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Guide of CHINA-GMP(2010 edition)

Date:2014-10-30 Label:沙漠风 Source:管理员

 

Good Manufacturing Practice for Pharmaceutical Products

(Amended in 2010) SDA Order #79

Order by Ministry of Health of the People’s Republic of China

      Published on February 12, 2011

No. 79

Good Manufacturing Practice for Pharmaceutical Products (Amended in 2010) has passed by Affairs Meeting on October 19, 2010. This Regulation is now published and shall be effective from March 1, 2011.

                                   Director Zhu CHEN

                               January 17, 2011

Chapter 1 General Provisions

Article1       In order to standardize good manufacturing for pharmaceutical products, this Regulation is enacted in accordance with the “Drug Administration Law of the People’s Republic ofChina” and “The Regulation on the Implementation of Drug Administration Law of the People’s Republic ofChina”.

Article2       A pharmaceutical enterprise shall establish pharmaceutical goods’ quality control system. The system shall contain all factors which may affect the quality of pharmaceutical goods, including all organized and planned activities ensuring pharmaceutical goods’ quality in accordance with intending purpose.

Article 3       This Regulation is part of quality control system, is basic requirement for manufacturing and quality control of pharmaceutical products. This Regulation aims to reduce the risks in pharmaceutical goods’ manufacturing process at its maximum, such as pollution, cross pollution and confusion, mistake, ensure for continuous stably manufacturing pharmaceutical goods in accordance with intending purpose and registered requirements.

Article 4       The enterprise shall obey this Regulation strictly, insist on honesty and keep faith, prohibit any ostensible and spurious activities.

                   

Chapter 2 Quality Control

                   

Section 1 Principle

Article 5       The enterprise shall establish quality target in accordance with pharmaceutical goods’ quality control requirements, carry out all requirements related to safety, effective and quality control into the process of pharmaceutical goods’ manufacturing, control and products’ discharging, storage, delivering, ensure all pharmaceutical goods are produced in accordance with intending purpose and registered requirements.

Article 6       Senior administrator in enterprise shall ensure the achievement of intending quality target. Personnel in different levels and provider, dealer shall participate in and take each responsibility. 

Article 7       The enterprise shall equip adequate personnel, workshop, establishment and equipment in accordance with requirements, and provide essential condition for achieving quality target.

Section 2 Quality Guarantee

Article 8       Quality guarantee is a part of quality control system. The enterprise must establish quality guarantee system, and establish integrate document system at the same time, in order to ensure the system’s effective running.

Article 9       Quality guarantee system shall ensure the following:

I.            Represent the requirements of this Regulation in pharmaceutical goods’ design and development.

II.           In accordance with the requirements of this Regulation in manufacturing management and quality control activities;

III.         Specific management responsibility;

IV.         Exact stocked and used raw material and wrapper;

V.          Effective control in semifinished product;

VI.         Implement of confirmation and validation;

VII.       Manufacture, examine, inspect and double examined according to rules strictly;

VIII.       Each batch of products shall only discharge after quality authorizing person’s approval;

IX.         Applicable measures to ensure pharmaceutical goods’ quality during the process of storage, delivering and all succedent operation process;

X.          According to self-examine rules, examine and evaluate the validity and applicability of the quality guarantee system quality.

Article 10     Basic requirements of pharmaceutical goods’ manufacture quality management:

I.            Frame manufacturing technique, systemic review and demonstrate it could continuous stably manufacturing products in accordance with requirements;

II.           Manufacturing technique and its important changes shall be validated;

III.         Equip all required resources, include, but not limited the following:

1.           Hold applicable qualification and the eligible trained personnel;

2.           Adequate workshop and space;

3.           Applicable equipment and maintain guarantee;

4.           Accurate raw material, wrapper and label;

5.           Approved technique rules and operate rules;

6.           Applicable storage and freight condition.

IV.         Use accurate and easy understand language to frame operate rules;

V.          The operate person could accurate operate according to operate rules after training;

VI.         The whole manufacture process shall be recorded. The windage shall be researched and be recorded;

VII.        Batch record and delivering record shall be traced back to the whole history of the batch of products, and the records shall be saved appropriately and be easy consult;

VIII.       Reduce the quality risk during the pharmaceutical goods’ delivering process;

IX.         Establish pharmaceutical goods’ recall system, and ensure any batch delivered and sold products could be recalled;

X.          Survey the reasons leading to pharmaceutical goods’ complaints and quality objections, take measures to prevent similar quality objections.

Section 3 Quality Control

Article 11     Quality control includes corresponding organization, document system and sampling, test and so on, to ensure material or products finish necessary examination before delivering, and to verify its quality is in accordance with the requirements.

Article 12     Basic requirements of quality control:

I.            Equip applicable establishment, equipment, instrument and trained personnel to effective and reliable finish all related quality control activities;

II.           Have approved operate rules, which used to sampling, examine, inspect raw material, wrapper, semifinished product, bulk product and finished product and products’ stability, monitor environment when necessary, to ensure the products is in accordance with the requirements of this Regulation;

III.         Authorized person shall sampling to raw material, wrapper, semifinished product, bulk product and finished product according to stated methods;

IV.         Inspect methods shall be confirmed and validated;

V.          Sampling, check, inspect shall be recorded, the windage shall be researched and be recorded;

VI.         Material, semifinished product, bulk product and finished product shall be checked and inspected according to quality standard and be recorded;

VII.        Material and packaged finished product shall have enough reserved samples so that necessary check or inspect shall be taken; except the finished product with too large package container, the reserved samples’ package shall be the same with the final package of the finished product.

Section 4 Quality Risk Management

Article 13     Quality risk management is evaluate, control, communicate, audit system process to quality risk during the whole product life period, via the manner of foresee or review.

Article 14     Quality risk shall evaluate according to science knowledge and experience in order to ensure products’ quality.

Article 15     The method, measure, form take during the quality risk management process and the documents formed in the said process shall accommodate to the level of the existent risk.

 Chapter 3 Organization and Personnel

                   

Section 1 Principle

Article16     An enterprise shall establish management organization which accommodate to the pharmaceutical goods’ product and have its organization framework chart.

The enterprise shall set up independent quality management department, which carries out the responsibilities of quality guarantee and quality control. The quality management department could set up quality guarantee department and quality control department respectively.

Article 17     Quality management department shall take part in all activities relating to quality, and take responsibility to audit all documents relating to this Regulation. The personnel in quality management department shall not relegate his responsibility to the personnel in other department.

Article 18     The enterprise shall be staffed by an appropriate number of management and technical personnel with appropriate qualification (including education background, training and practice experience), and the responsibilities of each department and each station shall be clarified. Station’s responsibility shall not be missed and cross responsibility shall be prescribed specifically. Responsibility taken by each person shall not be overfull.

Every person shall clear and understand his own responsibilities, be familiar with the requirements related to his responsibilities, and accept necessary training, including pre-job training and on-job training.

Article 19     Generally, one shall not relegate his responsibility to other person. If the responsibilities do need to be relegated, the one should relegate his responsibility to the designated person who has equivalent qualification.

Section 2 Important Person

Article 20     The important person shall be the full-time person of the enterprise, at least including the director of the enterprise, director of manufacturing management, director of quality management and authorized person of quality.

Director of quality management and director of manufacturing management shall be independent of each other. Director of quality management and authorized person of quality shall not be independent of each other. Operation proceduress shall be established so that authorized person of quality could take his responsibility independently, with no interference from director of enterprise and other person.

Article 21     Director of enterprise

Director of enterprise is the main responsible person of pharmaceutical goods’ quality, who comprehensive responsible to the daily management of the enterprise. In order to ensure the enterprise complete quality target and manufacture pharmaceutical goods according to this Regulation, the director of enterprise shall take responsible for providing necessary resources, reasonable plan, organize and correspond to ensure the quality management department could take its responsibility independently.

Article 22     Director of manufacturing management

I.            Qualification:

Director of manufacturing management shall at least have pharmacology or related specialty undergraduate education background (or secondary professional technical title or licensed pharmacist qualification), have at least three years’ pharmaceutical goods’ manufacturing and quality management experience, including at least one year’s pharmaceutical goods’ manufacturing management experience, have taken part in professional knowledge training related to manufacturing products.

II.          Main responsibility:

1.           Manufacture and storage the pharmaceutical goods according to approved technology procedure in order to ensure the quality of the pharmaceutical goods;

2.           Ensure every operation proceduress related to manufacturing operation are performed strictly;

3.           Ensure batch production record and batch package record are audited by designated person and submitted to quality management department;

4.           Ensure the maintenance of workshop and equipment in order to preserve its good working condition;

5.           Ensure all kind of necessary validation work is completed;

6.           Ensure person related to manufacturing have been trained by pre-job training and on-job training, adjust training content according to actual demands.

Article 23     Director of quality management

I.            Qualification:

Director of quality management shall at least have pharmacology or related specialty undergraduate education background (or secondary professional technical title or licensed pharmacist qualification), have at least five years’ pharmaceutical goods’ manufacturing and quality management experience, including at least one year’s pharmaceutical goods’ quality management experience, have taken part in professional knowledge training related to manufacturing products.

II.          Main responsibility:

1.           Ensure the raw material, wrapper, semifinished product, bulk product and finished product are in accordance with the registered approved requirements and quality standard;

2.           Ensure the products are audited to batch record before delivering;

3.           Ensure necessary inspection is finished;

4.           Approve quality standard, sampling method, inspection method and other operation proceduress of quality management;

5.           Audit and approve all changes related to quality;

6.           Ensure all important windage and exceed criterion inspection results have been researched and been dealt with in time;

7.           Approve and supervise consigned inspection;

8.           Supervise the maintenance of workshop and equipment in order to maintain its good working condition;

9.           Ensure to finish every necessary confirmation and validation work, checking and approving confirmation or validation scheme and report;

10.         Ensure to finish self-check;

11.         Evaluate and approve material supplier;

12.         Ensure all complaints related to product quality have been researched, and have been dealt with in time and accurately;

13.         Ensure to finish products’ persistent stability review plan, provide the data of persistent stability review;

14.         Ensure to finish product quality review analysis;

15.         Ensure quality control and quality guarantee person have been trained by pre-job training and on-job training, adjust training content according to actual demands.

Article 24     Director of manufacturing management and director of quality management often have the following common responsibility:

I.            Audit and approve the documents of products’ technology procedure, operation proceduress;

II.           Supervise the sanitation condition of factory;

III.         Ensure the key equipment have been confirmed;

IV.         Ensure to finish the validation of production technology;

V.          Ensure all related person in enterprise been trained by pre-job training and on-job training, adjust training content according to actual demands;

VI.         Approve and supervise consigned manufacture;

VII.        Ensure and monitor the storage condition of material and goods;

VIII.       Save the record;

IX.         Supervise the implement condition of this Regulation;

X.          Monitor the factors influence the quality of the products.

Article 25     Authorized person of quality

I.            Qualification:

Authorized person of quality shall at least have pharmacology or related specialty undergraduate education background (or secondary professional technical title or licensed pharmacist qualification), have at least five years’ pharmaceutical goods’ manufacturing and quality management experience, have the experience of manufacturing process control and quality check work.

