Pharmaceutical Validation

Wednesday, January 10, 2018

Equipment cleaning validation program

PROCEDURES / INSTRUCTIONS

equipment cleaning validation program

Equipments Cleaning Qualification Protocol

File No. Doc No .: File version Revision:. Revision Date Revision Date: Case Unit intends Issued by:

editor Author proofreading Reviewed by

auditing a Date Approved by date as Effective

1. the Description

Manufacturing Equipment's for Dermasil OTC skincare product includes vacuum emulsification mix tank group & Liquid Automatic Filling Machine. These equipments adopt stainless steel materials, and facilitate cleaning and resist disinfection. They are easy to control and have good design, flexible and stable system, sensitive temperature adjusting. These Skin are Used to Produce Equipments Care Products's Same, with the Active Ingredients. Control at The Microorganism IS Significant.

2.Purpose

OTC

This is to check and verify if these equipments for OTC products are scientific and designed to facilitate operation.

3.cope

3.1. Dermasil OTC

This protocol is applied for cleaning qualification of these equipments for Demersil OTC Skincare

4. Role & Responsibilities 4.1. QA manager

4.1.1.

Assign team leader, approve validation protocol and reports, issue validation certificate and decide re-validation frequency.

4.2. Team leader

4.2.1.

Team leader is the leader of specific qualification projects, lead to and coordinate qualification assignment, draft the protocol and collect the data and records and sort out reports. 4.2.2.

Draft first cleaning validation protocol and complete the reports, and guide the implementation, training and technical transfer of the qualification.

4.3. QA

4.3.1.Review of qualification data and results. 4.3.2.

Supervise the qualification and review validation report. 4.3.3.。Manage qualification documents.

4.3.4.

Develop validation plan and supervise the implementation of validation and manage the documents.

4.4. LAB

4.4.1.

Develop inspection methods and limits of residue (products left, microorganism, cleaning agent). 4.4.2. 。Establish sampling methods

and sample for tests, and evaluate the qualification results.

4.4.3. Guide the production department to

choose cleaning agent and cleaning methods.

4.5. Production

4.5.1. Make the

procedure for cleaning and conduct cleaning activities and do training for the operators.

4.5.2. 。Arrange personnel and adjust time, and

provide necessary resources.

4.6. Maintenance

4.6.1. Do training of de-assembly and

installation.

5.

Qualifications

5.1. 。Follow the procedure to clean the equipments after

production.

5.4.
Physical inspection: use sterile blue or color different from that of the product cloth with 75% ethanol to wipe their surfaces, no residue is visible。

5.5. Residue

concentration limits: active ingredients used include dimethicone, they are highly safe raw materials without toxin. So we use physical check after cleaning is accepted. And if necessary we will send once to 3rd party for checking residue.

5.6. Microorganism examination

5.6.1. WI-006&WI-008。

Vacuum emulsification mix tank group & Liquid Automatic Filling Machine use washing water to clean. After clean the tank and homo-mixer, we use purified water to wash the homo-mixer. Samplings refer to WI-006, and sent to micro lab. Micro test method refers to WI-006&WI-008.

5.7.Re-qualification frequency

QAQA to decide the re-qualification frequency after verifying the results. 6.

Deviation Handling

Any deviation found will follow Deviation control procedure for handling and investigation. 7.

Reference

7.1. WI-011 7.2.WI-006 7.3.WI-008 7.4. WI-001 8.

Attachment

8.1.Equipments Cleaning Qualification Records

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Cleaning validation program

1. Overview

**** Injection for my company research and development of new drugs varieties. To demonstrate the variety of its prescription and technology can produce products that meet corporate standards, I am in the air purification system, water system and equipment revalidation qualified and instruments by test within the validity period, participants trained and passing the examination, basic cleanliness level meet the requirements of this product on a process to verify the whole process. The entire process of pre-production process including the identification of relevant documents, confirming raw materials suppliers of materials, preparation, bottle washing, filling and sealing, sterilization, inspection lights and other production operations practice, and the product to stay kind study to determine stability of the product.

