.

Container closure system

The identification of potential elemental impurities that may be introduced from

container closure systems should be based on a scientific understanding of likely

interactions between a particular drug product type and its packaging. When a review

of the materials of construction demonstrates that the container closure system does

not contain elemental impurities, no additional risk assessment needs to be performed.

It is recognized that the probability of elemental leaching into solid dosage forms is

minimal and does not require further consideration in the risk assessment. For liquid

and semi-solid dosage forms there is a higher probability that elemental impurities

could leach from the container closure system during the shelf-life of the product.

Studies to understand potential leachables from the container closure system (after

washing, sterilization, irradiation, etc.) should be performed. This source of elemental

impurities will typically be addressed during evaluation of the container closure system

for the drug product.

Factors that should be considered (for liquid and semi-solid dosage forms) include but

are not limited to: hydrophilicity/hydrophobicity, ionic content, pH, temperature, contact

surface area, container/component composition, terminal sterilization, packaging

process, component sterilization, duration of storage.








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Only the primary packaging (parts in contact with the drug product) is taken into

account for the elemental impurities risk assessment.

Simvastatin film-coated tablets are packed in blisters. Blisters are the most common

presentation for oral dosage forms. There are four “blisters-lines”, referred as

ULHMANN (I and II) and IMA (I and II). The IMA-lines contain a blistering machine

IMATR135, among other parts that are not in contact with the drug product (a cartoning

machine IMA A83, etc.) and are not the aim of this review. Similarly, the ULHMANN-

lines contain a blistering machine ULHMANN UPS 1040. The blistering process is

described below (note that the systems to unload the drug product into the blistering

machine are interchangeable between lines):

The ULHMANN lines permit the blistering in Aluminum-PVC. For this, the drug product

is unloaded from the typical MCG or PEB container from the manufacturing process

and poured into a hopper, that is connected to a vibrating channel. All these materials

are made of ss316L. From the vibrating channel, the tablets are aspirated through a

plastic tube (Armorvin HNA plastic, food quality, Merlett technologies, Italy) and placed

by positioning rolls (Teflon rolls with microfibers for de-dusting) inside the

voids/cavities/pockets of one side of the blister, composed of PVC. These pockets are

formed in the machine by a thermal treatment with compressed air, and are formed

with a specific size and number, depending on the presentation of the drug product.

The PVC strips are carried horizontally in a conveyor, with the pocket opened upwards.

Once the strip is filled with the capsules/tablets, the conveyor continues moving to the

sealing part, in which the blisters are sealed with the aluminum strip. Another unloading

system consists in pouring the product from the PEB containers into a ss316L hopper

connected to a ss316L SIMTAP feeder (German acronym for simultaneous tablet

positioning system), which transfers the product through a Teflon classifier that

introduces the drug product inside the pockets of the PVC film, as described above.

The IMA lines permit the blistering in Aluminum-PVC and also Aluminum-Aluminum.

Herein, the product from the manufacturing process is poured into a hopper (made of

ss316L and with a methacrylate closure) and then placed in an ss316L plate, from

which the capsules/tablets come down through an ss316L and methacrylate ramp that

introduces them in the pockets of the PVC or aluminum strips. The conveyor transports

the filled strips to the closure part, where they are sealed with aluminum.

Further steps do not put in contact any materials with the drug product. The blistering

of the tablets and capsules is not an energetic process and is not performed under








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aggressive conditions. All the “blisters-lines” are qualified as preventive action to

minimize the risk and the packaging is performed under good manufacturing practices.

In relation to the packaging material, the blisters can be composed by different

combinations of polyamide, polyvinylchloride, and aluminum film. The different

presentations of drug products may require slightly different blisters, and these

differences are esthetic and do not represent significant differences in the composition

of the materials.

As result, it is not expected that the primary packaging process could introduce

elemental impurities in the final drug product. In addition, according to the ICH Q3D

guideline on elemental impurities, the probability of elemental leaching into solid

dosage forms is minimal and does not require further consideration in the risk

assessment. For these reasons, the container closure system of simvastatin tablets is

not considered as a potential risk in this assessment.

Drug substance

Simvastatin is a synthetic API that can be provided by Zhejiang Hisun (China) and/or

Zhejiang Jiangbei Pharmaceutical Co., Ltd (China). It should be noted that some drug

products manufactured by Atreiza may include only one API supplier. With the aim of

covering all the possible scenarios, the worst-case (for each elemental impurity) is

taken as the most conservative approach for the risk assessment. In this section, the

information provided by both suppliers is reviewed and the worst-case scenario is

identified:

Simvastatin (Hisun): Is supplied via Tiefenbacher API GmbH (Germany) and

manufactured by Zhejiang Hisun Pharmaceutical (Zhejiang Province, China). The

manufacturer provided documents that answered several questions in relation to the

elemental impurities in their drug substance: Regarding the intentionally added

elements, the manufacturer confirmed that lithium is the only catalyst used in the

manufacturing process of simvastatin. The residual lithium is the final drug substance is

demonstrated to be less than 0.10 ppm, detected with the graphite-AAS method

(document dated from June 2008). Later on, the manufacturer updated the information

in compliance with the ICH Q3D guideline: the manufacturer fulfilled and signed a

questionnaire, in which the specification for lithium is <0.1 ppm, measured by ICP-MS