Authorized person of quality shall have necessary professional theory knowledge, have taken part in the train about product delivering, and could take his responsibility independently.

II.          Main responsibility:

1.           Take part in the establishment of enterprise quality system, interior self-check, exterior quality audit, validate and pharmaceutical goods’ bad reaction report, product recall and other quality management activities;

2.           Take the responsibility of product delivering, to ensure the manufacturing, checking of every batch of delivered products are all in accordance with corresponding code, pharmaceutical goods’ registered requirements and quality standard;

3.           Before delivering the products, authorized person of quality must issue product delivering audit record according to the said item 2 and bring it into batch record.

Section 3 Training

Article 26     The enterprise shall designate department or person to take responsible for training management work, and shall have the training scheme or plan audited or approved by director of manufacture management or director of quality management. The training record shall be preserved.

Article 27     All personnel related to pharmaceutical goods’ manufacturing, quality shall be trained, the training content shall accommodate to the post. Except the training of theory and practice of this Regulation, responsibility, skill training about the related code, relevant post shall also be trained, and actual effect shall be periodic evaluated.

Article 28     The working person in high risk operating area (such as: manufacture area of high activity, high toxic, infective, high sensitive material) shall take expert training.

Section 4 Personnel Sanitation

Article 29     All personnel shall take sanitation requirements training, the enterprise shall establish personnel sanitation operation proceduress, so that to reduce the pollution risk to pharmaceutical goods taken by person at its maximum.

Article 30     Personnel sanitation operation procedures shall include the content related to health, sanitation practice and personnel dress. Personnel in manufacturing area and quality control area shall correctly understand related personnel sanitation operation procedures. The enterprise shall take measures to ensure the implement of personnel sanitation operation procedures.

Article 31     The enterprise shall manage personnel’s health and establish health file. The manufacture personnel contact pharmaceutical goods directly shall receive physical check, and take at least one physical check per year.

Article 32     The enterprise shall take appropriate measure to avoid the person have wound in body surface, have infection disease or other person may pollute pharmaceutical goods to take the manufacture work which directly contact pharmaceutical goods.

Article 33     Visiting person and untrained person shall not enter manufacture area and quality control area, if the persons need to enter in special conditions, the items of their individual sanitation, clothes changing and so on shall be instructed.

Article 34     Any person enters into manufacturing area shall change clothes according to prescription. The material, style and dressing method of work clothes shall be accommodate to the work engaged and the level of air clean degree.

Article 35     The person enters into clean manufacturing area shall not make up and adorn with accouterment.

Article 36     Manufacturing area, storage area shall forbid smoking and having meals, forbid to store food, beverage, cigarette and individual pharmaceutical goods and other non-manufacturing goods.

Article 37     Operation person shall avoid to touch the surface of pharmaceutical goods, wrapper material contact pharmaceutical goods directly and equipment by hand.

Chapter 4 Workshop and Establishment

                   

Section 1 Principle

Article 38     The workshop location’s choice, design, overall arrangement, construct, reconstruct and maintenance must in accordance with the pharmaceutical goods’ manufacturing requirements, which may avoid pollution, cross pollution, confusion and mistake at its maximum, and may convenient for clean, operate and maintenance.

Article 39     The workshop’s location shall consider according to the workshop and manufacturing safety measures. The environment of the workshop shall reduce the pollution risk to material or products at its maximum.

Article 40     The enterprise shall have tidy manufacturing environment. The floor, road surface of the workshop and transport shall not pollute the pharmaceutical goods’ manufacturing. The overall arrangement of the manufacturing area, administration area, living area and assistant area shall be reasonable arranged and do not interfere each other. Stream of people and material in factory area and workshop shall reasonable.

Article 41     The workshop shall take appropriate maintenance, and ensure the maintenance activity may not influence the quality of pharmaceutical goods. Clean or take necessary sterilization to workshop according to detailed written operation procedures.

Article 42     The workshop shall have appropriate illumination, temperature, humidity and aeration, to ensure the quality of produced and reserved products and the performance of related equipment shall not be influenced directly or indirectly.

Article 43     The design and installation of workshop, establishment shall effective prevent insect or other animal to enter in. Necessary measures shall be taken to prevent of using raticide, insecticide, smoke fumigant and so on which may pollute equipment, material, goods.

Article 44     Necessary measures shall be taken to prevent unauthorized person to enter in. Manufacturing, storage and quality control area shall not be the direct gate for staffs not in this area.

Article 45     Complete drawing of constructed or reconstructed workshop, public service, fixed pipeline shall be saved.

Section 2 Manufacturing Area

Article46     In order to reduce pollution and cross pollution risk, workshop, manufacturing establishment and equipment shall reasonable designed, overall arranged and used according to the characteristic, technique process and corresponding clean level, and in accordance with the following requirements:

I.            Comprehensive considering the pharmaceutical goods’ characteristic, technique and intending purpose and other factors, to confirm feasibility of using workshop, manufacturing establishment and equipment together, and hing related evaluating report;

II.           Special and independent workshop, manufacturing establishment and equipment must be used when manufacturing special character pharmaceutical goods, such as high sensitive pharmaceutical goods (i.e. Penicillin) or biologics goods (i.e. bcg vaccine or other pharmaceutical goods prepared by active microorganism). The operating area with large quantity of dust forpenicillin species pharmaceutical goods shall keep comparatively negative pressure, the exhaust gas discharged to outdoor shall carry cleanse management and make it be up to the mustard. Air outlet shall be away from air inlet of other air cleanse system;

III.         Special establishment (i.e. independent air cleanse system) and equipment must be used when manufacturing β-lactam structure species pharmaceutical goods, sex hormone  species prophylactic pharmaceutical goods, and shall be detached with other pharmaceutical goods’ manufacturing area strictly;

IV.         Special establishment (i.e. independent air cleanse system) and equipment shall be used when manufacturing some hormone species, cell toxicity species, high active chemical pharmaceutical goods; under special circumstance, if necessary validation shall be take before taking special protection measures, the above said pharmaceutical goods preparation could use the same establishment and equipment via manufacturing modes in different phases;

V.          Ventilation of air cleanse system in the above said item II, III, IV shall take cleanse management;

VI.         Pharmaceutical goods’ manufacturing workshop shall not used for manufacturing non-officinal used products which may have bad influence to pharmaceutical goods’ quality.

Article 47     Manufacturing area and storage area shall have enough space to ensure equipment, material, semifinished product, bulk product and finished product could storage in order, to prevent the confusion, cross pollution of different products or material, to prevent missing or mistake during the operation of manufacturing or quality control.

Article 48     Air condition cleanse system shall be equipped according to pharmaceutical goods’ variety, manufacturing operation’s requirement and exterior environment condition which let the manufacturing area can effective aeration, and have temperature, humidity control and atmosphere cleanse filtration, to ensure the manufacturing environment of pharmaceutical goods is in accordance with the requirements.

The pressure difference between clean area and non-clean area, clean areas in different level shall not lower than 10 Pascal. When necessary, appropriate pressure difference grads shall also be kept in different functional areas (operation area) with same clean level.

Exposure working procedure area for oral liquid and solid preparation, chamber use pharmaceutical goods (including rectal pharmaceutical goods), surface external use pharmaceutical goods and other non-asepsis preparation manufacturing and exposure working procedure area for wrapper material directly contact pharmaceutical goods shall equip according to the requirements of “Asepsis Pharmaceutical Goods” D level clean area in Annex. The enterprise could take appropriate microorganism monitor measures according to products’ standard and characteristic.

Article 49     Inner surface of clean area (wall, floor, sunshade) shall be slick, non-crack, narrow joint, non granule fell off, prevent stored dust, convenient for effective clean, and take sterilization when necessary.

Article 50     The design and installation of every kind of pipeline, lighting establishment, place with a draught and other public establishment shall prevent having the part of not easy to clean, and shall try best to maintain outside the manufacturing area.

Article 51     Sewerage shall have appropriate size and install the device of reversing flow. Try best to prevent drain in clear channel, if it is inevitably, the clear channel shall be flat so that it is convenient to clean and sterilize.

Article 52     Quantify of preparation’s raw material often carry on in the metage room special designed.

Article 53     Operation rooms which produce dust (such as sampling, metage, mix, package of dry material or products rooms and other operation rooms) shall keep comparatively negative pressure or take special measure, so as to prevent the diffusion of powder dust, avoid cross pollution and easy to keep clean.

Article 54     Pharmaceutical goods’ packaging workshop or area shall be reasonable designed and arranged, to prevent confusion or cross pollution. If there are several packaging lines in one area, isolation measures shall be taken.

Article 55     Manufacturing area shall have appropriate light, the light in contact manufacturing area shall satisfy the operation requirements.

Article 56     Manufacturing area could set middle control area. However, middle control operation shall not bring quality risk to pharmaceutical goods.

Section 3 Storage Area

Article 57     Storage area shall have enough space, which ensure the under-examined, qualified, disqualified, withdrew or recalled raw material, wrapper, semifinished product, bulk product and finished product and all kinds of material and products could store in order.

Article 58     The design and construct of storage area shall ensure good storage condition, and have aeration and lighting establishment. Storage area shall satisfy material or products’ storage condition (such as temperature, humidity, avoid of light) and safety storage requirements, and check and monitor shall be taken.

Article 59     High active material or product and printing package material shall storage in safe area.

Article 60     Receiving, extending and delivering area shall protect material, product out of influence of weather outside (such as rain, snow). The arrangement and establishment of receiving area shall ensure taking necessary cleaning to the received material’s outside packaging.

Article 61     If the under-examined material is stored in separate isolate area, the under-examine area shall have distinct mark, and only authorized person could in and out.

Disqualified, withdrew or recalled material or product shall be stored isolated.

If other method is used for replacing physics isolation, this method shall have equal security.

Article 62     Separate material sampling area is often set up. Air cleaning level of sampling area is the same with the manufacturing requirements. If sample is taken in other area or use other method, pollution or cross pollution shall prevent.

Section 4 Quality Control Area

Article 63     Quality control laboratory is often divided from manufacturing area. Biology examine, microorganism and radioactivity isotope laboratory shall also divided from each other.

Article 64     The design of laboratory shall ensure for applying it’s intending purpose, and prevent confusion and cross pollution, enough area shall have for disposing samples, reserved samples and samples for reviewing stability and keeping the records.

Article 65     When necessary, set a special instrument room to prevent static, shaking, humid or other outside factors’ disturbance to instrument with high sensitivity.

Article 66     The laboratory disposing special goods such as biology samples or radioactivity samples shall in accordance with the related requirements of the country.

Article 67     Experiment animal room shall be strictly divided from other area. Its design, construct shall in accordance with the related requirements of the country and have independent air disposing establishment and animal’s special channel.

Section 5 Assistant Area

Article 68     Retiring room shall not take bad influence to manufacturing area, storage area and quality control area.

