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Instruction for Inspection for Particulate Matter in Injectable Drugs RD-42-501-98 from 07.07.1998

Instruction for Inspection for Particulate Matter in Injectable Drugs RD-42-501-98 from 07.07.1998

RD 42-501-98

MINISTRY OF HEALTHCARE

OF THE RUSSIAN FEDERATION

 

RULING DOCUMENT (RD)

 

INSTRUCTIONS

for Inspection for Particulate Matter

in Injectable Drugs

 

 

Official Edition

 

Moscow, 1998

 

RD 42-501-98

 

INTRODUCTION

 

  1. PREPARED BY:

State Scientific-Research Institute for Standardization and Control of Medicinal Drugs. Director, Doctor of Pharmaceutics, N.S. Evtushenko

State Scientific Antibiotics Center. Director, Russian Academy of Medical Sciences (RAMS) Academician, S.M. Navashin

AUTHORS:

T.N. Bokovikova, D.Pharm.; L.K. Grakovskaya, D.Pharm., Prof.; S.V. Shilova, Cand. Sc. (Biology); I.A. Pavlova

 

SUBMITTED BY: State Drug and Medical Equipment Control Administration

 

  1. APPROVED: Deputy Minister of healthcare of the Russian Federation 07.07.98.
  2. FINALIZED by the Pharmacopeia State Committee
  3. PUT INTO EFFECT by a letter of State Drug and Medical Equipment Control Administration, dated _______, No._____
  4. REPLACES I 42-3-85 and RDI 42-1-89

 

It is prohibited to disclose, copy or distribute this standard either partially or in full as an official edition without prior permission of the Russian Ministry of Health.

 

 

MINISTRY OF HEALTHCARE OF THE RUSSIAN FEDERATION

RULING DOCUMENT

 

Approved

Deputy of the Minister

of Healthcare of the Russian

Federation

(signed)

V.I. Starodubov

July 07, 1998

 

 

INSTRUCTIONS

for Inspection for Particulate Matter

in Injectable Drugs

RD-42-501-98

 

Replaces I 42-3-85 and RDI 42-1-89

  1. General Provisions

    • These Instructions establish the procedure of inspection for particulate matter for all injectable drugs, including infusion and injection solutions, blood preparations, blood substitutes, preserved blood and dry formulations used in the form of solutions. Injectable medicinal drugs in ampoules, vials, bottles, syringes and other glass or clear polymer containers are subject to inspection.
    • These Instructions are obligatory for all enterprises and companies manufacturing and controlling the above-stated products, irrespective of their departmental affiliation or property category.
    • Particulate matter shall mean foreign insoluble particles (with the exception of gas bubbles) that may accidentally be present in drugs.
    • Sample shall mean the number of ampoules, vials, bottles and other containers that need to be taken for inspection from each batch of finished products.
    • Inspection for particulate matter takes into account the volume of injectable drug. Small volume drugs ≤100 ml, large volume drugs >100 ml whether they are formulated as solutions or obtained by dilution of dry medicinal drugs.
    • Inspection for particulate matter must be performed at conditions excluding the risk of contamination of inspected samples with foreign particles.
    • Inspection and counting of the number of particles may be performed using three methods:
  2. Visual inspection
  3. Counting-Photometric
  4. Microscopic

 

  1. Visual Inspection

    Inspection Conditions

Table 1

Light Power at Visual Inspection

Color of Solutions Light Power
incandescent electric lamp, W fluorescent lamp, W
Colorless 60 20
Colored 100 30

Notes.

  1. The “Colored” group includes colorless solutions in dimming glass vials and stained solutions in colorless glass vials, as well as solutions in limpid polymer containers.
  2. For inspection using KVLC-10 assembly it is allowed to use a 40W incandescent lamp.

 

Sampling

The number of samples taken from each batch of injectable drug depends on the physical state (solution or dry matter), volume (small or big), batch size, as well as method of inspection (destructive or non-destructive inspection).

2.2.1. For visual inspection of injectable drugs that do not require opening and dilution (non-destructive inspection), and for dry injectable formulations (destructive inspection) perform product sampling and assessment of inspection results using enhanced two-stage control according to GOST 18242-72 (reprint edition of 1983).

