Pharmaceutical Validation: granules cleaning validation program

Verification scheme approval:

Lysine and zinc gluconate granules cleaning validation program directory

1, verification purposes .................... ......... .................. 32, authentication realm ....................... .... .... ................................ 33, verifiers and responsibilities ....... ............... ..................... 34, to verify the relevant documents and information .................... .................... ............ 35, verify ................................ content. ............................... 3 5.1 Overview ................ ................. ............................... 3 5.2 before cleaning the risk confirm .............................................. before ......... 4 5.3 verification confirmation ........................ ...... ...... ...................... 4 5.4 Tests and sampling methods ...... ............ ... ............................. 4 5.5 residue allowable limits ........... .... ...... ...... ........ verification step .......................... 7 5.6 ............. ......... ............................ ..8 5.7 validation involves SOP directory ..................... ..................... .......... 86, deviation handling ,change.............

1, authentication purposes

The detection of the verification object is achieved by the continuous production of zinc gluconate particles lysyl residues chemically and physically, to permit

Cleaning equipment according to their standard operating procedures real operating equipment to achieve cleaning requirements, contamination of the next batch will not cause the product to change the product and the next production.

2, verification range:

Lysine and zinc gluconate particle cleaning all procedures and sampling method validation 3, verifiers and responsibilities 3.1 verifiers Leader: Members:

3.2 verification team duty

Leader: audit verification program and verification reports. In order to verify the smooth implementation of the provision of resources. 1 members: technology director, responsible for drafting the verification plan, organize relevant training verification.

Crew 2: Verify QA, is responsible for organizing and implementing verification, validation data collection and report drafting process validation. 3 members: laboratory members, responsible for verifying the test sample, and concludes that the evaluation of individual verification based on test results and evaluation criteria.

4 members: the members of the production department, responsible for participation in the drafting of the authentication scheme, in accordance with the requirements of the specific organization and implementation of authentication scheme verification, validation and make relevant records.

5 members: Equipment members of the Department, confirmed that the equipment and maintenance and technical services provided in the verification. Verification key process parameters involved in the monitoring instrumentation, calibration of measuring instruments.

4, verify the relevant documents and information

"Authentication Management Regulations", "Encyclopedia of Pharmaceutical Excipients", FAO / WHO provision (FAO / WHO)

5, verify the contents 5.1 Overview

Of the cleaning device has been sampled (sampling according to the sampling method has already been verified) in accordance with the cleaning procedures after the operation,

Whether the cleaning apparatus cleaning method is effective and consistent determined by visual inspection and the target residual amount of the compound.

5.2 Clean risks before confirmation

Assessed following is the hardest portion of each cleaning device, the position address these samples and measured the target remaining amount of the compound.

5.3 verification confirmation before

5.4 Sampling and Detection

See test method 5.4.1 test method validation test method 5.4.2 Sampling Method validation: 5.4.3 verification purposes and range:

By sampling swab cleaning validation method was proved by concentration of the sample taken with a cotton swab actual sampling

Consistent, no other effects, sampling method is effective.

5.4.4 criteria:

5.4.4.1 sample recovery rate of not less than 70%.

5.4.4.2 Calculation recovery and recovery RSD value, the relative standard deviation of multiple sampling should not exceed 20%. 5.4.5 verification steps:

5.4.5.1 Preparation of a material of the same surface of the device 304 stainless steel flat plate; draw 100mm × 100mm area on the steel sheet;

5.4.5.2 lysine hydrochloride 5 times the amount of the limit of 80%, 100% and 120% (0.19mg, 0.24mg

, 0.29mg) was dissolved with purified water 10ml, 10ml syringe quantitatively charged;

5.4.5.3 which was applied as uniformly as possible in the region of 100mm 100mm ×; 5.4.5.4 stainless steel natural drying;

5.4.5.5 Sassafras again with the selected solvent (purified water) wetted swab wiping the swab on the head by the sample surface, the force to bend smoothly and gently wipe the surface of the sample, particularly moving method shown in Figure (a ). After wiping, the swab into the test tube were sealed.