(limit of detection 0.07 ppm). In relation to the elemental impurities potentially present

even when not intentionally added, simvastatin is intended for oral administration and








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consequently, class 1 and class 2A elements should be considered. For these

elemental impurities, Zhejiang Hisun included specification limits that correspond to the

acceptable concentration limits established by the ICH Q3D for oral products (table

A.2.2 of the mentioned guideline). Since all the elemental impurities under assessment

in this component are below the acceptable limits of the ICH Q3D, it does not require

further assessment. The analytical method was ICP-MS (data regarding the limits of

detection and quantification was also provided and it is included in the table below).

These data was obtained from three representative batches, as required by the ICH

Q3D. The following table summarizes the analysis of the drug substance supplied by

Zhejiang Hisun:

Parameter Elements Specification Control

strategy API (Hisun)

Risk assessment

DP

Intentionally added elements

Catalysts/reagents intentionally added

Li <0.1 ppm ICP-MS (LoD

0.07 ppm; LoQ 6 ppm)

Li

Non-intentionally added elements

Source Synthetic

Class 1 elements

As <1.5 ppm

ICP-MS (LoD 0.003 ppm; LoQ 0.15

ppm)

-

Hg <3 ppm

ICP-MS (LoD 0.001 ppm;

LoQ 0.3 ppm)

-

Pb <0.5 ppm

ICP-MS (LoD 0.005 ppm; LoQ 0.05

ppm)

-

Cd <0.5 ppm ICP-MS (LoD 0.001 ppm; LoQ 0.05

-








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ppm)

Class 2A elements

Co <5 ppm

ICP-MS (LoD 0.001 ppm;

LoQ 0.5 ppm)

-

Ni <20 ppm ICP-MS (LoD

0.01 ppm; LoQ 1 ppm)

-

V <10 ppm ICP-MS (LoD 0.003 ppm; LoQ 1 ppm)

-

Equipment used - - - -

Grade of water used - - - -

Simvastatin (Jiangbei): Is supplied via Otto Brandes GmbH (Germany) and

manufactured by Zhejiang Jiangbei Pharmaceutical (Zhejiang Province, China). The

manufacturer provided documents that answered several questions in relation to the

elemental impurities in their drug substance: Regarding the intentionally added

elements, the manufacturer confirmed that lithium is used as reagent in the

manufacturing process of simvastatin. Lithium is consistently removed by purification

processes (such as filtration, distillation, etc.), and the given expected concentration is

975 ppm. Regarding the non-intentionally added elements (but potentially present),

class 1 and class 2A require consideration as simvastatin is intended for the oral route

of administration. The manufacturer confirmed that these elements are not added

during the manufacturing process and that all the raw materials, reagents and

excipients used in the manufacturing do not contain these elements. These elemental

impurities are routinely controlled as heavy metals in the API, and the manufacturer

confirmed that the elements will be tested according to the method published in the

Ph.Eur. after the test of heavy metals is deleted. According to this information, specific

analytical data for each elemental impurity is not available. Hence, the maximum

permitted limit by specifications (as ‘heavy metals’ in CoA) is taken as the most

conservative approach for the risk assessment. The analysis of elemental impurities by

the general ‘heavy metals’ test is not element-specific, and consequently, the worst








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case scenario would be represented by assuming that each elemental impurity under

assessment should comply with the given limit (in this case, <20 ppm). This highly-

conservative approach is expected to provide a large safety margin to cover the lack of

specific analytical data in this component. The following table summarizes the analysis

of the drug substance provided by Zhejiang Jiangbei:

Parameter Elements Actual/Predicted

data

Control strategy API (Jiangbei)

Risk assessment

DP



Li 975 ppm Purification processes

Li


Source Synthetic

Class 1 elements

As <20 ppm CoA As

Hg <20 ppm CoA Hg

Pb <20 ppm CoA Pb

Cd <20 ppm CoA Cd

Class 2A elements

Co <20 ppm CoA Co

Ni <20 ppm CoA Ni

V <20 ppm CoA V

Equipment used - - - -

Grade of water used - - - -

Both suppliers stated that lithium is intentionally added in the synthesis of simvastatin

as reagent and that the expected concentration is 975 ppm (in the case of Jiangbei)

and <0.1 ppm in the case of Hisun (measured with ICP-MS, limit of detection 0.07 ppm

and limit of quantification 6 ppm). From both statements, it is noted the enormous








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difference between the provided levels, and a possible explanation for this is that Hisun

provided analytical data while Jiangbei provided a predicted level based on the quantity

of lithium used. Despite this information regarding the intentionally added elements, no

predicted/actual levels of non-intentionally added elements (class 1 and class 2a) were

provided by Zhejiang Jiangbei, whereas Zhejiang Hisun demonstrated by ICP-MS

analysis that their drug substance complies with the ICH Q3D limits. Consequently, the

worst-case scenario up to now is represented by the simvastatin from Zhejiang

Jiangbei. It should be noted that this outcome is related to the lack of specific data

(Hisun provided analytical data while Jiangbei didn’t) and it is not due to actual

differences in the manufacturing processes. In addition, it should be noted that the

analytical data provided by Hisun showed very low levels for all the tested impurities,

which confirms that the use of the specification in the certificate of analysis (20 ppm,

measured by the heavy metals general test) taken for the API manufactured by

Jiangbei represents a very large safety margin in the risk assessment.