In order to ensure that the product formulation, stability and reproducibility of the process, the production equipment using the same three batches. 2. Authentication purposes

The entire process by verifying process, the text proved by the production process of the prepared product is in line with predetermined specifications and quality standards, to ensure the production of stable quality products. 3. Verify the organization and responsibilities

The company was founded by vice president of production headed to the department heads and all stakeholders workshop director and as a member of the product process validation teams to "**** injection process planning" as the basis, according to "**** injection process validation protocols "for product verification. 3.1 verification team responsibilities:

4. Verify plans and arrangements

It is validated by a date to date. 5. Verify Before You Go

in conclusion:

Checker: Date of inspection:

in conclusion:

Checker: Date of inspection:

in conclusion:

Checker: Date of inspection:

in conclusion:

Checker: Date of inspection:

Checker: Check the date: 6, product names and prescriptions 6.1 Product Name: Injection **** 6.2 Specifications: * ml: ** mg 6

7. Verify embodiment

Flow chart:

7.1 preparation process verification

7.1.1 before production on cleared, check to make sure cleanliness

7.1.2 Materials used name, batch number, lot number picking a case record form:

7.1.3 filter integrity test (bubble point test) methods, test criteria and the record table 7.1.3.1 Test Methods: "Bubble Point Test protocol" first cartridge loaded process water for injection 7.1.3.1.1 soak for 10 minutes. 7.1.3.1.2 pneumatic connections:

(1) The need to connect gas line in Figure 1.

(2) to close the valve V1, V2, V4 and V5, open the valve V3.

(3) have to carry out the leak detection filter housing before the test, when the valves closed is detected by function 6 can be used for air-tightness test.

(4) The air pressure is adjusted to slightly above the test pressure 0.2MPa. Control 30s, air bubbles were observed at the filter. For example, the barrel and the connection is not tight O-ring is mounted or not the cartridge is fully saturated, then continuous bubbles appear,

In this case all connections should be checked or replaced O-ring or re-impregnated filter.

(5) absence of bubbles, continuous compression until a continuous or stabilizing gas bubbles were observed to occur in a beaker, then the pressure is the minimum display instrument bubble point pressure.

7.1.3. Criteria 2

The minimum bubble point pressure: 0.22um ≥0.26 MPa, water for injection 0.45um ≥0.18 MPa, water for injection

7.1.3.3 test results are reported in Table

7.1.4 Process

Stir liquid verifier 7.1.5

7.1.5.1 verification method: the end of liquid feed, after adding water for injection to the total amount, stirring the liquid min, min, min PH value detected liquid were sampled at the sampling port adjusting tank content. 7.1.5.2 validation criteria:

Evaluation of the results:

Evaluation: Date: Approved by: Date: 7.1.6 7.1.6.1 liquid filtration system to verify the authentication method:

Before and after filtration of the liquid chemical trait, PH value, the content of related substances, microbial limits, sterile, projects visible foreign matter detection, validation and liquid filtration systems, and chemical compatibility with the filtration system proved to achieve sterilization filtering effect.

Liquid PH value measurement method: Take liquid stirring ml, with a pH meter uniformly detection result should meet

Provisions.

Chemical Determination Method: Stir chemical ml, detected by semi **** Injection quality standards, the results should be specified.

For determination of chemical substances: liquid take Stir ml, detected by the injection **** product quality standards, the results should be specified.

Visible foreign matter: when the liquid through the fine filter cartridge um reflux for 5 minutes, then take a flask 100ml, CM-1 in the check type detector clarity, and white point fibers can not be detected.

Microbial Limit Detection Method: liquid before filtration 100ml, detected by the detection limit of the microorganism. Sterility Testing Methods: filtered liquid 100ml, sterility test according to the detection method of the present project, the finished product, the results of compliance.

7.1.6.3 validation results

7.1.6.3.1 Liquid filter before the detection result

Evaluation of the results:

Evaluation: Date: Approved by: Date: 7.1.7 liquid formulated from the beginning to the end of the preparation time of confirmation

7.1.8 begin to filter sterilization filter to confirm completion time

7.2 ampoule washing procedure verifies

7.2.3 Cleaning process: → ampoule circulating purified water (2 times) → washing → drying water for injection sperm injection parameters 7.2.4 Water temperature: purified water temperature: pressure control: Compressed air pressure: Host Frequency:

Network with frequency: drying temperature: drying time:

7.2.6.1 Cleanliness inspection

(1) Visual inspection: An inside and outside the bottle should be clean, clear, anhydrous.

(2) taking poured into 200 ampoules fine chemical examination visible foreign matter was filtered off, visible foreign matter should be limited to one. 7.2.6.2 Microbial Limit Test

After cleaning and sterilizing the ampoule according to the 2010 edition of microbial limits test examination, the results should be

After cleaning and sterilizing the ampoule 2010 edition by bacterial endotoxin inspection results should be <0 .25eu="" 7.2.7="" font="" ml="" verification="">

Evaluation of the results:

Evaluation: Date: Approved by: Date: 7.3 potting process verification

7.3.2 Method validation: Properties of drug, pH, related substances, the content of visible foreign matter, sealing quality, microbial limits controlled by the potting process, to ensure product quality.