Article 69     Bathing room and washing room shall be convenient for person’s use, and accommodate with the using number of people. Washing room shall not connect with manufacturing room and storage room.

Article 70     Maintain room shall be away from manufacturing area as far as possible. Spare parts and tools used for maintenance stored in clean area shall be placed in special room or tool cabinet.

Chapter 5 Equipment

                   

Section 1 Principle

Article 71     The design, model choosing, installing, reconstructing and maintenance of equipment shall in accordance with the intending purpose. The risk of pollution, cross pollution, confusion and mistake shall reduce at the maximum. The design shall be easy to operation, clean, maintain and shall take sanitization or sterilization when necessary.

Article 72     Operation procedures for equipment’s using, cleaning, maintaining and servicing shall be established. Corresponding operation records shall be kept.

Article 73     The equipment’s ordering, installing, confirmation documents and records shall be established and kept.

Section 2 Design and Installation

Article 74     Manufacturing equipment shall not bring any bad influence to pharmaceutical goods’ quality. The surface of manufacturing equipment contact with pharmaceutical goods directly shall be neat, smooth, easy to clean or sterilization, be able to bear cauterization. It could not take chemistry reaction with pharmaceutical goods, adsorb pharmaceutical goods or release substance to pharmaceutical goods.

Article 75     Weighing apparatus, measure, apparatus and instrument with appropriate capacity and precision shall be equipped.

Article 76     Appropriate rinse, cleansing device shall be chose, and prevent such devices become pollution resource.

Article 77     Lubricant, refrigerant used for equipment shall not pollute the pharmaceutical goods or container. Try best to use edible lubricant or lubricant at comparative level.

Article 78     The ordering, checking and accepting, keeping, maintaining, extending and discarding of mould for manufacturing shall establish corresponding operation procedures. Set special person and special cabinet to maintain the mould and keep related record.

Section 3 Maintaining and Servicing

Article 79     The maintenance and service of equipment shall not influence the product’s quality.

Article 80     Establish the equipment’s defending maintain plan and operation procedures. The maintaining and servicing of equipment shall have corresponding record.

Article 81     The equipment with reconstruction or material maintenance shall make reconfirmation. It could only be used after it is confirmed of according with requirements.

Section 4 Usage and Cleansing

Article 82     Main manufacturing and inspection equipment shall have specific operation procedures.

Article 83     Manufacturing equipment shall use between the confirmed parameter scope.

Article 84     Manufacturing equipment shall clean under the operation procedures with detailed prescription.

Manufacturing equipment’s clean operation procedures shall prescribe detailed and integrated clean method, clean equipment or tool, cleanser’s name and preparation method, the method of wiping the last batch’s marker off, the method of protecting the cleaned equipment out of pollution before used, the longest preserve time limit of cleaned equipment, the method of checking the clean condition of the equipment before used, and let the operator could use the repeated, effective method to clean every kind of equipment.

If the equipment needs to be removed, the order and method of removing equipment shall be prescribed; if the equipment needs to be sanitized or sterilized, the detailed method, disinfector’s name and preparation method of sanitization or sterilization shall be prescribed. If necessary, the allowed longest interval time limit between end of manufacturing and cleaning shall be prescribed.

Article 85     Cleaned manufacturing equipment shall be preserved in clean, dry condition.

Article 86     The equipment and apparatus used for pharmaceutical goods’ manufacturing or inspection shall have using log, the record content includes using, cleaning, maintenance and servicing condition and date, time, the manufactured and inspected pharmaceutical goods’ name, specification and batch number and so on.

Article 87     The manufacturing equipment shall have obvious condition identification which indicates the equipment’s serial number and content (such as name, specification, batch number); if there is no content in the equipment, the clean condition shall be indicated.

Article 88     Unqualified equipment shall move out of manufacturing and quality control area if possible, before moving, obvious condition identification shall have.

Article 89     The main fixing channel shall indicate the content’s name and direction.

Section 5 Adjustment

Article 90     Adjustment and inspection to weighing apparatus, measure, appearance, record and control equipment and apparatus used for manufacturing and inspection shall be done regularly under operation procedures and adjustment plan, and the related records shall be kept. Adjustment’s capacity scope shall cover the actual manufacturing and inspection’s using scope.

Article 91     Ensure the key weighing apparatus, measure, appearance, record and control equipment and apparatus used for manufacturing and inspection shall be adjusted, and the data shall be accurate and credible.

Article 92     Adjustment shall be done by measure standard instrument, and the measure standard instrument shall in accordance with the related state prescription. The adjustment record shall indicate the name, serial number, adjustment period of validity and measure eligible certificate number of the measure standard instrument, which could ensure the record’s traceability.

Article 93     Weighing apparatus, measure, appearance, record and control equipment and apparatus shall have obvious identification, and indicate its adjustment period of validity.

Article 94     Out of adjustment, out of adjustment period of validity, inaccurate weighing apparatus, measure, appearance, record and control equipment and apparatus shall not be used.

Article 95     If an automatic or electron equipment is used during the process of manufacturing, packaging, storage, it shall be regular adjusted and inspected according to operation procedures, to ensure its operation function is normal. Adjustment and inspection shall have corresponding record.

Section 6 Water for Preparation of Pharmaceutical Goods

Article 96     Water used for preparation of pharmaceutical goods shall adapt to its purpose, and in accordance with the quality standard and related requirements of Pharmacopoeia of the Peoples’ Republic of China. Water used for preparation of pharmaceutical goods shall use drinking water at least.

Article 97     The design, installation, function and maintenance of water disposal equipment and its transportation system shall ensure the water used for preparation of pharmaceutical goods achieve the set quality standard. The function of water disposal equipment shall not exceed its designed ability.

Article 98     The material used for purified water, injection water store tin and transportation pipe shall be innocuous, bear corruption; the vents of store tin shall install non-desquamating fibrous remove bacterium colander; the design and installation of pipe shall avoid dead angle, blind pipe.

Article 99     The preparation, storage and distribution of purified water, injection water shall prevent the reproduction of microorganism. Purified water could circle, and injection water could heat preservation circle above70 ℃.

Article 100   The water quality of preparation water and original water shall monitor regularly, and do corresponding record.

Article 101   The pipe of purified water, injection water shall be cleaned and sterilized according to operation procedures, and do corresponding record. If the microorganism pollution of preparation water achieves the alarm limit, deviation rectify limit, disposal shall be done under operation procedures.

 Chapter 6 Material and Product

                   

Section 1 Principle

Article 102   The raw material used for pharmaceutical goods’ manufacturing, wrapper material direct contact with pharmaceutical goods shall in accordance with the quality standard. Printing ink direct printed in pharmaceutical goods shall in accordance with edible standard requirements.

Imported raw material shall in accordance with state related import management rules.

Article 103   Material and product operation procedures shall be constituted, to ensure correct receiving, storage, extending, usage and delivering of material and product, to prevent pollution, cross pollution, confusion and mistake.

Disposal of material and product shall perform in accordance with the operation procedures or technique rules and do corresponding record.

Article 104   The confirmation and changing of material supplier shall take quality evaluation and order after quality management department’s approval.

Article 105   The transportation of material and product shall satisfy quality requirement, if the transportation needs special requirements, the transportation condition shall be confirmed.

Article 106   The receiving of raw material, wrapper and printing wrapper direct contact with pharmaceutical goods shall have operation procedures. All material of goods shall be checked to ensure it is the same with the order form, and ensure the supplier is approved by quality management department.

The outer wrapper of material shall have label and indicate the prescribed information. Cleaning shall be done if necessary. If outer wrapper is damaged or have other problems may influence material quality, report to quality management department and do investigation and record.

Receiving every time shall have record, the content includes the following:

I.            The name of material indicated in the delivering form and packaging container;

II.           Material name and (or) code used in the enterprise;

III.         Receiving date;

IV.         The name of supplier and manufacturer (if different);

V.          The batch number of supplier and manufacturer’s mark (if different);

VI.         Total amount of receiving and quantity of packaging container;

VII.        Designated batch number or running number after receiving by enterprise;

VIII.       Related explanation (i.e. packaging condition).

Article 107   The received material and manufactured finished product shall manage as quarantine, till discharging.

Article 108   The material and product shall store and turnover in order according to its characteristics, its extending and freighting shall in accordance with the principle of early-in-early-out and recent period of validity early out.

Article 109   The material and product managed by computer storage management shall have corresponding operation procedures, to prevent the confusion and mistake bring by system failure, out of service and other special conditions.

If the material and product is identified by complete computer storage management system, the related information may not indicate by written method.

Section 2 Raw Material

Article 110   Corresponding operation procedures shall be constituted, checking or inspection and other appropriate measures shall be done to confirm all raw material in each package is accurate.

Article 111   If material of several batches is received for one time, sampling, inspection, discharging shall be done under batch number.

Article 112   Raw material stored in storage area shall have appropriate mark, and indicate at least the following contents:

I.     The name of designated material and material code in enterprise;

II.    Batch number set when the enterprise receiving the raw material;

III.  Quality condition of raw material (such as under examination, qualified, unqualified, sampling);

IV.  Period of validity or period of double examination.

Article 113   Only the raw material approved by quality management department and within the period of validity or period of double examination could be used.

Article 114   The raw material shall be stored according to period of validity or period of double examination. During the period of validity, if there is special condition which influence the quality, the raw material shall be double examined.

Article 115   Material shall be matched by designated person according to operation procedures. After the material is checked, accurate quantify or measure, and make identification.

Article 116   Each material prepared and its weight or volume shall be double examined by other person independently, and do double examination record.

Article 117   All material used in pharmaceutical goods’ manufacturing in the same batch shall be concentrated stored and make identification.

 Section 3 Semifinished Product and Bulk Product

Article 118   Semifinished product and bulk product shall be stored under appropriate condition.

Article 119   Semifinished product and bulk product shall have obvious identification, and indicate at least the following contents:

I.     The name of product and product code in enterprise;

II.    Batch number of product;

III.  Amount or weight (such as gross weight, net weight and so on);

IV.  Production working procedure (if necessary);

V.   Product’s quality condition (if necessary, such as quarantine, qualified, unqualified, sampling).

Section 4 Wrapper

Article 120   The management and control requirements of the wrapper and printing wrapper contact directly with pharmaceutical goods is the same with the raw material.

Article 121   The wrapper shall be extended by assigned person according to operation procedures, and take measures to avoid confusion and mistake, and ensure the wrapper used for manufacturing pharmaceutical goods is accurate.

Article 122   The operation procedures for printing wrapper’s design, auditing, and approval shall be constituted, to ensure the printed content of printing wrapper is the same with the approved content by pharmaceutical goods’ quality management department, establish special document, keep the original edit sample of approved printing wrapper by execution.

Article 123   When the edition of printing wrapper is changed, measures shall be taken, to ensure the edition used for printing wrapper is accurate. The former printing stencil shall be withdrew, cancelled and destroyed.

Article 124   Special area shall be set for printing wrapper for its appropriate storage. Unauthorized person shall not enter in. Incised label or other bulk printing wrapper shall store in airtight container separately to avoid confusion.