Excipients

The excipients used in the drug products included in this assessment are:

pregelatinized starch, microcrystalline cellulose, magnesium stearate, anhydrous

lactose, talc, butylated hydroxyanisole, titanium dioxide, hydroxypropyl cellulose, and

hydroxypropyl methylcellulose. The most relevant data, for each excipient, is

summarized as follows:

Pregelatinized starch: is manufactured by Colorcon (in Indianapolis, USA), under the

brand Starch 1500®. The manufacturer provided data regarding elemental impurities

analyzed in their pregelatinized starch, and stated that no elements are intentionally

added in this process. The supplier informed that the presented data was obtained

from a limited analysis of several batches made for several years. The analytical

methods reported and the limits of detection are represented in the following table:

PREGELATINIZED STARCH


data

Analytical method + LoD (ppm)

Risk assessment

DP



None added

- NA None









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Source Plant

Class 1 elements

As <0.05 ppm ICM-MS

0.05 As

Hg <0.1 ppm ICP-MS 0.1 Hg

Pb ≤0.07 ppm ICP-MS

0.05 Pb

Cd <0.2 ppm ICP-MS 0.2 Cd

Class 2A elements

Co <0.2 ppm ICP-MS 0.2 Co

Ni ≤0.2 ppm ICP-MS 0.1 Ni

V <0.2 ppm ICP-MS

0.2 V

Equipment used Not

specified NA None

Grade of water used Not

specified NA None

Microcrystalline cellulose: is provided by JRS (Weissenborn, Germany), under the

brand Vivapur® 101. Vivapur® is manufactured of cellulose pulp derived from wood.

The pulp is processed by sulfate digestion and bleached without chlorine. MCC

process aids are only of synthetic origin (diluted hydrochloric acid and diluted ammonia

solution). Vivapur® is manufactured on a mono-purpose production line. The process

excludes any step of fermentation, irradiation or another microbial reduction step. It is

performed without metal catalysts and organic solvents. There is no contact with latex

materials, materials of animal or human origin. JRS provided analytical data from the

elemental analyses using ICP-MS in VIVAPUR® products. The most relevant data is

presented below (the symbol “<” indicates that the measurement was below the limit of

quantification):

MICROCRYSTALLINE CELLULOSE VIVAPUR® 101


data

Control strategy

MCC

Risk assessment

DP



None added

- NA None


Source Plant derived








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Class 1 elements

As <0.05 ppm Initial

product matrix testing

As

Hg <0.05 ppm Hg

Pb <0.1 ppm Pb

Cd <0.01 ppm Cd

Class 2A elements

Co <0.1 ppm and continued

annual testing

Co

Ni <0.6 ppm Ni

V <0.2 ppm V

Equipment used Not

specified NA None


specified NA None

Magnesium stearate: is provided by Peter Greven Nederland CV (The Netherlands),

under the brand Ligamed MF-2-V®. The supplier sent a document regarding the

elemental impurities in their product, in which, according to the ICH Q3D, the following

statements are signed: i) In Peter Greven Nederland CV, a risk-based approach with

validated processes and supply-chain control is applied to assess the potential

presence of elemental impurities; ii) Adequate testing is done to demonstrate

compliance, and iii) all potentially present elements are included in the testing and

representative testing results are provided. The source of this excipient is mainly

synthetic, no metal catalysts or metal reagents are used in the manufacturing process,

package and controlled handling of the product. Peter Greven Nederland provided

analytical information from several elements, including class 1, class 2A, class 2B and

class 3 elemental impurities according to the ICH Q3D. However, since the drug

product under assessment is intended for the oral route of administration and there are

no intentionally added elements, only class 1 and class 2A elements require

assessment. It is noted that, in the provided data, the elements Li, Ba, Cu and Cr were

marked as potentially present because they showed levels above the limit of

quantification of ICP-OES. However, the reported values were well below the option 1

concentration limit of table A.2.2 of the ICH Q3D (which is consistent with the definition

of the class 3 elements: elemental impurities with low oral toxicity). For this reason, the

above mentioned elements are not taken into account further in the risk assessment

from this source. The following table summarizes the analytical results and control

strategy (all the measurements were performed by ICP-OES):