Sealing quality: Each casting machine inspection of drugs from each of 100, no stains sealed clean appearance, no blistering, without pores, the focus head, smooth, flat, etc., to meet the requirements length, should be greater than 98% pass rate.

Visible foreign matter: potting beginning, middle, near the end of each machine when 40 samples were obtained drugs foreign matter inspection, the foreign matter 40 can be seen in not more than one visible *** branched.

Microbial Limit Test: the beginning of potting, potting middle stage and end stage depicting good potting drugs *** branch, microbial limit test examination according to the 2010 edition, the results should be <*** CFU / 100ml. Bacteria resistant test: Take the remaining liquid microbial limit test, with *** um membrane filter (filter sterilized 5% Tween sufficiently wetted). This membrane was transferred into a test tube containing 10ml of sterile 0.1% peptone aqueous solution and boiled *** min on a boiling water bath, and then cultured at 30 ~ 35 ℃ days thioglycollate broth, observing whether bacteria growth. 7.3.3 Compressed air pressure conditions:

Mpa 7.3.5 validation results

Evaluation: Date: Approved by: Date: 7.4 sterilization process challenge

7.4.1 verify clearance before, check to make sure cleanliness

7.4.2 criteria:

7.4.4 Method validation: 7.4.4.1 conditions

Sterilization temperature: Time: Pressure Sterilization: 7.4.4.2 sterilization process *******************

7.4.4.3 sterility test and verification method related substances: sterile hottest spot checks and validation of related substances:

Sterility test specimen sampling: After sterilization, the method in accordance with the provisions of the coldest spot sterilizer and initial filling, final random filling out 50, according to two methods "Chinese Pharmacopoeia" 2010 edition do sterility test should be Compliance.

Related substances Sampling: Samples were taken from each pot at the hottest point sterile, individually packaged and marked evacuation central laboratory after sampling, by injection vinpocetine product quality inspection method under a predetermined standard related substances. 7.4.5 authentication result: a lot number:

Evaluation: Date: Examination: Date: light inspection step verification 7.5

7.5.1 before verification of clearance, cleanliness inspection

7.5.2 CM-1 light detecting means

(1) source: illuminance LX (2) Shape: Umbrella shed type apparatus.

(3) Background: non-reflective black and white. (4) Distance: test human eye distance of 20 ~ 25cm. (5) check: should be indoors or in dark shadows.

(6) Check the art: vision subject light (not including vision correction) distance and near vision test are 5.0 or 5.0 (i.e. 1.0 or 1.0) or more. There should be no color blindness. 7.5.2.1 inspection methods

The test shown with the gripping support, ampoules wipe blot outer wall, the edge of the shelf in the umbrella, so that liquid gentle inversion, with

Eye view.

7.5.3 intelligent automatic light inspection machine: the machine parameters, the binary threshold level of the center line, the level variation.

7.5.4 criteria

Press the "Chinese Pharmacopoeia" 2010 edition two visible foreign matter inspection method to determine the results should be consistent with the evaluation results:

Evaluation: Date: Approved by: Date:

Deviation analysis results:

Analysis: Date: Approved by: Date:

Result analysis:

7.8 sample observation

In order to investigate the stability of the product quality, our company for verification of three batches of the product to stay kind of investigation, the present experiment still in progress. 8. Deviations processing

Should be strictly in accordance with the design inspection and verification process to determine, verify does not affect the quality of the final product, in line with the deviation within the allowable range, there are processed according to the following procedure when the individual projects do not meet the requirements: written and variance analysis.

8.1 Any deviations from the production process, material balance limits, quality standards, test methods, procedures, etc. are to be recorded and immediately reported to the competent personnel and quality management department, should have clearly stated, significant deviations shall, together with the quality control department other departments to conduct a thorough investigation and a survey report. Deviation investigation report should be reviewed and signed by the designated officer quality management.

8.2 If the reasons for equipment, systems genus, should be reported to verify a leading group for systems and equipment for processing.

9. Verify that the results of the review and verification report

Once verified, the verification team responsible for the preparation of the verification report, shall be evaluated, countersigned members, final approval by the Qualified Person.

Validation Report

10. Verify the certificate

After verification report approved by the Qualified Person who signed the authentication certificate.

Verification certificate

This article from the first library network (www.wenku1.com)

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.