2.2.2. Small Volume Solutions (Non-Destructive Inspection)

2.2.2.1. From each batch take random samples in two stages: stage 1 and stage 2, according to Table 2.

Table 2

Sample Size for Visual Inspection of Small Volume Solutions and Assessment Parameters

Batch Size, units Visual Inspection Stage Sample Size for Visual Inspection, Units Number of Containers with Small Volume Solutions with Particulate Matter
Acceptance Number Rejection Number
1 2 3 4 5
1,201-3,200 First

Total (two stages)

80

160

2

6

5

7

3,201-10,000 -‘’- 200

400

6

15

10

16

>10,000 -‘’- 315

630

9

23

14

24

2.2.3. Large Volume Solutions (Non-Destructive Inspection).

2.2.3.1. From each batch take random samples in two stages: stage 1 and stage 2, according to Table 3.

2.2.3.2. At hemotransfusion stations for the purpose of inspection of injectable products the Quality Control (QC) department performs sampling of 10% of containers of a batch, at least 10 bottles. If at least one bottle with particulate matter is found, return the whole batch for repeated original inspection.

Table 3

Sample Size for Visual Inspection of Large Volume Solutions and Assessment Parameters

Batch Size, units Visual Inspection Stage Sample Size for Visual Inspection, Units Number of Containers with Small Volume Solutions with Particulate Matter
Acceptance Number Rejection Number
1 2 3 4 5
151-280 First

Total (two stages)

20

40

0

1

2

2

281-500 -‘’- 32

64

0

1

2

2

501-1,200 -‘’- 50

100

0

2

2

3

1,201-3,200 -‘’- 80

160

0

3

3

4

>3,200 -‘’- 125

250

1

5

4

6

Table 4

Sample Size for Visual Inspection of Dry Formulations and Assessment Parameters

Group of Products Number of Vials (ampoules) in a Batch
≥ 35,000 ≥ 70,000 ≥ 105,000*
Number of Sample Groups Number of Samples Number of Sample Groups Number of Samples Number of Sample Groups Number of Samples
1 2 3 4 5 6 7
1. Products for intravenous injections, with an indication “for injections” on the label:

– ≤1g

– >1 g (≤5g)

 

 

 

 

1

1

 

 

 

 

8

5

 

 

 

 

2

2

 

 

 

 

16

10

 

 

 

 

3

3

 

 

 

 

24

15

2. Products for intravenous injections, with an indication “for injections” on the label:

– ≤1g

– >1 g (≤5g)

 

 

 

 

1

1

 

 

 

 

5

3

 

 

 

 

2

2

 

 

 

 

10

6

 

 

 

 

3

3

 

 

 

 

15

9

*One group of samples is taken from every further 35,000 vials (ampoules)

Notes

  1. For products at a dosage of > 5 g the number of sampling groups, the number of samples in the sampling group and the acceptable level of particulate matter are specified in pharmacopoeia monographs.
  2. For inspection at the State Scientific-Research Institute for Standardization and Control of Medicinal Drugs, at analytical laboratories, Centers of Drug Quality Control and at pharmaceutical warehouses of the Ministry of healthcare of the Russian Federation and other institutions, duplicated number of samples from one sampling group regardless of the group the product belongs to (see Table 4). If required, State Scientific-Research Institute for Standardization and Control of Medicinal Drugs may request additional samples on top of the duplicated number stated above.
    • Arbitrary Inspection

Product samples at an amount equal to the total sample size (for both inspection stages) and the corresponding analysis protocol are submitted for arbitrary inspection. If required, the state controlling entity may request additional number of samples.

Sample Preparation

2.3.1. Before performing a visual inspection of injectable drugs of large and small volume, that do not require opening or dilution, ensure that the surface of ampoules, vials, bottles, syringes or other clear polymer containers is clean and dry.

2.3.2. While performing a visual inspection of dry injectable formulations, the selected samples must be washed with particulate matter free purified water 3 times before opening. All labels and aluminum caps must be removed from the vials prior to washing. Dry the washed samples under a laminar sterile air flow.

2.3.3. For dilution of the product use purified water or another solvent specified in a pharmacopoeial monograph or in the drug prescribing information. The water or solvent must be preliminary filtered through a ≤1.2 mm membrane filter.

2.3.4. Visual inspection of the solvent is performed according to the following method: take 10 thoroughly washed 10 ml vials and using a washed injection syringe or filtering device like “Pistol” (Pistolet) inject about 5 ml of the solvent into each vial. Close the vials with rubber stoppers free of particulate matter and inspect the samples as specified in section 2.4.3. The solvent conforms if 9 of 10 vials do not contain visible particles.

