HEBEI HUAYANG BIOLOGICAL TECHNOLOGY CO.

,LTD
NO.645 FUYANG EAST ROAD,JIZHOU DISTRICT,HENGSHUI CITY,HEBEI PROVINCE,CHINA
Phone: +86-318-8638826
Fax: +86-318-8638826

1. STABILITY

1.1 Stability Studies Summary and Conclusions

A formal stability program has been established to determine a retest date from at least these
different batches of the bulk chemical product. The three batches are required to ensure a
statistically acceptable level of confidence during the proposed storage period. The first three
batches of N-Acetyl-L-Cysteine that were produced (2010082101, 2010082801, 2010082901) were
planned on the formal stability program at accelerated and at ambient conditions.

The conditions and the test periods of this two stability program are as follows.

Accelerated stability conditions:

Temperature: 40℃± 2℃
Related Humidity: 75% ± 5%

Long term stability conditions:

Temperature: 25℃± 2℃
Related Humidity: 60% ± 5%

Retest date:
At present time and based on available stability data, the factory has established a 3 years retest
date for N-Acetyl-L-Cysteine manufactured and stored in accordance with the methods described.
HEBEI HUAYANG BIOLOGICAL TECHNOLOGY CO.,LTD
NO.645 FUYANG EAST ROAD,JIZHOU DISTRICT,HENGSHUI CITY,HEBEI PROVINCE,CHINA
Phone: +86-318-8638826
Fax: +86-318-8638826

2 Post Approval Stability Protested and Stability Commitment

2.1 Stability Protocol

2.1.1Stability Batches

These batches of N-Acetyl-L-Cysteine manufactured by Hebei Huayang Biological Technology

CO.,LTD. at 3000kg scale, which were of the normal production batch size, are being evaluated
for stability. The batches were manufactured using the process for the marked product described in
Section 3.2 S 2.2. Description of Manufacturing Process, and packed in the LDPE( low-density
polyethylene) bags for marked product described in Section 3.2S 6.6 Container Closure.
Information concerning the batches in presented in Table 1, which includes the batch numbers,
batch sizes, date of manufacture, storage conditions, and month of data presented in this report.

Table 1 Stability Study Batches

Batch Batch Manufacturing Start Date of Storage Condition Months

number size (kg) date Stability Studies of Data
2010082701 1000kg Aug. 27st, 2010 Sep. 1st, 2010 25℃± 2℃ /60% ± 5% 36
40℃± 2℃ /75% ± 5% 6
2010082802 1000kg Aug.28nd, 2010 Sep. 1st, 2010 25℃± 2℃ /60% ± 5% 36
40℃± 2℃ /75% ± 5% 6
2010082903 1000kg Aug. 29rd, 2010 Sep. 1st, 2010 25℃± 2℃ /60% ± 5% 36
40℃± 2℃ /75% ± 5% 6

2.12 Stability Testing Frequency, Storage Conditions and Specifications

The stability batches are being evaluated at the general-case conditions prescribed in the ICH
Guidelines：QIAR Stability Testing of New Drug Substance and Products. The testing frequency
and storage conditions are presented in Table 2. Samples are evaluated at each time-point
according to the stability specifications provided in Table 3.

Table 2 Stability Testing Frequency and Storage Conditions

Storage Condition Time-Point (months)

0 1 2 3 4 5 6 9 12 18 24 36
25℃± 2℃ /60% ± 5% X … … X … … X X X X X X
40℃± 2℃ /75% ± 5% X X X X X X X … … … … …
HEBEI HUAYANG BIOLOGICAL TECHNOLOGY CO.,LTD
NO.645 FUYANG EAST ROAD,JIZHOU DISTRICT,HENGSHUI CITY,HEBEI PROVINCE,CHINA
Phone: +86-318-8638826
Fax: +86-318-8638826

X =Specific rotation[a]D20°
State of solution
Chloride(Cl)
Ammonium(NH4)
Sulfate(SO4)
Iron(Fe)
Arsenic(As2O3)
Heavy metals(Pb)
Loss on drying
Other amino acids
Residue on ignition
Assay
PH
…= Not tested