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MAGNESIUM STEARATE


data Control strategy

Mg Stearate

Risk assessment

DP



None added

- NA None


Source Synthetic

Class 1 elements

As <LoD Monitoring -

Hg <LoD Monitoring -

Pb <LoD Test each batch -

Cd <LoD Test each batch -

Class 2A elements

Co <LoD Monitoring -

Ni 1.0±0.9 ppm Test each batch Ni

V <LoD Monitoring -

Equipment used Not

specified NA None


specified NA None

Anhydrous lactose: is supplied by Quimidroga S.A. (Spain) and manufactured by DMV-

Fonterra excipients (DFE pharma) (in Nörten-Hardenberg, Germany), under the brand

name Supertab 21AN®. The manufacturer provided a document in which it is stated

that a risk assessment was performed in the framework of the ICH Q3D. The

manufacturer confirmed that the elements listed in the ICH Q3D are not intentionally

added during the production process of anhydrous lactose and therefore DFE pharma

performed analysis on relevant elemental impurities (potentially present although not

intentionally added, class 1 and class 2A elements for oral dosage forms). This

document is available for review during audits, and the conclusion of the risk

assessment is that all values obtained are below 30% of the limits and thus the

elemental impurities do not need additional control (the levels of ICH Q3D relevant

elemental impurities are monitored on regular basis). According to this statement, this

component does not represent a risk of inclusion of elemental impurities in the final

drug product. The following table summarizes the analysis of the anhydrous lactose:








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ANHYDROUS LACTOSE (SUPERTAB® 21AN)


data

Control strategy lactose

Risk assessment

DP



None added

- NA None


Source Animal

Class 1 elements

As <1.5 Option 1 concentration limits of ICH Q3D (table

A.2.2)

-

Hg <3 ppm -

Pb <0.5 ppm -

Cd <0.5 ppm -

Class 2A elements

Co <5 ppm Option 1 concentration limits of ICH Q3D (table

A.2.2)

-

Ni <20 ppm -

V <10 ppm -

Equipment used Not known NA None

Grade of water used Not known NA None

Talc: is provided by IMERYS (Italy), under the brand Luzenac Pharma®. Talc is a

mined excipient, and no intentionally added elements are added. IMERYS provided the

results from elemental impurities analyses according to the ICH Q3D guideline. In this

document, the supplier states that all the elements found were limited to natural

background levels. In addition to the Class 1 and Class 2A elements, barium and

chromium were also analyzed. It was found that the concentration of these two

elements were 2 and 5 ppm, respectively. Since these elements are not intentionally

added and simvastatin is intended for the oral administration route, they do not require

consideration in the risk assessment (class 3: their oral PDE values are high: 1400 and

11000 µg/day, respectively). The data available for Class 1 and Class 2A elements is

included in the table below (the symbol “<” indicates that the measured level was below

the limit of detection):








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TALC


data

Analytical method +

LoD

Risk assessment

DP



None added

- NA None


Source Mineral

Class 1 elements

As < 1 ppm ICP-MS (1

ppm) As

Hg 0.001 ppm AAS (0.001

ppm) Hg

Pb < 0.2 ppm ICP-MS

(0.2 ppm) Pb

Cd < 0.1 ppm ICP-MS

(0.1 ppm) Cd

Class 2A elements

Co 3 ppm ICP-MS

(0.1 ppm) Co

Ni 31 ppm ICP-MS

(4.6 ppm) Ni

V 4.5 ppm ICP-MS

(1.1 ppm) V

Equipment used Not

specified NA None


specified NA None

Butylated hydroxyanisole: is provided by Merck (Germany), under the brand

Butylhydroxyanisol Ph Eur, NF, E 320. BHA is a conservative excipient of synthetic

source. To date, no analytical data from the supplier is available. Alternatively, the

supplier’s compliance specifications can be used as a conservative approach for the

elemental impurities risk assessment. The manufacturer’s certificate of analysis shows

that the maximum heavy metal content is 10 ppm, and that As, Pb and Hg contents are

individually measured. Thus, the maximum level from the general heavy metals test is

taken for those elements which are not individually measured. According to a literature

review, it is not expected that the manufacturing process of BHA requires the addition

of elemental impurities as catalysts/reagents. The following table summarizes the

analysis from this component:








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BUTYLATED HYDROXYANISOLE


data

Control strategy

BHA

Risk assessment

DP



Not expected

- NA None


Source Synthetic

Class 1 elements

As ≤3 ppm None As

Hg ≤1 ppm None Hg

Pb ≤2 ppm None Pb

Cd <10 ppm None Cd

Class 2A elements

Co <10 ppm None Co

Ni <10 ppm None Ni

V <10 ppm None V

Equipment used Not

specified NA None


specified NA None

Titanium dioxide: is provided by KRONOS (Germany), under the brand KRONOS

1171® (Titanium dioxide E171). Titanium dioxide is a mined excipient, and no

intentionally added elements are added. KRONOS provided a document in relation to

the ICH Q3D guideline for elemental impurities, in which they confirmed that their

product contains elemental impurities which have not been intentionally added during

the manufacturing process, but are trace elements originating from the raw material

used. The levels of the 24 elemental impurities listed in the ICH Q3D were provided.