Article 125   Printing wrapper shall be kept by assigned person, and shall be extended according to operation procedures and demanding amount.

Article 126   The wrapper or printing wrapper direct contact with pharmaceutical goods of each batch or extending for each time shall all have identification, which indicate the name and batch number of the used product.

Article 127   Overdue or scrapped printing wrapper shall be destroyed and make records.

Section 5 Finished Product

Article 128   The finished product shall be quarantine storage before discharging.

Article 129   The storage condition for finished product shall in accordance with the requirements of pharmaceutical goods’ registration approval.

Section 6 Material and Product under Special Management

Article 130   The checking and accepting, storage, management of stupefacient, mental pharmaceutical goods, toxicity pharmaceutical goods for medical use (including medicinal materials), radioactivity pharmaceutical goods, chemical material which easy to cause toxicity of pharmaceutical goods species, and flammable, explosive and other dangerous material shall perform the related state prescription.

Section 7 Others

Article 131   Each package container for unqualified material, semifinished product, bulk product and finished product shall have obvious symbol, and keep appropriate storage in isolated area.

Article 132   The disposal of unqualified material, semifinished product, bulk product and finished product shall approved by the director of quality management, and do record.

Article 133   Product’s callback shall be approved in advance, and take sufficient evaluation to the related quality risk, to decide callback or not according to the evaluation decision. Product’s callback shall take according to the scheduled operation procedures, and do corresponding record. The product after callback shall set period of validity according to the production date of the callback products with the earliest batch.

Article 134   The preparation product shall not take renewed process. Generally, unqualified preparation semifinished product, bulk product and finished product shall not come back for manufacturing again. Only when the product does not influence the product’s quality, according to corresponding quality standard, and is in accordance with the scheduled, approved operation procedures and after related risk evaluation, it could be disposed by coming back for manufacturing again. The product of coming back for manufacturing again shall have corresponding record.

Article 135   For the products coming back for manufacturing again or manufactured after callback, the quality management department shall consider to do extra related inspection and stability review.

Article 136   The enterprise shall constitute operation procedures for pharmaceutical goods’ return back, and do corresponding record. The content shall include at least the following: the product’s name, batch number, specification, quantity, unit and address, reason and date, final disposal opinion.

The returned back pharmaceutical goods of same product, same batch number and different channel shall record, store and dispose separately.

Article 137   Only after examination, inspection and investigation, there is evidence proved that the returned back products’ quality does not influenced, and after the evaluation of quality management department according to operation procedures, it is considered to re-packaging, re-delivering and selling the returned back products. The factors of evaluation shall at least include the pharmaceutical goods’ characteristics, the required storage condition, pharmaceutical goods’ current condition, history, and duration between the products’ delivering and returning back. If the returned back products do not accord with the storage and transportation requirements, the products shall be destroyed under the supervision of quality management department. If there is doubt on the quality of the returned back products, re-delivering is not allowed.

If the returned back product is called back, the called back products shall in accordance with the intending quality standard and the requirement of Article 133.

The process and result of returning back shall have corresponding record.

Chapter 7 Confirmation and Validation

                   

Article 138   The enterprise shall confirm the required confirmation and validation work, to prove the key factors of related operation could control effectively. The scope and degree of confirmation and validation shall confirm after risk valuation.

Article 139   The workshop, establishment, equipment and inspection apparatus of enterprise shall be confirmed, and manufacturing, operation and inspection shall be done under validated production technology, operation procedures and inspection method, and keep persistent validation condition.

Article 140   Establish the document and record for confirmation and validation, and the document and record shall prove the following intending aims:

I.     Design confirmation shall prove the design of workshop, establishment, equipment is in accordance with the intending purpose and the requirements of this Regulation;

II.    Installation confirmation shall prove the constructing and installation of workshop, establishment, and equipment is in accordance with designed standard;

III.  Running confirmation shall prove the running of workshop, establishment, equipment is in accordance with designed standard;

IV.  Function confirmation shall prove the workshop, establishment, equipment could persistent according with requirements under normal operation method and technology condition;

V.   Technology validation shall prove the production technology according to prescribed technology parameter could persistent produce the product in accordance with the intending purpose and registered requirements.

Article 141   Before using new production prescription or production technology, validate its applicability of routine production. When the production technology is using the prescribed raw material and equipment, the products in accordance with the intending purpose and registered requirement shall be produced.

Article 142   When the main factors influence the products’ quality, such as raw material, wrapper direct contact with pharmaceutical goods, production equipment, production environment (or workshop), production technology, inspection method are changed, confirmation and validation shall be done. If necessary, approval shall be done by pharmaceutical goods’ supervision management department.

Article 143   The cleansing method shall be validated to approve its cleaning effect, to effective avoid pollution and cross pollution. Cleaning validation shall integrated consider the equipment’s using condition, the cleanser and disinfector under used, sampling method and place and corresponding sampling callback rate, leftover’s property and limit, sensitive rate of leftover’s inspection method and other factors.

Article 144 Confirmation and validation is not a one-off action. After initial confirmation or validation, re-confirmation or re-validation shall be done according to product’s quality review analysis condition. The key production technology and operation procedures shall do re-validation regularly, to ensure achieving intending result.

Article 145   The enterprise shall constitute validation overall plan, indicates the key information of confirmation and validation work in the form of document.

Article 146   Validation overall plan or other related document shall have the prescription to ensure workshop, establishment, equipment, inspection apparatus, production technology, operation procedures and inspection method could keep persistent stability.

Article 147   Establish confirmation or validation scheme according to the object of confirmation or validation, and the scheme shall be audited, approved. Confirmation or validation scheme shall have specific responsibility.

Article 148   Confirmation or validation shall perform under the in advance confirmed and approved scheme, and do record. After the confirmation or validation work is finished, write the report, and the work shall be audited, approved. The result and conclusion of confirmation or validation (including evaluation and suggestion) shall be recorded and keep in file.

Article 149   Technology procedure and operation procedures shall be confirmed according to validated result.

Chapter 8 Document Management

                   

Section 1 Principle

Article 150   Document is the basic factor of quality guarantee system. The enterprise must have written quality standard, production prescription and technology procedure, operation procedures and record and other documents with accurate content.

Article 151   The enterprise shall constitute the operation procedures of document management, systemic design, constitute, audit, approve and extending document. The document related to this Regulation shall audit by quality management department.

Article 152 The document’s content shall be the same with the requirements of pharmaceutical goods’ manufacturing permission, pharmaceutical goods’ registration, and help to carry up history condition of products for each batch.

Article 153   Document’s drafting, editing, auditing, approving, replacing or removing, reproduction, keeping and destroying shall manage according to operation procedures, and have corresponding record for document’s distribution, removing, reproduction, and destroying.

Article 154   Document’s drafting, editing, auditing, approving shall execute by appropriate person and indicate the execution date.

Article 155   The document shall indicate title, variety, purpose, and document number and edition number. The characters in the document shall be accurate, clear, understandability, and not on the line.

Article 156   The document shall be stored according to category and have clear consecution, and easy to consult.

Article 157   When reproduction the original document, no mistake could be made; reproduced document shall be clear and easy to be read.

Article 158   The document shall be regular audited, edited; after the document is edited, it shall be managed according to the related regulation, to prevent misusage of former document. The distributing, using document shall be the approved document at current edition. The removed or former edition document could only appear in working locale as keeping file for future reference.

Article 159   Each activity related to this Regulation shall be recorded, to ensure the activities of product’s manufacturing, quality control and quality guarantee could be carried up. The record shall remain enough blank for filling data. The record shall be filled in time, have true content, clear handwriting, easy to read, and not easy to erase.

Article 160   Use auto printing record, a collection of illustrative plates and graph and etc of manufacturing and inspection equipment, and indicate the information of product or sample’s name, batch number and record the equipment’s information, the operator shall indicate his name and date.

Article 161   The record shall keep clean, shall not tear to shreds and altered. Any changes of the record shall indicate name and date, and keep original information clean, if necessary, indicate the reason for changing. If the record shall be copies out again, the original record shall not be tore to shreds, and shall be kept as the annex of the copied out record.

Article 162   Each batch of pharmaceutical goods shall have batch record, including batch production record, batch packaging record, batch inspection record and pharmaceutical goods discharging audit record, and other record related to the batch of products. The batch records shall be managed by quality management department, keep at least one year after the pharmaceutical goods’ period of validity.

Quality standard, technology procedure, operation procedures, stability review, confirmation, validation, changing and other important document shall keep for a long time.

 

Article 163   If electric data processing system, picture taking technique or other credible method is used for recording data information, system’s operation procedures shall have; accuracy of the record shall be checked.

If electric data processing system is used, only authorized person could input or change data, the change and delete condition shall have records; the system’s logging in shall be controlled by the way of inputting password or other methods; after inputting key data, it shall be double examined by other person independently.

For the batch record stored by electric method, shall copy by the way of magnetic tape, microfilm, paper duplicate or other methods, to ensure the safety of the record, and let the data could be convenient to review during the preservation period.

Section 2    Quality Control

Article 164   The material and finished product shall have approved current quality standard; if necessary, semifinished product or bulk product shall also have quality standard.

Article 165   Material’s quality standard often includes the following:

I.     Basic information of material:

1.    Enterprisedesignated material’s name and inner used material’s code;

2.    Gist of quality standard;

3.    Approved supplier;

4.    Actual sample or sample manuscript of printing wrapper.

II.    Sampling, inspection method or related operation procedures’ serial number;

III.  Limit requirements for determination of property and quantity;

IV.  Storage condition and notice items;

V.   Period of validity or period of double examination.

Article 166   Outsourcing or export semifinished product and bulk product shall have quality standard; if the inspection result of semifinished product is used for finished product’s quality evaluation, semifinished product’s quality standard corresponding to finished product’s quality standard shall be constituted.

Article 167   Finished product’s quality standard shall include the following:

I.     Product’s name and product’s code;

II.    Corresponding product prescription serial number (if any);

III.  Product’s specification and package’s style;

IV.  Sampling, inspection method or related operation procedures’ serial number;

V.   Limit requirements for determination of property and quantity;

VI.  Storage condition and notice items;

VII. Period of validity.

Section 3 Technology Procedure

Article 168   Each manufacturing batch of each kind of pharmaceutical goods shall has its technology procedure approved by enterprise. Each kind of packaging style of different pharmaceutical good’s specification shall have its own package operation requirements. Technology procedure’ constitution shall base on the registered approving craft.

Article 169   Technology procedure shall not change at will. If it needs to be changed, edit, audit, approval shall be done according to related operation procedures.

Article 170   The content of preparation’s technology procedure shall include at least the following:

I.     Manufacturing prescription:

1.    Product’s name and product’s code;

2.    Product’s type, specification and batch;

3.    List of used raw material (including the material used in manufacturing process, but not appeared in the finished product), indicate each material’s designated name, code and dosage; if the dosage of raw material needs to convert, calculate method shall be indicated.