Table 3 Specifications for Glycine

Test Method Acceptance criterion
Specific rotation[a]D20° AJI92 +21.3°～+27.0°
State of solution AJI92 ≥98.0%
Chloride(Cl) AJI92 ≤0.04%
Ammonium(NH4) AJI92 ≤0.02%
Sulfate(SO4) AJI92 ≤0.030%
Iron(Fe) AJI92 ≤10PPm
Arsenic(As2O3) AJI92 ≤1PPm
Heavy metals(Pb) AJI92 ≤10PPm
Loss on drying AJI92 ≤0.5%
Other amino acids AJI92 Chromatographically Not
detectable
Residue on ignition AJI92 ≤0.20%
Assay AJI92 98.5～101.0%
PH AJI92 2.0～2.8
HEBEI HUAYANG BIOLOGICAL TECHNOLOGY CO.,LTD
NO.645 FUYANG EAST ROAD,JIZHOU DISTRICT,HENGSHUI CITY,HEBEI PROVINCE,CHINA
Phone: +86-318-8638826
Fax: +86-318-8638826

2. Stability Date
3.2 Accelerated Stability Study
Product: N-Acetyl-L-Cysteine Storage Condition: 40℃± 2℃ /75% ± 5%
Batch No. 2010082701 Length of Study: 6 months
Manufacturing Date: Aug. 27th, 2010 Container: Simulated Marked Container

Table 4
Test Acceptance criterion Months
Initial 1 2 3 4 5 6
Specific rotation[a]D20° +21.3°～+27.0° +21.7° +21.7° +21.7° +21.7° +21.7° +21.7° +21.7°
State of solution ≥98.0% 98.5% 98.5% 98.5% 98.5% 98.5% 98.5% 98.5%
Chloride(Cl) ≤0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04%
Ammonium(NH4) ≤0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02%
Sulfate(SO4) ≤0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030%
Iron(Fe) ≤10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm
Arsenic(As2O3) ≤1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm
Heavy metals(Pb) ≤10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm
Loss on drying ≤0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5%
Chromatographically Not
Other amino acids Qualified Qualified Qualified Qualified Qualified Qualified Qualified
detectable
Residue on ignition ≤0.20% 0.16% 0.16% 0.16% 0.16% 0.16% 0.16% 0.17%
Assay 98.5～101.0% 99.2% 99.2% 99.2% 99.2% 99.2% 99.2% 99.2%
PH 2.0～2.8 2.4 2.4 2.4 2.4 2.4 2.4 2.3
HEBEI HUAYANG BIOLOGICAL TECHNOLOGY CO.,LTD
NO.645 FUYANG EAST ROAD,JIZHOU DISTRICT,HENGSHUI CITY,HEBEI PROVINCE,CHINA
Phone: +86-318-8638826
Fax: +86-318-8638826

Product: N-Acetyl-L-Cysteine Storage Condition: 40℃± 2℃ /75% ± 5%

Batch No. 2010082801 Length of Study: 6 months
Manufacturing Date: Aug. 28th, 2010 Container: Simulated Marked Container

Table 5
Test Acceptance criterion Months
Initial 1 2 3 4 5 6
Specific rotation[a]D20° +21.3°～+27.0° +21.9° +21.9° +21.9° +21.9° +21.9° +21.9° +21.9°
State of solution ≥98.0% 98.6% 98.6% 98.6% 98.6% 98.6% 98.6% 98.6%
Chloride(Cl) ≤0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04%
Ammonium(NH4) ≤0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02%
Sulfate(SO4) ≤0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030%
Iron(Fe) ≤10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm
Arsenic(As2O3) ≤1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm
Heavy metals(Pb) ≤10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm
Loss on drying ≤0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5%
Chromatographically Not
Other amino acids Qualified Qualified Qualified Qualified Qualified Qualified Qualified
detectable
Residue on ignition ≤0.20% 0.16% 0.16% 0.16% 0.16% 0.16% 0.16% 0.17%
Assay 98.5～101.0% 99.4% 99.4% 99.4% 99.4% 99.4% 99.4% 99.4%
PH 2.0～2.8 2.4 2.4 2.4 2.4 2.4 2.4 2.3
HEBEI HUAYANG BIOLOGICAL TECHNOLOGY CO.,LTD
NO.645 FUYANG EAST ROAD,JIZHOU DISTRICT,HENGSHUI CITY,HEBEI PROVINCE,CHINA
Phone: +86-318-8638826
Fax: +86-318-8638826