However, since the drug product under assessment is intended for the oral route of

administration, only class 1 and class 2A elements require further consideration. The

data including the specified concentration, method of analysis and limit of detection

(LoD) is showed in the following table:








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TITANIUM DIOXIDE


data

Analytical method + LoD TiO2

Risk assessment

DP



None added

- NA None


Source Mineral

Class 1 elements

As <1 ppm ICP-MS

(0.1 ppm) As

Hg <0.1 ppm AAS (0.1

ppm) Hg

Pb <10 ppm ICP-MS

(0.1 ppm) Pb

Cd <0.1 ppm ICP-MS

(0.1 ppm) Cd

Class 2A elements

Co <0.1 ppm ICP-MS

(0.1 ppm) Co

Ni <5 ppm ICP-MS

(0.1 ppm) Ni

V <10 ppm ICP-MS

(0.1 ppm) V

Equipment used Not

specified NA None


specified NA None

Hydroxypropyl cellulose: is provided by ASHLAND (USA), under the brand Klucel® EF.

HPC is a plant derived excipient. The supplier provided analytical information for Class

1, 2A, 2B and 3 elements. Only class 1 and class 2A elements are included in the

assessment, since the data suggests that there are no intentionally added elements in

the manufacturing process. The analytical method, according to ASHLAND, was ICP-

OES and the number of tested samples was 6. The analytical data is summarized in

the following table:

HYDROXYPROPYL CELLULOSE


data

Analytical method

HPC

Risk assessment

DP








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None added

- NA None


Source Plant

Class 1 elements

As <0.5 ppm ICP-OES As

Hg <0.5 ppm ICP-OES Hg

Pb <0.5 ppm ICP-OES Pb

Cd <0.5 ppm ICP-OES Cd

Class 2A elements

Co <2.5 ppm ICP-OES Co

Ni <2.5 ppm ICP-OES Ni

V <2.5 ppm ICP-OES V

Equipment used Not

specified NA None


specified NA None

Hydroxypropyl methylcellulose (HPMC): HPMC: is provided by J. Rettenmaier & Söhne

(JRS) (Weissenborn, Germany), under the brand Vivapharm® E5. JRS provided a

document with a statement of elemental impurities according to the ICH Q3D guideline.

In this document, JRS Pharma used the following approach: all raw materials were

tested for compliance; selected raw material suppliers were queried if metal catalysts

are used during production; all processing aids were tested for compliance; and final

products were tested for compliance. According to the statement provided by JRS, in

the production process of the above mentioned product, elements are not intentionally

added in form of metal catalysts, metal reagents etc. JRS provided analytical data

regarding the elemental impurities in Vivapharm® products, tested by ICP-MS. The

control strategy followed by JRS consists in an initial product matrix testing and

continued annual testing. The most relevant data is presented in the following table

(the symbol “<” indicates that the value was below the limit of quantification):








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HPMC (VIVAPHARM®)


data

Analytical method +

LoQ HPMC

Risk assessment

DP



None added

- NA None


Source Plant

Class 1 elements

As <0.5 ppm ICP-MS

(0.5) As

Hg <0.05 ppm ICP-MS (0.05)

Hg

Pb <0.3 ppm ICP-MS

(0.3) Pb

Cd <0.02 ppm ICP-MS (0.02)

Cd

Class 2A elements

Co <0.1 ppm ICP-MS

(0.1) Co

Ni <2 ppm ICP-MS

(2.0) Ni

V <0.1 ppm ICP-MS

(0.1) V

Equipment used Not

specified NA None


specified NA None








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Having analyzed all the potential elemental impurities that could be present in each of

the potential sources of contamination, the outcome of the assessment is given in the

following table:

Table 7. Elemental impurities that require evaluation in the drug product simvastatin

tablets.

Source Intentionally added Non-intentionally added (potentially present)

Water - -

Container closure system - -

Manufacturing equipment - -

Simvastatin Li As, Hg, Pb, Cd, Co, Ni, V

Pregelatinized Starch - As, Hg, Pb, Cd, Co, Ni, V

Microcrystalline cellulose - As, Hg, Pb, Cd, Co, Ni, V

Magnesium stearate - Ni

Anhydrous lactose - -

Talc - As, Hg, Pb, Cd, Co, Ni, V

BHA - As, Hg, Pb, Cd, Co, Ni, V

Titanium dioxide - As, Hg, Pb, Cd, Co, Ni, V

HPC - As, Hg, Pb, Cd, Co, Ni, V

HPMC - As, Hg, Pb, Cd, Co, Ni, V

Elements to be included in the evaluation As, Hg, Pb, Cd, Co, Ni, V, Li








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6. EVALUATION OF THE LEVELS OF THE POTENTIAL ELEMENTAL IMPURITIES

In this step, the analyzed data is processed to obtain the predicted levels of the

potential elemental impurities. These levels are compared with the permitted daily

exposure (PDE) values to obtain the outcome of the evaluation.