2.3.5. Open the ampoules in the following way: Make an incision on the ampoule neck surface using a tungsten-carbide cobalt knife, then touch the rim of the incision with a red-hot molybdenum or wolframium wire. Cool and carefully remove the tip. Any other method of opening is possible, if it prevents penetration of particles of glass into the ampoule contents.

2.3.6. Injection of solvent into vials (ampoules) is performed through the neck using a filtering device like “Pistol” or a preliminary washed syringe. It is possible to inject the solvent through the stopper using a N 0840 needle syringe, preliminary washed from the outside and from the inside with particle-free purified water.

2.3.7. Inject the solvent at an amount sufficient for complete dilution of the drug (about half of vial or ampoule volume) or at a volume specified in the corresponding Ph Monograph or in the product prescribing information. Then close the vials with stoppers again. The product must be completely dissolved at shaking.

Notes.

  1. Dissolve easily hydrolyzed immediately before inspection.
  2. For high-molecular compounds (proteins, polysaccharides, glycoproteins etc.) the corresponding Ph Monograph or drug prescribing information must contain the information about solvents, pH, time and conditions of dilution and other factors that may influence the dilution process.

Analysis and Results

Table 5

Sample Size, Duration and the Rate of Inspection

Number of Containers Taken for Inspection Duration of Inspection of Simultaneously Taken Containers Rate of Inspection, pcs./hour
Ampoules Vials, Bottles Syringes Ampoules Vials, Bottles Syringes Ampoules Vials, Bottles Syringes
Volume, ml N, max. Volume, ml N Volume, ml N
1 2 3 4 5 6 7 8 9 10 11 12
SMALL VOLUME
1.0 15 5.0 5-6 1.0 7-8 15 8-10 15 <2,000 <1,700 < 870
2.0 – 3.0 13 30.0 – 50.0 2 15 <1,750 <600
5.0 10 50.0 – 100.0 2 15 <1,600 <400
10.0 9 15 <1,400 <300
20.0 – 30.0 8 15 <1,250
LARGE VOLUME
>100.0 1-2 <20 <300

Notes.

  1. The number of ampoules, simultaneously taken for inspection, must not exceed the number specified in the table, but usually it must be at least 50%.
  2. In case it is required (for example, for the purpose of training), the number of simultaneously taken ampoules, vials, bottles, syringes is decreased by 2-3-fold.
  3. The time of control is determined by the period, when inspectors only view injectable drugs in containers (illegible)К.И.1 The inspector takes the containers, carries them to the inspection area and places into the tare. The duration of inspection must be at 40 – 60% of the total time of viewing, including secondary operations. With automatic feeding of containers to the inspection area, the duration of inspection must be at 70% of the total time. The duration of inspection of injectable formulations in dark glass and clear polymer containers, of colored solutions and non-aqueous solutions is increased by 20%, while the rate of inspection is decreased correspondingly.
  4. The “Rate of Inspection” column includes containers with clear injectable drugs and with those containing particles, including the time needed for secondary operations. The rate of inspection in case of automated feeding of injectable products to the inspection area is increased by 20 – 50%.

 

2.4.7. The whole batch is rejected if the number of units of products with mechanic particles exceeds or equals to the number specified in Column 5 for the total volume of the first and second samplings.

2.4.8. In case of rejected products:

– QC department returns the products to the workshop (to the site);

– State regulatory authorities, pharmaceutical laboratories, analytical laboratories, Centers of drug quality control or laboratories of other institutions, and laboratory of pharmaceutical warehouses draw up a report and simultaneously inform the manufacturer and the State Drug and Medical Equipment s Control Administration under the Ministry of Healthcare of the Russian Federation in the appropriate manner.

2.4.9. The Principle of Inspection On-Site

2.4.9.1. The site performs a triple control of purity of injectable products.

Primary intradepartmental one hundred percent inspection, secondary – intradepartmental and tertiary selective control is performed by the QC inspector.

2.4.9.2. Primary inspection is performed on 100% of ampoules, vials, bottles, syringes and other polymer packages of injectable products that passed sterilization or prepared at aseptic conditions, before labeling and packaging.

Primary and secondary inspection is performed by viewers at the site. Viewers must have their numbers. The viewer’s number is inserted into the packaging and stamped on the cap of the vial.