II.    Manufacturing operation requirements:

1.    Explanation to manufacturing place and used equipment (such as the place and serial number of the operation room, the level of cleaning level, required requirements to temperature and humidity, the type and serial number of equipment, and so on);

2.    The method of preparing key equipment (such as cleaning, assembling, adjustment, sterilization, and so on) or corresponding operation procedures’ serial number;

3.    Detailed manufacturing procedure and explanation of craft parameter (such as checking, pretreatment of material, order of adding material, mixing time, temperature, and so on);

4.    Method and standard of all middle control;

5.    Limit of expected ultimately output, if necessary, indicate the limit of semifinished product’s output, and the calculating method and reconciliation of inventory limit;

6.    Storage requirement of bulk product, including container, label and special storage condition;

7.    Notice items shall be indicated.

III.  Package operation requirements:

1.    Package type indicated by the amount, weight or volume of products in ultimately packaged container;

2.    Full list of all required wrapper material, including the name, amount, specification, type of wrapper and the code of each wrapper related to quality standard;

3.    Actual sample or duplicate of printing wrapper, and indicate the printing place of product’s batch number, period of validity;

4.    Notice items needs to be indicated, including the examination done to manufacturing area and equipment, confirmation of the package manufacturing line’s clear work has been done before the package operation is begin, and so on;

5.    Package operation procedures’s indication, including the important assistant operation and notice items of using equipment, checking of used wrapper;

6.    Detailed operation of middle control, including sample method and standard;

7.    The calculating method and reconciliation of inventory limit of bulk product, printing wrapper.

Section 4 Batch Production Record

Article 171   Each batch of product shall have corresponding batch production record, which could trace this batch of products’ manufacturing history and related information of quality.

Article 172   Batch production record shall be done according to related content to current approved technology procedure. When design the form of record, shall avoid appearing filling mistake. Each page of batch production record shall indicate product’s name, specification and batch number.

Article 173   Original blank batch production record shall be audited and approved by the director of manufacturing management and the director of quality management. The duplicate and extending of batch production record shall control and record according to operation procedures. Manufacturing of each batch of products shall only extend one copy of the original blank batch production record.

Article 174   During manufacturing, each operation shall be recorded in time, when the operation has done, manufacturing operator shall confirm and execute his name and date.

Article 175   The content of batch production record shall include the following:

I.            The product’s name, specification, batch number;

II.           Beginning, ending date and time of manufacturing and middle procedure;

III.         Signatures of directors in each manufacturing procedure;

IV.         Signature of manufacturing procedure operator; if necessary, signature of operation (i.e. metage) double examined person shall have;

V.          Batch number of each raw material and actual amount (including the batch number and amount of the products devoted for callback or renew disposal);

VI.         Related manufacturing operation or activity, technology parameter and control scope, and the serial number of main manufacturing equipment;

VII.        Record of middle control’s result and signature of operator;

VIII.       Output in different manufacturing procedure and calculating of reconciliation of inventory when necessary;

IX.         Record to special problems or abnormity affairs, including detail indication or research report to the windage condition of departure technology procedure, and approved by execution.

Section 5 Batch Package Record

Article 176   Package of each batch of products or part of products in each batch of products shall have batch package record, to trace this batch of products’ package operation and related information of quality.

Article 177   Batch package record shall be done according to the content related to package in technology procedure. When design the form of record, shall avoid appearing filling mistake. Each page of batch production record shall indicate wrapped product’s name, specification and batch number.

Article 178   Batch package record shall indicate the bulk product’s batch number, amount and finished product’s batch number and projected amount. The requirement of auditing, approving and extending the original blank batch package record is the same with the requirement of original blank batch production record.

Article 179   During packaging, each operation shall be recorded in time, when the operation has done, packaging operator shall confirm and execute his name and date.

 

Article 180   The content of batch packaging record shall include the following:

I.            The product’s name, specification, package type, batch number, date of production, and period of validity;

II.           Package operation date and time;

III.         Signatures of director of packaging operator;

IV.         Signature of packaging procedure operator;

V.          Name, batch number of each wrapper and actual amount;

VI.         Inspection record done according to technology procedure, including middle control result;

VII.        Detailed information of package operation, including the serial number of used equipment and package manufacturing line;

VIII.       Actual sample of printed wrapper, and print batch number, period of validity and other printing content; the printing wrapper hard to keep file with batch package record could printing the duplicate of the above said content;

IX.         Record to special problems or abnormity affairs, including detail indication or research report to the windage condition of departure technology procedure, and approved by execution;

X.          Name, code of all printing wrapper and bulk product, and amount of extending, using, destroying or withdrawing product, actual output and inspection of reconciliation of inventory.

Section 6 Operation procedures and Record

Article 181   The content of operation procedures shall include the following: title, serial number, version number, issued department, effective date, distributing department and signatures of constitutor, auditor, authorized person and indicate the date, heading, text and changing history.

Article 182   Workshop, equipment, material, document and record shall have serial number (or code), the operation procedures of serial number (or code) shall be set up, to ensure the serial number (or code) is exclusive.

Article 183   The following activities shall also have corresponding operation procedures, and its process and result shall have records:

I.            Confirmation and validation;

II.           Installation and adjustment of equipment;

III.         Maintenance, cleaning and sterilization of workshop and equipment;

IV.         Training, changing clothes and sanitation and other matters related to person;

V.          Environment monitor;

VI.         Insect pest control;

VII.        Alteration control;

VIII.       Windage disposal;

IX.         Complaint;

X.          Recall of pharmaceutical goods;

XI.         Withdraw of pharmaceutical goods.

Chapter 9 Manufacturing Management

                   

Section 1 Principle

Article 184   All pharmaceutical goods’ manufacturing and package shall operate and record according to standard technology procedure and operation procedures, to ensure the pharmaceutical goods’ quality standard, and achieve pharmaceutical goods’ manufacturing admission and registration approved requirements.

Article 185   Operation procedures of dividing products’ manufacturing batch shall be set up. Dividing of products’ manufacturing batch shall have the ability to ensure the quality and characteristic of products in one batch are the same.

Article 186   Operation procedures of setting pharmaceutical goods’ batch number and confirming manufacturing date shall be set up. Each batch of pharmaceutical goods shall be set with exclusive batch number. Except legal requirements, manufacturing date shall not be later than the beginning date of mixing operation of product moulding or fill installing (enveloping), and shall not take product’s package date as the manufacturing date.

Article 187   Output and reconciliation of inventory of each batch of product shall be checked, to ensure the reconciliation of inventory is in accordance with the set limit. If there is diversity, find out the reason, only after confirmation of no potential quality risk, they could be disposed as normal products.

Article 188   Pharmaceutical products of different variety and specification could not manufacture in the same manufacturing operation room, unless there is no possibility of confusion or cross pollution.

Article189   In every stage of manufacturing, product and material shall be protected to avoid microorganism and other pollution.

Article 190   During the process of manufacturing dry material or product, especially high activity, high toxic or high sensitive material or product, special measures shall be taken, to avoid bringing and diffusing of powder.

Article 191   Container and main equipment, essential operation room used for all material, semifinished product or bulk product during the manufacturing process shall mark label or indicate the name, specification and batch number of the manufactured product or material in other way, if necessary, manufacturing procedure shall also be indicated.

Article 192   Mark used for container, equipment or establishment shall obvious and clear, the format of mark shall approved by related department of the enterprise. Except words explanation could use in the mark, different color could also be used to distinguish the condition of the marked object (such as quarantine, qualified, unqualified or cleaned, and so on).

Article 193   When the product is transporting from one area to another area, the connection between the pipe and other equipment shall be checked, to ensure the connection is accurate.

Article 194   The area shall be cleared after each manufacturing is end, to ensure no material, product and document related to the manufacturing has left in the equipment and working place. Before the beginning of the next manufacturing, the area shall be confirmed again.

Article 195   Avoid any windage of departing technology procedure or operation procedures at the maximum. If any windage appears, perform according to windage disposal operation procedures.

Article 196   Only authorized person could come in and out of the manufacturing workshop.

Section 2 Avoid Pollution and Cross Pollution during Manufacturing Process

Article 197   Take the following measures in manufacturing process to avoid pollution and cross pollution at maximum:

I.            Manufacture pharmaceutical goods of different variety in isolated area;

II.           Take phase manufacturing method;

III.         Set essential air lock and ventilator; press difference control shall be taken in areas with different air cleaning level;

IV.         Reduce the risk of air not disposed or fully disposed entering manufacturing area to cause pollution;

V.          In the manufacturing area which is easy to cross pollute, the operator shall dress special exposure suit in this area;

VI.         Clean the equipment with validated or the effective cleaning and wiping pollution off operation procedures; if necessary, test the leftover in the surface of equipment which direct contact with material;

VII.        Manufacture by airtight system;

VIII.       Intake of dry equipment shall have inhaler, outtake shall have the equipment of preventing air flow backwards;

IX.         Fragile, debris removal, easy to be mouldy apparatus shall avoid to use in manufacturing and cleaning process; when using screen net, take measures to prevent the pollution bringing from the rupture of screen net;

X.          The preparation, filtration, fill envelop, sterilization and other procedure of liquid preparation shall finish in prescribed time;

XI.         Semifinished products of semisolid preparation, such as ointment, cream, jellies and so on and suppository shall prescribe storage period and storage condition.

Article 198   Take regular examination to the measures of preventing pollution and cross pollution and evaluate its applicability and validity.

Section 3 Manufacturing Operation

Article 199   Before the manufacturing is begin, do examination to ensure no product, document and material irrespective to the manufacturing this time has left in the equipment and working place, the equipment is in the cleaned and under used condition. The result of examination shall be recorded.

Before manufacturing operation, the name, code, batch number and mark of material or semifinished product shall be checked to ensure the material or semifinished product used in manufacturing are correct and in accordance with requirements.

Article 200   Middle control and essential environment monitor shall be taken, and take record.

Article 201   The area must be cleared by manufacturing operator after each manufacturing stage of each batch of products is finished, and fill in clear record. The content of clear record includes the following: serial number of operation room, name of the product, batch number, manufacturing procedure, area clearing date, inspection items and result, signatures of director of are clearing and double examined person. Clear record shall bring into batch production record.

Section 4 Package Operation

Article 202   Package operation procedures shall prescribe the measures of reducing the risk of pollution and cross pollution, confusion or mistake.

Article 203   Examination shall be done before the package operation is begin, to ensure working place, package manufacturing line, imprinter and other equipment are in the cleaned or under used condition, there is no product, document or material irrespective to the manufacturing this time has left. The result of examination shall be recorded.

Article 204   Before the package operation is begin, check the wrapper are accurate, check the name, specification, quantity, quality condition of bulk product and the used wrapper, and confirm it is in accordance with the technology procedure.

Article205   In each package operation room or package manufacturing line, product’s name, specification, batch number and batch manufacturing condition shall be indicated in the mark.

Article 206   If there are several packaging lines package at the same time, isolate or take other measures to effective prevent pollution, cross pollution or confusion.

Article 207   The under used load container shall keep clean before loading to prevent there is glass chipping, metal grain and other infectant in the container.