The PDE values for the potential elemental impurities have been calculated for the oral,

inhalation and parenteral routes of administration. These PDE values were established

following element-specific health-based risk assessments, which are available in the

ICH Q3D guideline. The summarized table with the PDE values is included in annex I.

If the route of administration of the finished product is different from oral, parenteral or

inhalation, a route-to-route extrapolation should be performed. The route-to-route

extrapolation is based on bioavailability data and on the known local effects of the

contaminant.

From the previously assessed elemental impurities and sources of contamination, the

following data was used:

Table 8. Summary of the analysis (with predicted/actual levels of elemental impurities).


Man. Proc. - - - - - - - -

Simvastatin 20 20 20 20 20 20 20 975

Preg. Starch 0.05 0.1 0.07 0.2 0.2 0.2 0.2 -

MCC VIVAPUR®

0.05 0.05 0.1 0.01 0.1 0.6 0.2 -

Mg Stearate - - - - - 1.9 - -

Anhydrous lactose

- - - - - - - -

Talc 1 0.001 0.2 0.1 3 31 4.5 -

BHA 3 1 2 10 10 10 10 -

TiO2 1 0.1 10 0.1 0.1 5 10 -








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HPC KLUCEL®

0.5 0.5 0.5 0.5 2.5 2.5 2.5 -

HPMC VIVAPHARM®

0.5 0.05 0.3 0.02 0.1 2 0.1 -

* The units of the numeric values are ppm (= µg/g = mg/kg). The line of manufacturing

process takes into account the contribution of all the general (not product specific)

sources of potential elemental impurities (including the potential introduction from the

materials of the manufacturing equipment and steps involved, from the container

closure system and from the common services, when applicable).

There are 4 options to compare the levels of elemental impurities with the PDE values.

A brief explanation of these options is given below, for more information please refer to

the ICH Q3D guideline.

Option 1: Considers that all the components could be mixed in any proportion and that

the daily dose is 10 g/day. The concentration limit (CL) (ppm) is calculated as PDE/10.

Option 2a: Considers that all the components could be mixed in any proportion, but the

daily dose is adjusted to the real exposure (as maximum daily dose) to the drug

product. The concentration limit (CL) (ppm) is calculated as PDE/DDmax (in grams).

Option 2b: Takes into account the quantitative composition of the drug product and the

adjusted daily dose for each component (based on the DDmax of the product).

Option 3: It does not require calculations, since it is based on the analysis of elemental

impurities directly on the finished product.

The evaluation by options 1 and 2a is given below:

Table 9. Evaluation of the elemental impurities in simvastatin tablets by options 1 and 2a.


Man. Proc. - - - - - - - -

Simvastatin 20 20 20 20 20 20 20 975

Preg. Starch 0.05 0.1 0.07 0.2 0.2 0.2 0.2 -








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MCC VIVAPUR®

0.05 0.05 0.1 0.01 0.1 0.6 0.2 -

Mg Stearate - - - - - 1.9 - -

Anhydrous lactose

- - - - - - - -

Talc 1 0.001 0.2 0.1 3 31 4.5 -

BHA 3 1 2 10 10 10 10 -

TiO2 1 0.1 10 0.1 0.1 5 10 -

HPC KLUCEL®

0.5 0.5 0.5 0.5 2.5 2.5 2.5 -

HPMC VIVAPHARM®

0.5 0.05 0.3 0.02 0.1 2 0.1 -

PDE (oral) 15 30 5 5 50 200 100 550

Concentration Limit (opt. 1)

1.5 3.0 0.5 0.5 5 20 10 55

Acceptance* NO NO NO NO NO NO NO NO

Concentration Limit (opt.2a)

24.101 48.202 8.033 8.033 80.336 321.34 160.67 883.70

Acceptance** YES YES NO NO YES YES YES NO

The Concentration Limit for Option 2a is calculated dividing the PDE by the maximum

daily dose (in grams): CL (2a) = PDE/0.62238 g

* Acceptance criteria: None of the individual limits of each component is equal or higher

than the concentration limit (CL).

** Acceptance criteria: None of the individual limits of each component is equal or

higher than the concentration limit (CL). Since the option 2a provides a higher margin,

it is possible to accept elements that were not accepted in option 1.

Note that all units are ppm (= µg/g = mg/kg).

If all the potential elemental impurities have been accepted, the evaluation step would








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be finished. If not, option 2b should be considered. In option 2b it would not be

necessary to include the already accepted elemental impurities by options 1 and 2a,

since they will also be accepted by option 2b.

Option 2b combines the quali-quantitative composition of the drug product with the

maximum daily intake in a product-specific assessment. With this option it would be

possible to obtain acceptable limits in drug products containing one (or more) highly

potentially contaminant sources that is (are) present in a very small quantitative

amount.

The evaluation by option 2b requires the derivation of the maximum daily dose for each

elemental impurity and each excipient. This is done by multiplying the

predicted/potential level of a certain element by the excipient daily dose (DDmax ·

weight of the excipient).