2.4.9.3. For the purpose of the secondary inspection from each batch that passed the primary control, an average sample of 5% of a 2000 batch of ampoules, vials, bottles, syringes, and 250 pcs. of larger batches is taken. If over 2% of ampoules, vials, bottles (illegible)К.И.3an average sample selected, is returned for repeated primary control.

Note. The requirements of secondary selective control do not apply to the blood service institutions (hemotransfusion stations).

2.4.9.4. The tertiary selective inspection is performed by QC inspectors. For the purpose of control select a mean sample of each batch of the manufactured product before labeling and packaging. The sample size for inspection of solutions for particles and assessment parameters must conform for small sized containers- to the data in Table 2 and for large sized containers – to the data in Table 3.

Note. For certain sites the Administration of the public control of drugs and medical devices of the Ministry of Healthcare of the Russian Federation may establish another procedure of in-house inspection of injectable drugs for particles.

2.4.10. Dry formulations used as solutions

2.4.10.1. For the purpose of the visual inspection view the total samples (depending on the number of vials (ampoules) in the batch according to Table 4) and calculate for each sample the number of particles. If more than 5 particles are found in a single vial (ampoule), no further counting is performed. In that case the result is determined as 7. Count the total number of particles in all samples of the first complete set of samples and divide it by the number of samples.

2.4.10.2. If products for intravenous administration with an indication on the label “for injections” contain:

If products for intramuscular administration contain:

In case the inspection is performed on two samples, the results for the first and for the second samples are added up.

If products for intravenous administration with an indication on the label “for injections” contain:

If products for intramuscular administration contain:

2.4.10.3. If just one particle of glass is found in the total sample, additional samples are taken in the same amount.

The batch is considered accepted, if no particles of glass are found in any of the vials (ampoules) in the additional sample.

  1. Counting-Photometric Method of Inspection

3.1. Inspection Conditions

3.1.1. Perform the analysis using devices based on the light-obscuration and allowing of automatically determining particle size, the number of particles of the corresponding size. For example, light obscuration particle count analyzers FC-151, FC-151.1 or A03-101.

3.1.2. The instrument-aided inspection is performed at conditions described in section 2.1.7.

3.2.1. Small Size Solutions

3.2.1.1. Out of each batch randomly select a sample of 8 vials (ampoules).

3.2.2. Large Size Solutions

3.2.2.1. Out of each batch randomly select the first sample of 3 vials (if the volume of the solution is less than 500 ml) or 2 vials (if the volume of the solution is 500 ml and more).

3.2.3. Dry Formulations Used as Solutions

3.2.3.1. Sampling is performed according to section 2.2.4.1.

3.3. Analysis and Results

3.3.1. The analyzer sensitivity is performed every time it is switched on, when changing one liquid analyzed for another one, and every 4 hours in case of continuous work of the device. Before inspection a blank test is performed to control the purity of air in the working area, of the chemical glassware and solvent used. Using a cylinder measure 50 ml of the solvent (section 2.3.3) and transfer the measured amount into the analyzer glass. Analyze 4 10 ml samples, discard the result for the first sample. The test conditions are considered satisfactory, if every one in three samples contain ≤ 2 particles 25mm in size. Otherwise the purity of air is controlled using an air dust load analyzer A3 and repeat the steps of preparation of glassware and solvent (sections 2.1.7, 2.3.3, 2.3.4) until complying results are obtained.

3.3.2. Small Size Solutions, Including Dry Formulations for Injections Administered in the Volume of ≥100 ml after dilution.

3.3.2.1. Carefully shake samples or aliquots for obtaining the total volume of 50 ml for one sample according to sections 2.3.2, 2.3.3, 2.3.6 and 2.3.7 and transfer into a measuring cylinder, then bring to the volume of 50 ml with solvent (Section 2.3.3). In case of need extract the solutions from the ampoules using a syringe, that had been preliminary prepared (illegible) into the analyzer measuring glass. Set on the dosing block of the device the number of the samples being analyzed (10 ml). Turn on the mixer and in 2-3 minutes (after removal of bubbles of air) analyze sequentially 4 to 5 samples.

3.3.2.2. Results are treated in the following way: results for the first sample are discarded; for each successive sample record the result of count of the total number of particles of ≥5mm, as well as of ≥25 mm. Then calculate the arithmetical mean for results for all samples on both standardized particle size ranges.