Article 208   Labels shall be marked in time after the product is loaded, enveloped. If labels are not marked in time, operate according to related operation procedures to prevent the mistake of confusion or mislabel.

Article 209   The information of separate printing or online printing during packaging process (i.e. product batch number or period of validity) shall be checked, to ensure it is accurate, and take record. If the information is printed by hand, add the frequency of check.

Article 210   If incision label or separate printing labels outside the package line are used, take special measures to prevent confusion.

Article 211   Check the function of electric code reading machine, label arithmometer or other similar equipments to ensure it could run correctly. Take record to the check.

Article 212   Printing or mould pressing content in the wrapper should be clear, hard to fade and erase.

Article213   In the manufacturing process, product’s middle control examination shall at least include the following:

I.     Appearance of package;

II.    Integrity of package;

III.  Accuracy of product and wrapper;

IV.  Accuracy of printing information;

V.   Whether the function of online monitor equipment is normal.

Sample shall not return after taking away from package manufacturing line, to avoid product’s confusion or pollution.

Article 214   If the product needs to re-package due to abnormal condition in package process, special inspection, research and designated person’s approval shall be done. Detail record shall be done to re-package.

Article215   In reconciliation of inventory inspection, if the amount of bulk product, printing wrapper and finished product has obvious difference, investigation shall be done, the finished product shall not be discharged before conclusion is taken.

Article 216   When the package is done, the remained wrapper with printed batch number shall be counted and destroyed by special person, and take the record. If the printing wrapper with no printed batch number is returned to the storage, perform according to operation procedures.

Chapter 10 Quality Control and Quality Guarantee

                   

Section 1 Quality Control Laboratory Management

Article 217   The person, establishment, equipment in quality control laboratory shall accommodate with the product’s characteristic and manufacturing scope.

Generally, the enterprise shall not consign other’s to check, if consigned check is necessary, the enterprise shall consign exterior laboratory to check according to the prescription of consigned check in Chapter 11, and explanation shall be made in check report.

Article 218   Director of quality control shall have enough qualification and experience of managing laboratory, and could manage one or more laboratories in one enterprise.

Article 219   Inspection person of quality control laboratory shall have education background of technical secondary school with related specialty or senior high school, and have experienced and passed the examination of practice training related to inspection operation.

Article 220   Quality control laboratory shall equipped with Pharmacopoeia, standard illustrative plates collection and necessary reference books, and standard objects or contrast objects and other related standard matter.

Article 221   The document of quality control laboratory shall in accordance with the principle of Chapter 8, and in accordance with the following requirements:

I.     Quality control laboratory shall at least have the following detailed documents:

1.    Quality standard;

2.    Sampling operation procedures and record;

3.    Inspection operation procedures and record (including inspection record or laboratory working memo);

4.    Inspection report or certificate;

5.    Essential environment monitor operation procedures, record and report;

6.    Essential inspection method validation report and record;

7.    Apparatus adjustment and equipment’s usage, cleaning, maintenance operation procedures and record.

II.    Each batch of products’ inspection record shall include the quality inspection record to semifinished product, bulk product and finished product, in order to trace the related quality inspection information of this batch of products;

III.  Keep certain data (i.e. inspection data, environment monitor data, microorganism in water used for pharmacy monitor data) by the method of easy to do direction analysis;

IV.  Except the related data of batch record, other source material or record shall also be kept to review.

Article 222   Sampling shall in accordance with at least the following requirements:

I.     Person in quality management department could enter in manufacturing area and storage area to take sampling and inspection;

II.    Sampling shall in accordance with the approved operation procedures, and the operation procedures shall detailed prescribe the following:

1.    Authorized sampling person;

2.    Sampling method;

3.    Used apparatus;

4.    Quantity of samples;

5.    Method of dividing samples;

6.    Type and condition of sample stored container;

7.    Disposal and mark of remain part after sampling and samples;

8.    Notice items of sampling, includes the prevention measures taken to reduce all kinds of risks produced in sampling process, especially the sampling of asepsis or baleful material, and notice items to prevent pollution and cross pollution during sampling process;

9.    Storage condition;

10.  Cleaning method and storage requirements of sampling apparatus.

III.  The method of sampling shall scientific and reasonable to ensure the sample is representative;

IV.  The reserved sample shall be able to represent the sampled batch of products or material, it is also possible to take out other samples to monitor the most important tache (i.e. the beginning or ending or the manufacturing) of manufacturing;

V.   Sample’s container shall mark with label, which indicates the sample’s name, batch number, sampling date, take from which package container, person of sampling and other information;

VI.  Samples shall be kept according to prescribed storage requirements.

Article 223   Inspection to material and products in different manufacturing levels shall in accordance with at least the following requirements:

I.            The enterprise shall ensure the pharmaceutical goods are inspected completely under the registered approved method;

II.           Inspection method shall be validated if there is one case of the following:

1.           New inspection method is used;

2.           Inspection method shall have changes;

3.           Use the inspection method which is not recorded in Pharmacopoeia of the Peoples’ Republic of China or other legal standard;

4.           Inspection method needs to be validated prescribed by this Regulation.

III.         For the inspection method does not need to validate, the enterprise shall confirm the inspection method to ensure the inspection data is accurate and credible;

IV.         Inspection shall have written operation procedures which prescribe the method, apparatus and equipment, the content of inspection operation procedures shall be the same with the confirmed or validated inspection method;

V.          Inspection shall have the traceable record and shall be double examined, to ensure the result is the same with the record. All calculation shall have strict check;

VI.         Inspection record shall include at least the following contents:

1.           Product or material’s name, type of preparation, specification, batch number or goods’ supplying batch number, if necessary, indicate the name or resource of supplier and manufacturer (if different);

2.           Quality standard and inspection operation procedures based on;

3.           The type and serial number of apparatus or equipment used for inspection;

4.           Confecting serial number of test solution and culture medium used for inspection, resource and serial number of contrast object or standard object;

5.           Related information of animal used for inspection;

6.           Inspection process, including the preparation of contrast liquid, each detailed inspection operation, essential environment temperature and humidity;

7.           Inspection result, including the observed information, calculation and illustrative plates collection or graph, and the serial number of the inspection report based on;

8.           Inspection date;

9.           Signature and date of inspection person;

10.         Signature and date of double examined person for inspection, calculation.

VII.        All middle control (including middle control take by manufacture person) shall be done under the method approved by quality management department, the inspection shall take record;

VIII.       Quality inspection shall be done to the glass apparatus, reagent, test solution, contrast object and culture medium used for laboratory capability analysis;

IX.         Experiment animal used for inspection shall be inspected or isolated quarantine before use when necessary. The animal’s breeding and management shall in accordance with the related prescription of experiment animal management. The animal shall be marked, and the used history record shall be kept.

Article 224   Quality control laboratory shall set up inspection result of criteria exceeding operation procedures. Any criteria exceeding inspection result must inspect completely according to operation procedures, and take corresponding record.

Article 225   The material, samples of products kept according to enterprise’s prescription, used for tracing pharmaceutical goods’ quality or investigation are reserved samples. The samples used for products’ stability review are not reserved samples.

Reserved samples shall in accordance with at least the following requirements:

I.     Management to reserved samples according to operation procedures;

II.    Reserved samples could represent the sampled batch of material or product;

III.  Reserved samples of finished products:

1.    Each batch of products shall have reserved samples; if one batch of products is packaged for several times, reserve one finished product of smallest commercial package for each package at least;

2.    Package of reserved samples shall be the same with the package of pharmaceutical goods in commercial, if the reserved samples of original pharmaceutical goods could not use the package in commercial, simulated package could be used;

3.    Amount of reserved samples for each batch of products shall ensure two times’ full examination of registered and approved quality standard at least (except asepsis inspection and pyrogen inspection);

4.    At least one time visual inspection per year shall be done to reserved samples during storage period if it does not influence reserved samples’ package, if there is abnormity, completely investigation shall be done and shall take corresponding measures;

5.    Review to reserved samples shall take record;

6.    Reserved samples shall store under the registered storage condition for at least one year after the period of validity of pharmaceutical goods;

7.    If the enterprise stop manufacturing the pharmaceutical goods or is closed, the reserved samples shall deliver to authorized unit for storage, and inform the local pharmaceutical goods’ supervision management department, so that the reserved samples could be got when necessary.

IV.  Reserved samples of material:

1.    Each batch of raw material used for preparation manufacturing and wrapper directly contact with pharmaceutical goods shall have reserved samples. If the finished products have already have reserved samples, the wrapper directly contact with pharmaceutical goods (i.e. infusion bottle) may not have reserved samples separately;

2.    Amount of material’s reserved samples shall at least satisfy the requirements of distinguishing;

3.    Except the raw material with worse stability, the reserved samples of raw material used for preparation manufacturing (excluding the impregnant, gas or pharmacy water used in manufacturing process) and wrapper directly contact with pharmaceutical goods shall store at least two years after the products’ discharging. If the material’s period of validity is short, the time for storing reserved samples could corresponding shorten;

4.    Material’s reserved samples shall store according to the prescribed condition, and shall appropriate airproof it when necessary.

Article 226   Management of reagent, test solution, nutrient medium and certified bacterium shall in accordance with at least the following requirements:

I.     Reagent and nutrient medium shall order from credible supplier, if necessary, the supplier shall be evaluated;

II.    Record of receiving reagent, test solution, nutrient medium shall have, if necessary, receiving date of reagent, test solution, nutrient medium shall be indicated on the container;

III.  Reagent, test solution and nutrient medium shall prepare, stored and used according to related prescription or using instruction. In special cases, before receiving or using, distinguish or other inspection shall be done to the reagent;

IV.  Reagent and prepared nutrient medium shall indicate preparation batch number, preparation date and preparation person’s name, and have preparation (including sterilization) record. Unstable reagent, test solution and nutrient medium shall indicate the period of validity and special storage condition. Standardized solution, volumetric solution shall indicate the last standardized date and adjustment gene, and have standardized record;

V.   Prepared nutrient medium shall take applicable examination, and take corresponding record. Nutrient medium shall have using record;

VI.  Inspect all required certified bacterium, and set up certified bacterium’s storage, passage, usage, destroying operation procedures and corresponding record;

VII. Certified bacterium shall have appropriate mark, its content shall include at least the name of bacterium, serial number, passage number, passage date, passage operator;

VIII.Certified bacterium shall be stored according to prescribed condition, the method and time of storage shall not have bad influence to the develop characteristics of certified bacterium.

Article 227   Management of standard objects or contrast objects shall in accordance with at least the following requirements:

I.     Standard objects or contrast objects shall store and use in accordance with the prescription;

II.    Standard objects or contrast objects shall have appropriate mark, the content shall at least include name, batch number, preparation date (if any), period of validity (if any), initial opening date, content or titer, storage condition;

III.  If the enterprise needs to prepare working standard objects or contrast objects itself, it shall set up the quality standard of working standard objects or contrast objects and preparation, distinguish, inspection, approval and storage operation procedures, each batch of working standard objects or contrast objects shall standardize using legal standard objects or contrast objects, and confirm the period of validity, and prove working standard objects or contrast objects’ titer or content stay stable during the period of validity by regular standardize. The process and result of standardize shall have corresponding record.