FIG. (A) sampling a schematic swab wiping

5.4.5.6 prepared sample solution and the reference solution: 30ml purified water three times eluting with a swab (10ml each), the eluate were combined, 100ml flask, dissolved in water and diluted to the mark, filtered , the filtrate as the test solution; other precision learn lysine hydrochloride reference standard amount of 105 dried deg.] C for 3 hours, dissolved in water and given

The amount of diluting 1ml of each solution containing about 200μg of, as the reference solution. The precise amount of the test solution and reference solution 2ml, each set 20ml volumetric flask, add water successively precision 8ml ninhydrin test solution 4ml, shaken, incubated in a water bath for 25 minutes, allowed to cool, water was added to the mark, shake, according to the UV - visible spectrophotometry (Chinese Pharmacopoeia 2010 Appendix IVA), absorbance was measured at a wavelength of 480nm were calculated by comparing the reference method, i.e., too.

5.4.5.7 Test method:

Blank zero: the ratio of the cuvette, the solvent (water) sample was used for the preparation of 16ml was placed ninhydrin test solution 4ml, incubated in a water bath for 25 minutes at zero blank 480nm wavelength. Since the absorption cell and to deduct possible gaps solvent absorption.

Sample measurement: take the test solution and reference solution, the cuvette absorbance was measured at the same wavelength of 480nm, the reading was repeated twice.

5.4.5.8 recovery was calculated (F) and the relative standard deviation (RSD) above operation is repeated. Sampling is usually carried out in conjunction with recovery and recovery test, the total recovery is generally not less than 70%, the relative standard deviation be less than 20%.

= Theoretical amount of coating applied to the volume of solution concentration ×

Measured = the measured amount of lysine hydrochloride concentration (C) × 20/2 × 100

Measured amount of F = × 100%

Sampling theory verification records 5.4.5.9

Recovery (F) and the relative standard deviation (RSD) is calculated table

Checker: Date:

Review: Date:

5.4.5.10 sampling method validation rating:

Evaluation: Date:

Review: Date: 5.5 residue allowable limit

Lysine due mainly containing zinc gluconate lysine hydrochloride granules, zinc gluconate, sucrose, citrate four components, wherein the non-toxicity of sucrose and citrate (no maximum amount) and easy to clean, is not the target compound; lysine hydrochloride, an active material and zinc gluconate two substances soluble in water is easy to clean, and therefore, the proportion of prescriptions cleaning validation select more active ingredient-lysine hydrochloride as the target for checking the residual cleaning composition.

5.5.2 List of utility equipment

Metformin hydrochloride sustained-release tablets for the next production article design utilities area (54700 cm2) list:

5.5.3 residue limit calculation

Parameter selection:

A: The next item in the smallest quantities --45kg B: swab sampling area --100cm2

C: The total area of the device (utilities) in contact with the material --95800cm2 D: safety factor --10

Calculating the amount of remaining license: A × B × 10 × 10-6

45×100×10×10-6

C×D

= 95800×10

=4.7×10-2 mg/100cm2

In the rear area of 100cm2 sampling swab test the residual amount of lysine hydrochloride is less than 4.7 × 10-2 mg / 100cm2, it is considered that the cleaning mill according to standard operating procedures to make cleaning operations required equipment.

5.5.4 Clean inspection standards

5.5.4.1 ammonia was visually observed to be rogue particulate zinc gluconate visible residues.

After swabbing the area of the test sample 5.5.4.2 100cm2 clarithromycin residual amount is less than 4.7 × 10-2

mg/100cm2

5.6 Verification Step

5.6.1 standard operating procedures for each cleaning equipment be cleaned after each batch production is completed.

5.6.2 Sampling by the sampling method of verification sampling in the sampling device and each test site. 5.6.3 verification records See Schedule I to Schedule 5.7 validation involves six SOP directory

6, process variation and changes see "discordance management order" 7, 8 verification result analysis and evaluation, the recording and Accessories

Schedule I

Universal grinder cleaning validation records

Notes: 1 sampling cutting chamber inner wall portion; represents pulverized gear sampling site; 3 spout sampling site. Each sampling site to select two sample points is detected.