The average number of particles in one ampoule (vial), for one of the standardized sizes (C vol) is calculated according to the following formula:

Cav.sample – is an arithmetic average number of particles of one of the standardized sizes contained in one sample;

Vsol. – the total volume of the tested solution, ml;

Vsample – volume of one controlled sample, ml;

Nvol – number of ampoules (vials) taken for analysis

3.3.2.3. If not otherwise stated in Ph. Monographs, on average, in one container the number of particles of ≥5 mm must not exceed 6,000, including NMT 600 particles of ≥ 25 mm. Otherwise no secondary analysis is performed and the batch is rejected.

3.3.3 Large Size Solutions, Including Dry Formulations Administered at >100 ml after Dilution

3.3.3.1. From an individual sample transfer about 100 ml of thoroughly mixed solution into an analyzer measuring glass. Let the solution settle for 2-3 min. to remove air bubbles. Set the volume of samples analyzed in the dosing block of the device (10 or 25 ml), turn on the mixer and after 1-2 min. successively test 4-5 samples.

Discard the results of the first sample. For each successive sample record the result of count of the total number of particles of ≥5mm, as well as of ≥25 mm. Then calculate the arithmetical mean for results for all samples on both standardized particle size ranges.

The number of particles in one ml of the study drug for each of the standardized sizes (N)is calculated according to the following formula:

Nav.sample – arithmetic average number of particles of one of the standardized sizes per one sample;

Vsample – sample volume, ml

3.3.3.3. If not otherwise specified in Monographs, on average one milliliter of the tested product the number of particles of ≥5mm must not exceed 100, including NMT 4 particles of ≥25mm. Otherwise repeated analysis is not performed and the batch is rejected.

  1. Microscopic Method of Inspection

The sampling procedure is performed according to section 3.2.

Using a pipette place on the object plate silica emulsion in a thin layer, e.g. КE-10-16 for further secure fixation of membranes.

Then place the membrane into a filter holder and accurately set the vortex avoiding touching the surface of the membrane.

4.3.1.3. Before starting the operation perform a blank test for the membrane, vortex and purified water preparation quality control. For that pour into the filter holder vortex about 30 ml of particle-free purified water. Filter water under vacuum. Then switch off vacuum, carefully remove the vortex, accurately (illegible)К.И.6 left in the Petri dish to dry the membrane.

4.3.1.4. Place the object plate and the membrane on the object table of the microscope, set the required magnification.

Set the light source sidewise so that the ray of light falls on the membrane surface under an angle of 10-20º. Adjust the light and focus the membrane to obtain the maximum sharpness of the visible particles.

4.3.1.5. Count the particles and determine their size along the whole surface of the membrane, shifting it from left to right and from top to bottom under the microscope lens. The particle size shall mean the maximum diameter of particles or the maximum linear size. The maximum number of >25mm particle size is 5. If a larger amount of particles is observed, repeat the preparation of equipment and purified water to obtain the required result.

4.3.2.2. If not otherwise specified in Monographs, on average, in one container the number of particles of 5-25 mm in size must not exceed 5,000, including NMT 500 particles of 25mm. Otherwise no repeated analysis is performed and the batch is rejected.

4.3.3. Large Size Solutions, Including Dry Formulations for Injections Administered in the Volume of ≥100 ml after dilution

4.3.3.1. Invert the container with the drug solution 10 times, take 25 ml of the solution with a pipette and transfer the contents to the filter holder vortex. Filter the solution under vacuum conditions. After completion of filtration rinse the membrane and the walls of the vortex with 3-5 portions of 5 ml of particle-free purified water. Filter the contents of the vortex under vacuum, count the particles and determine their size as described in sections 4.3.1.3 – 4.3.1.5.
Perform the same steps with other samples of the same batch.

Record the particles in the following ranges:
– 5-25 mm
– >25mm.
Count the total and the average (calculated for one container) number of particles of each range. Out of the average number of particles of >25mm in size abstract the number of particles of > 25mm of the same range present in the water or in the solvent during blank test (section 4.3.1.3).

4.3.3.2. If not otherwise specified in Monographs, on average, 1 milliliter of the tested product the number of particles of 5-25 mm must not exceed 50, and the number of particles of >25 mm – 3 particles. Otherwise no repeated analysis is performed and the batch is rejected.

The microscopic method allows establishing the nature of particles in injectable drugs, which is particularly important for drug manufacturers, as it helps to identify and in certain cases eliminate the sources of contamination. As the most objective method, it may be used as arbitrary.

 

Head of the Drug and Medical Equipment State Control Administration (signed) R.U. Khabriev

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