Section 2 Discharging of Material and Product

Article 228   Set up the operation procedures of material and product discharging separately, specific indicate the standard, responsibility of approving discharging, and take corresponding record.

Article 229   Discharging of material shall in accordance with at least the following requirements:

I.    Material’s quality evaluation content shall at least include manufacturer’s inspection report, examination condition and inspection result on integrality and airtightness of material’s package;

II.   Material’s quality evaluation shall have specific conclusion, such as approve to discharge, unqualified or other decision;

III. Material’s discharging shall approve by designated person’s signature.

Article 230   Discharging of product shall in accordance with at least the following requirements:

I.    Before approving of discharging, each batch of products shall take quality evaluation, to ensure the pharmaceutical goods and its manufacturing are in accordance with the requirements of registration and this Regulation, and confirm the following contents:

1.   Validation of main production technology and inspection method;

2.   All necessary examination, inspection shall be finished, and compositive consider the actual manufacturing condition and manufacturing record;

3.   All necessary manufacturing and quality control are all finished and signed by related directors;

4.   Modification has finished according to related prescription, the modification needs the approval of pharmaceutical goods’ supervision management department has been approved;

5.   Modification or windage have finished all necessary sampling, examination, inspection and auditing;

6.   All windage related to the batch of products halve specific explanation or indication, or have completely investigated and appropriately disposed; if windage involves other batches of products, the products shall be disposed together.

II.   Material’s quality evaluation shall have specific conclusion, such as approve to discharge, unqualified or other decision;

III. Each batch of products’ discharging shall approve by quality authorized person’s signature.

IV. Before the discharging of vaccine goods, blood goods, diagnose reagent in vitro used for blood origin screening and other biology goods prescribed by state food and drug administration, qualified certificate shall be issued.

 

Section 3 Persistent Stability Review

Article 231   The purpose of persistent stability review is to monitor the quality of pharmaceutical goods come into market during the period of validity, to find pharmaceutical goods’ stability problems related to manufacture (i.e. the change of impurity content or dissolution characteristic), and confirm the pharmaceutical goods could stored in the indicated storage condition, and in accordance with all requirements of quality standard.

Article 232   Persistent stability review mainly aims to package pharmaceutical goods in commercial, and shall also aim to bulk product. For example, before the bulk product finishes packaging, or there is a long time for storage from manufacturing factory to packaging factory, the influence to package product’s stability in corresponding environment condition shall be evaluated. In addition, the semifinished product with longer storage time shall also be reviewed.

Article 233   Persistent stability review shall have review scheme, the result shall have report. The equipment used for persistent stability review (especially the equipment or establishment for stability test) shall confirm and maintain according to the requirements in Chapter 7 and Chapter 5.

Article 234   The time of persistent stability review shall cover the period of validity of pharmaceutical goods, the review scheme shall include at least the following contents:

I.     Each specification, each manufacturing batch pharmaceutical goods’ review batch number;

II.    Related physics, chemistry, microorganism and biology inspection method, special inspection method of persistent stability review could be used;

III.  Gist of inspection method;

IV.  Qualified standard;

V.   Description of container airproof system;

VI.  Examination interval time (test time point);

VII. Storage condition (persistent stability test standard condition prescribed by Pharmacopoeia of the Peoples’ Republic of China corresponding to pharmaceutical goods’ marked storage condition shall be used);

VIII.Inspection items, if the test items are less than the items of finished products’ quality standard, reasons shall be indicated.

Article 235   Review batch number and test frequency shall get enough data for direction analysis. In general, for the pharmaceutical goods of each specification, each kind of inner package, one batch review shall be done for at least per year, unless the products are not manufactured this year.

Article 236   Sometimes, persistent stability review shall add additional batch number, the pharmaceutical goods of important changes or manufacturing and packaging have important windage shall be listed into stability review. In addition, the batch of renew, come back or callback shall also be listed into review, unless the products have already been validated and stability review.

Article 237   Key person, especially quality authorized person, shall know the result of persistent stability review. When the persistent stability review is not doing in the manufacturing enterprise of bulk product and finished product, related parties shall have written agreement, and shall keep the result of persistent stability review for examination of pharmaceutical goods’ supervision management department.

Article 238   The result falls short of quality standard or has important abnormity direction shall be investigated. For any confirmed unqualified result to quality standard or important bad direction, the enterprise shall consider whether it influences to pharmaceutical goods in commercial, recall shall be done when necessary, investigated result and measures taken shall report to local pharmaceutical goods’ supervision management department.

Article 239   Summarize report shall be made according to the entire data information, including the stage conclusion of review, and shall be kept. Summarize report shall be regular audited.

Section 4 Change Control

Article 240   Enterpriseshall set up change control system to evaluate and manage the changes influence to products’ quality. The change needs pharmaceutical goods’ supervision management department’s approval shall perform after approving.

Article 241   Operation procedures shall be set up, which to prescribe the change of application, evaluation, auditing, approval and performance of raw material, wrapper, quality standard, inspection method, operation procedures, workshop, establishment, equipment, apparatus, production technology and computer software. Quality management department shall designate special person to take charge of changing control.

Article 242   Changes shall evaluate its potential influence to products.Enterprisecould classify the changes (such as main change, minor changes) according to changes’ characteristic, scope, degree of potential influence to products’ quality. The required validation, additional inspection and stability review for judgment to changes shall base on science.

Article 243   After the changes related to products’ quality is brought forward by application department, evaluation, performance scheme and specific performance responsibility shall be confirmed, and finally audited and approved by quality management department. Performance of changes shall have corresponding complete record.

Article 244   When the raw material, wrapper directly contact with pharmaceutical goods, production technology, main manufacturing equipment and other main factors influence pharmaceutical goods’ quality is changed, at least three batches of pharmaceutical goods’ quality after the performance of changing shall be evaluated. If the changes may influence the period of validity of pharmaceutical goods, quality evaluation shall include the persistent review of the pharmaceutical goods manufactured after the performance of changing.

Article 245   When the changes are performing, ensure the documents related to changes have already been edited.

Article 246   Quality management department shall keep all documents and records of changing.

Section 5 Windage Disposal

Article 247   Director of each department shall ensure all people perform production technology, quality standard, inspection method and operation procedures correctly, in order to avoid windage.

Article 248   Enterpriseshall set up windage disposal operation procedures, prescribe windage’s report, record, investigation, disposal and correct measures taken, and have corresponding record.

Article 249   Any windage shall evaluate its potential influence to products’ quality.Enterprisecould classify the windage (such as important windage, minor windage) according to windage’s characteristic, scope, degree of potential influence to products’ quality. Evaluation to important windage shall also consider whether additional inspection to products is needed and whether it influences the pharmaceutical goods’ period of validity, when necessary, stability review shall be done to important windage products.

Article 250   Any windage production technology, reconciliation of inventory limit, quality standard, inspection method, operation procedures and so on shall take record, and report to director and quality management department, the record shall have clear explanation, important windage shall completely investigate by quality management department and other departments, investigation report shall be issued. Windage investigation report shall be audited and executed by designated person of quality management department.

Enterprise shall take prevention measures to effective prevent similar windage happening again.

Article 251   Quality management department shall be responsible for windage’s classification, keep the documents and records of windage investigation, disposal.

Section 6 Correction Measures and Prevention Measures

Article 252   Enterpriseshall set up correction measures and prevention measures system, to investigate and take correction and prevention measures to complaint, recall, windage, self-test or exterior examination result, technology performance and quality monitor direction and so on. The depth and form of investigation shall accommodate with the level of risk. Correction measures and prevention measures system shall enhance the understanding to product and technology, improve product and technology.

Article 253   Enterpriseshall set up correction and prevention measures operation procedures, the content shall include at least the following:

I.     Analyze to complaint, recall, windage, self-test or exterior examination result, technology performance and quality monitor direction and quality data from other resources to confirm the existent and potential quality problems. If necessary, take appropriate statistic method;

II.    Investigate the related reasons to product, technology and quality guarantee system;

III.  Confirm the required correction and prevention measures to prevent the problem happening again;

IV.  Evaluate the rationality, validity and sufficiency of correction and prevention measures;

V.   All changes happened in correction and prevention measures shall be recorded;

VI.  Ensure the related information have transferred to quality authorized person and direct principal preventing the problems happening again;

VII. Ensure the related information and correction and prevention measures have passed the approval by senior administrator.

Article 254   Correction and prevention measures’ performance shall have document record, and shall keep by quality management department.

Section 7 Supplier’s Evaluation and Approval

Article 255   Quality management department shall take quality evaluation to the supplier manufacturing material. Quality management department and related department shall take locale quality audit to the quality system of the main material supplier (especially the manufacturer), and take veto power to unqualified supplier.

The confirmation of main material shall compositive consider the manufactured pharmaceutical goods’ quality risk, material dosage and influence degree from material to pharmaceutical goods’ quality and other factors.

Legal representative of enterprise, director of enterprise and person in other department could not interfere or disturb the quality management department take quality evaluation independently to material supplier.

Article 256   Material supplier evaluation and approval operation procedures shall be set up, to definite the supplier’s qualification, principle of choosing, quality evaluation method, evaluation standard, and material supplier approval procedures.

If quality evaluation takes locale quality audit method, audit content, period, group and qualification of audit person shall be indicated. If trial production of sample small lot production shall be done, manufacturing batch, production technology, product quality standard, stability review scheme shall also be indicated.

Article 257   Quality management department shall designate special person to be responsible for material supplier’s quality evaluation and locale quality auditing, distributing the list of approved qualified suppliers. The designated person shall have knowledge on related codes and specialty, and have enough practice experience of quality evaluation and locale quality auditing.

Article 258   Locale quality audit shall verify the accuracy of supplier’s qualification approving documents and inspection reports, verify whether the supplier have the condition of inspection. Supplier’s personnel institution, workshop establishment and equipment, material management, production technology process and manufacturing management, equipment, apparatus, and document management of quality control laboratory shall be checked, in order to completely evaluate its quality guarantee system. Locale quality audit shall have report.

Article 259   When necessary, samples provided by main material supplier shall take trial production of sample small lot production, and take stability review on the trial produced pharmaceutical goods.

Article 260   Evaluation to material supplier taken by quality management department shall include at least the following: supplier’s qualification approving document, quality standard, inspection report, inspection data and report to material’s sample. If locale quality audit and samples’ small lot production carries on, locale quality audit report and small lot production products’ quality inspection report and stability review report shall also include.

Article 261   If material supplier changes, new supplier shall be quality evaluated; if main material supplier changes, related validation and stability review to products shall also be done.

Article 262   Quality management department shall distribute the list of approved qualified supplier to material management department, the list shall include at least material’s name, specification, quality standard, manufacturer’s name and address, dealer’s name (if any) and so on, and the information shall be updated in time.

Article 263   Quality management department shall conclude an agreement with main material supplier, quality responsibilities of two parties shall be indicated in the agreement.