DDmax = 1 tablet/day

Weight of the excipient = Please see Table 3

Max. Excipient daily dose = Weight (g) x DDmax (day-1)

For each element, the predicted value (in ppm, equivalent to µg/g) is multiplied by each

maximum excipient daily dose (in g/day). The total level of an elemental impurity is the

summation of all the values for that element.

The results from the calculations with the option 2b are given in the table below:

Table 10. Evaluation of the elemental impurities in simvastatin tablets by option 2b.


Man. Proc. - - - - - 0 - -

Simvastatin 1.2 1.2 1.2 1.2 1.2 1.2 1.2 58.5

Preg. Starch 0.003 0.006 0.0042 0.012 0.012 0.012 0.012 -

MCC VIVAPUR®

0.0015 0.0015 0.003 0.0003 0.003 0.018 0.006 -

Mg Stearate - - - - - 0.057 - -








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Anhydrous lactose

- - - - - - - -

Talc 0.0078 7.8·10-6

0.00156 0.00078 0.0234 0.2418 0.0351 -

BHA 0.00036 0.00012 0.00024 0.0012 0.0012 0.0012 0.0012 -

TiO2 0.0045 0.00045 0.045 0.00045 0.00045 0.0225 0.045 -

HPC KLUCEL®

0.0024 0.0024 0.0024 0.0024 0.012 0.012 0.012 -

HPMC VIVAPHARM®

0.002 0.0002 0.0015 0.0001 0.0004 0.01 0.0005 -


1.22 1.21 1.26 1.22 1.26 1.52 1.31 58.5

PDE (oral) 15 30 5 5 50 200 100 550


*** Acceptance criteria: the total level of impurities does not exceed the PDE.

If one or more elemental impurities could not be accepted by options 1, 2a and 2b, then

option 3 (finished product analysis) should be performed.








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7. CONTROL STRATEGY BASED ON THE ASSESSMENT

In this step, a control strategy is defined to limit the elemental impurities in the finished

drug product. The control strategy is based on the outcome of the evaluation in the risk

assessment, and it is divided into three levels of action:

a) When evaluated levels are < 30% of PDE: This value is defined as the “control

threshold”. If appropriate predicted levels are below 30% of the PDE value, no control

is required.

b) When 30% PDE < evaluated levels < 100% PDE: Herein the evaluated levels are

above the control threshold, and therefore specific actions are required to guarantee

that levels will not be above the PDE (e.g. specification in the finished product).

c) When evaluated levels > 100% PDE: Control strategy may require changes in the

process and/or suppliers. Evaluated levels above the PDE would be accepted with a

rational, risk-based toxicological assessment.

The following table summarizes the risk assessment process (results evaluated by

option 2b), the comparison with the control threshold levels for each elemental impurity

and the control strategy (if required) proposed to minimize the risk.

Table 11. Summary of the outcome of the risk assessment: comparison between total

levels (option 2b) and the control threshold.


Man. Proc. - - - - - 0 - -

Simvastatin 1.2 1.2 1.2 1.2 1.2 1.2 1.2 58.5

Preg. Starch 0.003 0.006 0.0042 0.012 0.012 0.012 0.012 -

MCC VIVAPUR®

0.0015 0.0015 0.003 0.0003 0.003 0.018 0.006 -

Mg Stearate - - - - - 0.057 - -

Anhydrous lactose

- - - - - - - -

Talc 0.0078 7.8·10-6

0.00156 0.00078 0.0234 0.2418 0.0351 -








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BHA 0.00036 0.00012 0.00024 0.0012 0.0012 0.0012 0.0012 -

TiO2 0.0045 0.00045 0.045 0.00045 0.00045 0.0225 0.045 -

HPC KLUCEL®

0.0024 0.0024 0.0024 0.0024 0.012 0.012 0.012 -

HPMC VIVAPHARM®

0.002 0.0002 0.0015 0.0001 0.0004 0.01 0.0005 -


1.22 1.21 1.26 1.22 1.26 1.52 1.31 58.5

PDE (oral) (µg/day)

15 30 5 5 50 200 100 550


CT (30% of PDE)

4.5 9 1.5 1.5 15 30 60 165

Value < CT? YES YES YES YES YES YES YES YES

Outcome No control

No control

No control

No control

No control

No control

No control

No control

This table is representative of the risk assessment for potential elemental impurities in

simvastatin tablets.

The outcome of the risk assessment is that no further controls are required, since the

actual controls included in the raw materials and manufacturing process are sufficient

to guarantee that the levels of elemental impurities are consistently below their PDE

values.








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8. CONCLUSIONS OF THE ASSESSMENT

This section includes a brief comment from the reviewer in relation with the risk

assessment.

The risk assessment of potential elemental impurities in simvastatin film coated tablets

was performed following the ICH Q3D component-approach. The identified sources of

elemental impurities were the following: water, manufacturing equipment, container

closure system, drug substance and excipients. The risk associated to non-intentionally

added sources (water, manufacturing equipment and container closure system) was

considered negligible according to the ICH Q3D. In relation to the components, the

available information of the drug substance and the excipients permitted to accept the

predicted levels by the evaluation with option 2b. When analytical information was not

available, a large safety margin was applied according to the worst-case scenario

approach. The outcome of the assessment showed that the predicted levels of all the

elemental impurities under assessment are below their control threshold (30% of PDE):

consequently, the actual controls are sufficient to consistently control the elemental

impurities in the final drug product within acceptable limits and therefore no further

controls or actions are required.