Product:N-Acetyl-L-Cysteine Storage Condition: 40℃± 2℃ /75% ± 5%

Batch No. 2010082901 Length of Study: 6 months
Manufacturing Date: Aug. 29th, 2010 Container: Simulated Marked Container

Table 6
Test Acceptance criterion Months
Initial 1 2 3 4 5 6
Specific rotation[a]D20° +21.3°～+27.0° +21.8° +21.8° +21.8° +21.8° +21.8° +21.8° +21.8°
State of solution ≥98.0% 98.6% 98.6% 98.6% 98.6% 98.6% 98.6% 98.6%
Chloride(Cl) ≤0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04%
Ammonium(NH4) ≤0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02%
Sulfate(SO4) ≤0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030%
Iron(Fe) ≤10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm
Arsenic(As2O3) ≤1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm
Heavy metals(Pb) ≤10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm
Loss on drying ≤0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5%
Chromatographically Not
Other amino acids Qualified Qualified Qualified Qualified Qualified Qualified Qualified
detectable
Residue on ignition ≤0.20% 0.14% 0.14% 0.14% 0.14% 0.14% 0.14% 0.16%
Assay 98.5～101.0% 99.2% 99.2% 99.2% 99.2% 99.2% 99.2% 99.3%
PH 2.0～2.8 2.4 2.4 2.4 2.4 2.4 2.4 2.3
HEBEI HUAYANG BIOLOGICAL TECHNOLOGY CO.,LTD
NO.645 FUYANG EAST ROAD,JIZHOU DISTRICT,HENGSHUI CITY,HEBEI PROVINCE,CHINA
Phone: +86-318-8638826
Fax: +86-318-8638826

3.3 Long Term Stability Study

Product: N-Acetyl-L-Cysteine Storage Condition: 25℃± 2℃ /60% ± 5%
Batch No. 2010082701 Length of Study: 36 months
Manufacturing Date: Aug. 27th, 2010 Container: Simulated Marked Container

Test Acceptance criterion Months

Initial 3 6 9 12 18 24 36
Specific rotation[a]D20° +21.3°～+27.0° +21.7° +21.7° +21.7° +21.7° +21.7° +21.7° +21.7° 21.7
State of solution ≥98.0% 98.5% 98.5% 98.5% 98.5% 98.5% 98.5% 98.5% 98.5%
Chloride(Cl) ≤0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04%
Ammonium(NH4) ≤0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02%
Sulfate(SO4) ≤0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030%
Iron(Fe) ≤10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm
Arsenic(As2O3) ≤1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm
Heavy metals(Pb) ≤10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm
Loss on drying ≤0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5%
Chromatographically Not
Other amino acids Qualified Qualified Qualified Qualified Qualified Qualified Qualified Qualified
detectable
Residue on ignition ≤0.20% 0.16% 0.16% 0.17% 0.17% 0.16% 0.17% 0.17% 0.17%
Assay 98.5～101.0% 99.2% 99.2% 99.2% 99.2% 99.2% 99.2% 99.2% 99.2%
PH 2.0～2.8 2.4 2.4 2.3 2.4 2.4 2.4 2.4 2.4
HEBEI HUAYANG BIOLOGICAL TECHNOLOGY CO.,LTD
NO.645 FUYANG EAST ROAD,JIZHOU DISTRICT,HENGSHUI CITY,HEBEI PROVINCE,CHINA
Phone: +86-318-8638826
Fax: +86-318-8638826