Despite this, it is noted that the total predicted levels of Pb and Cd are relatively close

to the control threshold for these elements. This is due to the high values taken as

predicted levels in the API. In fact, the drug substance presents the major contribution

to the total level (1.2 µg for both Pb and Cd out of 1.26 and 1.22 µg, respectively) (see

section 7). As detailed in section 5 (drug substance), the worst-case scenario was

based on the lack of specific analytical data and the maximum heavy metals limit by

specification (general test) was taken as the maximum potential value for each

elemental impurity under assessment. This worst-case provides a very large safety

margin, considering that the actual levels would be much lower than the predicted

levels (as demonstrated in the API supplied by the other manufacturer as well as other

components).

As overall conclusion, the drug products covered by this review comply with the

requirements established in the ICH Q3D guideline because the levels of elemental

impurities are below their PDE: the levels are controlled within acceptable limits and

there is no risk (associated to elemental impurities) for the patients that take these drug

products according to their recommended posology and method of administration.








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9. REFERENCES

1. Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Ficha

técnica (equivalent to summary of Product Characteristics): Simvastatin (10, 20,

and 40 mg, film coated tablets). Aristo Pharma Iberia SL. Authorization

numbers 64240, 64241 and 64242. Revised on April 2015 (in Spanish).

2. Atlas Specialty Metals. Stainless Steel – Grade 316L – Properties, Fabrication

and Applications (UNS S31603). Feb 18 2004.

3. European Medicines Agency (EMA) (2015). Committee for Human Medicinal

Products. ICH guideline Q3D on elemental impurities.

EMA/CHMP/ICH/353369/2013. 25 August 2015.

4. Food and Drug Administration (FDA). Center for Drug Evaluation and Research

(CDER). Guidance for Industry: Container Closure Systems for Packaging

Human Drugs and Biologics. U.S. Department of Health and Human Services.

May 1999.

5. Handbook of Pharmaceutical Excipients (2009). Rowe RC, Sheskey PJ, Quinn

ME. Sixth edition. Pharmaceutical Press, London (UK). ISBN 978 0 85369 792

3.

6. ICH Q3D (R4) “Guideline for Elemental Impurities”. 16 December 2014.

7. Internal information of Atreiza available if necessary: statements and data

received from suppliers of excipients and APIs, certificates of analyses,

qualification and information of the services, certification of consumable

materials, manufacturing instructions, packaging instructions, equipment books

of instructions and specifications, etc.

8. Jenke D, Rivera C, Mortensen T, Amin P, Chacko M, Tran T, Chum J. A

compilation of metals and trace elements extracted from materials relevant to

pharmaceutical applications such as packaging systems and devices. J Pharm

Sci Technol 2015; 69: 1-48.

9. Li G, Schoneker D, Ulman K, Sturm J, Thackery L, Kauffman J. Elemental

impurities in Pharmaceutical Excipients. J Pharm Sci. 2015; 104 (12): 4197-

4206.








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10. Sandmeyer Steel Company. Specification Sheet: Alloy 316/316L (UNS S31600

S31603) W. Nr. 1.4401, 1.4404.

11. Santonen T, Stockmann-Juvala H, Zitting A. Review on Toxicity of Stainless

Steel. Finnish Institute of Occupational Health. Helsinki 2010-11-07. ISBN 978-

952-261-039-3.

12. Teasdale A, Chéry CC, Cook G, Glennon J, Lee CW, Harris L, Lewen N, Powell

S, Rockstroh H, Rutter L, Smallshaw L, Thompson S, Woodward V, Ulman K.

Implementation of ICH Q3D Elemental Impurities Guideline: Challenges and

Opportunities. Pharmaceutical Technology Volume 39 Issue 3, March 2015.

Available online at http://www.pharmtech.com/

http://www.pharmtech.com/








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ANNEX I. PDE VALUES

Annex I: Permitted Daily Exposure values for elements as a function of the route of

administration (taken from ICH Q3D guideline)








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ANNEX II. ABBREVIATIONS

DP = Drug Product

DS = Drug substance

API = Active Pharmaceutical Ingredient

PDE = Permitted Daily Exposure

EI = Elemental Impurity

GMP = Good Manufacturing Practice

USP = United States Pharmacopeial Convention

Ph.Eur. = The European Pharmacopoeia

ppm = parts per million (equivalent to mg/g and to µg/mg)

LOD = Limit of Detection

LoQ = Limit of Quantification

Man. Proc. = Manufacturing Process

CCS = Container Closure System

CL = Concentration Limit

DD = Daily Dose

DDmax = Maximum Daily Dose

CT = Control Threshold (30% of PDE)








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