Table 7
Product: N-Acetyl-L-Cysteine Storage Condition: 25℃± 2℃ /60% ± 5%
Batch No. 2010082801 Length of Study: 36 months
Manufacturing Date: Aug. 28th,2010 Container: Simulated Marked Container

Table 8
Test Acceptance criterion Months
Initial 3 6 9 12 18 24 36
Specific rotation[a]D20° +21.3°～+27.0° +21.9° +21.9° +21.9° +21.9° +21.9° +21.9° +21.9° 21.9°
State of solution ≥98.0% 98.6% 98.6% 98.6% 98.6% 98.6% 98.6% 98.6% 98.6%
Chloride(Cl) ≤0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04%
Ammonium(NH4) ≤0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02%
Sulfate(SO4) ≤0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030%
Iron(Fe) ≤10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm
Arsenic(As2O3) ≤1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm
Heavy metals(Pb) ≤10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm
Loss on drying ≤0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5%
Chromatographically Not
Other amino acids Qualified Qualified Qualified Qualified Qualified Qualified Qualified Qualified
detectable
Residue on ignition ≤0.20% 0.16% 0.16% 0.17% 0.17% 0.17% 0.17% 0.17% 0.17%
Assay 98.5～101.0% 99.4% 99.4% 99.4% 99.4% 99.4% 99.4% 99.4% 99.4%
PH 2.0～2.8 2.4 2.4 2.3 2.3 2.3 2.3 2.3 2.3
HEBEI HUAYANG BIOLOGICAL TECHNOLOGY CO.,LTD
NO.645 FUYANG EAST ROAD,JIZHOU DISTRICT,HENGSHUI CITY,HEBEI PROVINCE,CHINA
Phone: +86-318-8638826
Fax: +86-318-8638826

Product: N-Acetyl-L-Cysteine Storage Condition: 25℃± 2℃ /60% ± 5%

Batch No. 2010082901 Length of Study: 36 months
Manufacturing Date: Aug. 9th,2010 Container: Simulated Marked Container

Table 9
Test Acceptance criterion Months
Initial 3 6 9 12 18 24 36
Specific rotation[a]D20° +21.3°～+27.0° +21.8° +21.8° +21.8° +21.8° +21.8° +21.8° +21.8° +21.8°
State of solution ≥98.0% 98.6% 98.6% 98.6% 98.6% 98.6% 98.6% 98.6% 98.6%
Chloride(Cl) ≤0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04% <0.04%
Ammonium(NH4) ≤0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02% <0.02%
Sulfate(SO4) ≤0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030% <0.030%
Iron(Fe) ≤10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm
Arsenic(As2O3) ≤1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm <1PPm
Heavy metals(Pb) ≤10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm <10PPm
Loss on drying ≤0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5% <0.5%
Chromatographically Not
Other amino acids Qualified Qualified Qualified Qualified Qualified Qualified Qualified Qualified
detectable
Residue on ignition ≤0.20% 0.14% 0.14% 0.16% 0.16% 0.16% 0.16% 0.16% 0.16%
Assay 98.5～101.0% 99.2% 99.2% 99.3% 99.3% 99.3% 99.3% 99.3% 99.3%
PH 2.0～2.8 2.4 2.4 2.3 2.3 2.3 2.3 2.3 2.3
HEBEI HUAYANG BIOLOGICAL TECHNOLOGY CO.,LTD
NO.645 FUYANG EAST ROAD,JIZHOU DISTRICT,HENGSHUI CITY,HEBEI PROVINCE,CHINA
Phone: +86-318-8638826
Fax: +86-318-8638826

Examination conclusion:
1 Within 6 months Accelerate testing, the sample is relatively stable.

2 Within 36 months long-term testing, the sample is relatively stable.

The effect factor testing, Accelerated stability testing and Long term stability testing for N-Acetyl-L-Cysteine will last as per updated standard, such as AJI. We,
HEBEI HUAYANG BIOLOGICAL TECHNOLOGY CO.,LTD commit that we will continue to carry out on the test according to requirements described above.

HEBEI HUAYANG BIOLOGICAL TECHNOLOGY CO.,LTD.