Article 264   Quality management department shall regular evaluate or locale quality audit, review and analyze material quality inspection result, quality complaint and unqualified disposal record to material supplier. If material has quality problems or its manufacturing condition, technology, quality standard and inspection method and key factors may influence quality changes, locale quality audit shall take as soon as possible.

Article 265   Enterprise shall set up quality file to each material supplier, the file shall include supplier’s qualification approving document, quality agreement, quality standard, samples’ inspection data and report, supplier’s inspection report, locale quality audit report, products’ stability review report, regular quality review analysis report and so on.

Section 8 Product’s Quality Review Analysis

Article 266   Product’s quality review analysis shall be done to all manufactured pharmaceutical goods per year according to operation procedures, to ensure the technology is stable and credible, and the applicability of raw material, finished products’ quality standard, find bad direction in time, and ensure the improving direction of product and technology. Former review analysis history data shall be considered and validity self-check of products’ quality review analysis shall be done.

When there is reasonable science bases, quality review could be done according to product’s types, such as sold preparation, liquid preparation and asepsis preparation and so on.

Review analysis shall have report.

Enterprise shall take review analysis to at least the following conditions:

I.            All changes to product used raw material, especially raw material supplied by new supplier;

II.           Key middle reference point and finished products’ inspection result;

III.         All batches and investigation fall short of quality standard;

IV.         Validity of all important windage and related investigation, reform measures and prevention measures taken;

V.          Changes on production technology or inspection method and so on;

VI.         Changes on approved or recorded pharmaceutical goods registration;

VII.        Result and any bad direction of stability review;

VIII.       All withdraw, complaint, recall and investigation caused by quality reasons;

IX.         Performance and effect of taking correction measures related to products’ technology or equipment;

X.          For the new approved pharmaceutical goods or pharmaceutical goods have changes, accomplished working condition after coming into the market according to registration requirements;

XI.         Confirmed condition of related equipment and establishment, such as air condition cleanse system, water system, compress air and so on;

XII.        Consign manufacturing or inspection technique contract’s performance condition.

Article 267   Review analysis’ result shall be evaluated, whether correction and prevention measures need to be taken, or bring forward the evaluation opinions of re-confirmation or re-validation and state reasons, finish correction in time and effectively.

Article 268   When the pharmaceutical goods are consigned for manufacturing, written technique agreement shall conclude between assignor and assignee, which prescribe the responsibilities of two parties in product’s quality review analysis, to ensure product’s quality review analysis carries on in time and is in accordance with the requirements.

Section 9 Complaint and Bad Reaction Report

Article 269   Pharmaceutical goods’ bad reaction report and monitor management system shall be set up, special institution shall be set up and special person shall be designated for management.

Article 270   Collect the bad reaction of pharmaceutical goods actively, specific record, evaluation, investigation and disposal shall be done to bad reaction, take measures in time to control the risk may exist, and report to pharmaceutical goods’ supervision management department according to requirements.

Article 271   Set up operation procedures to prescribe the procedure of complaint registration, evaluation, investigation and disposal, and prescribe the measures shall be taken when receiving the complaint may cause by product limitation, including the advisement of whether recalling pharmaceutical goods from market.

Article 272   Special person and enough assistants shall have to be responsible for investigation and disposal to quality complaint, all information about complaint, investigation shall advise to quality authorized person.

Article 273   All complaint shall be registered and audited, the complaint related to product’s quality limitation shall record every details of complaint, and taking investigation.

Article 274   If any limitation is found or doubted in some batch of pharmaceutical goods, other batches of products shall consider for checking, and find whether it was influenced.

Article 275   Complaint investigation and disposal shall have record, and indicate the related information of batch of products.

Article 276   Complaint review shall be regular reviewed and analyzed, to find the problems need to be warned, repeated problems and pharmaceutical goods may need to recall, and take corresponding measures.

Article 277   When enterprise has manufacturing mistake, pharmaceutical goods are transformed or other important quality problem, corresponding measures shall be taken in time, when necessary, the enterprise shall report to local pharmaceutical goods’ supervision management department.

Chapter 11 Consigned Manufacturing and Consigned Inspection

                   

Section 1 Principle

Article278   In order to ensure the accuracy and reliability of the quality of consigned manufacturing products and consigned inspection, the assignor and assignee must conclude written agreement, which specific prescribe the responsibilities of each party, content and related technique items of consigned manufacturing or consigned inspection.

Article 279   All activities of consigned manufacturing or consigned inspection, including any changes in technique or other factors, shall in accordance with the related requirements of pharmaceutical goods’ manufacturing consent and registration.

Section 2 Assignor

Article 280   The assignor shall evaluate the assignee by locale examination on assignee’s condition, technique level, and quality management condition, confirm its ability of finishing assigned job, and ensure to finish in accordance with the requirements of this Regulation.

Article 281   Assignor shall provide all necessary data to assignee, so that the assignee could correct operate the assigned operation according to pharmaceutical goods’ registration and other legal requirements.

Assignor shall let the assignee understand all kinds of problems related to product or operation completely, including the possible harms product or operation may caused to assignee’s environment, workshop, equipment, person and other material or product.

Article 282   Assignor shall supervise the whole process of consigned manufacturing or inspection.

Article 283   Assignor shall ensure material and products are in accordance with related quality standard.

Section 3 Assignee

Article 284   Assignee shall equip with enough workshop, equipment, knowledge and experience and personnel, to satisfy the consigned manufacturing or inspection work by assignor.

Article 285   Assignee shall ensure the material, semifinished product and bulk product provided by assignor are applicable to the intending purpose.

Article 286   Assignee could not take activities which have bad influence to the consigned manufactured or inspected product quality.

Section 4 Contract

Article 287   The contract conclude between assignor and assignee shall particular prescribe each party’s product manufacturing and control responsibility, the technique articles in the contract shall draw out by the directors with pharmacy technology, inspection specialty knowledge and who know this Regulation well. All work of consigned manufacturing and inspection shall in accordance with the requirements of pharmaceutical goods’ manufacturing consent and pharmaceutical goods’ registration and shall consent by two parties.

Article 288   The contract shall specific prescribe the procedure of approving to discharge each batch of pharmaceutical goods by quality authorized person, to ensure each batch of products have finished manufacturing and inspection according to the requirements of pharmaceutical goods’ registration.

Article 289   The contract shall prescribe which party is responsible for material’s ordering, inspection, discharging, manufacturing and quality control (including middle control), and shall prescribe which party is responsible for sampling and inspection.

When it is consigned inspection, the contract shall prescribe whether the assignee could sampling in assignor’s workshop.

Article 290   The contract shall prescribe that assignor could review or check the manufacturing, inspection and discharging record and samples kept by assignee at any time; if there is complaint, the products may have quality limitation or recall, assignor shall be able to review all records related to product quality evaluation.

Article 291   The contract shall specific prescribe the assignor could check or take locale quality audit to assignee.

Article 292   Consigned inspection contract shall definite that the assignor has duty to receive the check by pharmaceutical goods’ supervision management department.

Chapter 12 Product’s Delivering and Recall

                   

Section 1 Principle

Article 293   Enterpriseshall set up product recall system. It could recall any batch of product with safety problems promptly, effectively when necessary.

Article 294   For the withdrawn and recalled products caused by quality reasons, shall be supervised and destroyed according to prescription, unless the products’ quality is proved to be no influence.

Section 2 Delivering

Article 295   Each batch of products shall have delivering record. According to delivering record, sales condition of each batch of products shall be traced, so that all products could be recalled when necessary. The content of delivering record shall include: product’s name, specification, batch number, amount, receiving unit and address, contact information, delivering date, transport method and so on.

Article 296   Scattered package of pharmaceutical goods’ delivering is limited to two batches as one combined box, the combined box shall indicate all the batch number, and set up combined box record.

Article 297   Delivering record shall keep at least one year after the period of validity of pharmaceutical goods.

Section 3 Recall

Article 298   Recall operation procedures shall be set up, to ensure the validity of recall.

Article 299   Special person shall be designated to be responsible for organize and assort with recall, and enough person shall be equipped. The director of product recall shall be independent with sale and market department; if the director of product recall is not the quality authorized person, the information of recall shall be reported to quality authorized person.

Article 300   Recall shall startup at any time, and shall perform promptly.

Article 301   If the product is recalled from market because of safety limitation, the information shall be reported to local pharmaceutical goods’ supervision management department immediately.

Article 302   Director of product recall shall review pharmaceutical goods’ delivering record immediately.

Article 303   The recalled products shall be marked, and shall storage independent and appropriate to wait for final disposal decision.

Article 304   Development of recall shall have records and have final report. Product’s delivering amount, recalled amount and amount balance shall be indicated in the report.

Article 305   Regular evaluation shall be done to the validity of product recall system.

Chapter 13 Self-check

                   

Section 1 Principle

Article 306   Quality management department shall regular organize self-check to enterprise, monitor performance condition of this Regulation, evaluate the enterprise and bring forward essential correction and prevention measures.

Section 2 Self-check

Article 307   Plans shall be done before self-check. Regular check shall be done to organization and personnel, workshop and establishment, equipment, material and product, confirmation and validation, document management, manufacturing management, quality control and quality guarantee, consigned manufacturing and consigned inspection, product delivering and recall and other items.

Article 308   Enterpriseshall designate person to take independent, system, complete self-check, and shall take independent quality audit by exterior person or expert.

Article 309   Self-check shall have record. After the self-check is finished, self-check report shall be done, the content shall include at least all condition reviewed in self-check process, evaluated conclusion and advises of correction and prevention measures. The self-check condition shall report to senior administrator of enterprise.

Chapter 14 Supplementary Articles

                   

Article 310   This Regulation is the basic requirements to pharmaceutical goods’ manufacturing quality management. For the special requirements on asepsis pharmaceutical goods, biology preparation, blood preparation and other pharmaceutical goods or manufacturing quality management activity, shall constitute by state food and drug administration in appendix.

Article 311   Enterprisecould achieve the requirements of this Regulation by a validated substitute method.

Article 312   The meaning of the terms (arranged by Chinese pinyin) in this Regulation are as following:

1.    Package

All operation proceduress from bulk product to finished product, including load, mark with label and so on. However, products’ asepsis filling package in asepsis production technology, and finally sterilization products’ filling package are not regarding as package.

2.    Wrapper

Material used for wrapper, including wrapper and container, printing wrapper directly contact with pharmaceutical goods, but not including exterior package material used for delivering.

3.    Operation procedures

Currency document approved for instructing equipment’s operation, maintenance and cleaning, validation, environment control, sampling and inspection and other pharmaceutical goods’ manufacturing activities, is also called as standard operation procedures.

4.    Product

Product includes pharmaceutical goods’ semifinished product, bulk product and finished product.

5.    Product’s lifecycle

All stages from product’s initial develop, coming into the market and withdrawing from market.

6.    Finished product

Product has finished all manufacturing procedures and final package.

7.    Reprocessing

Reprocess by different production technology to part or full of semifinished product or bulk product which one manufacturing procedure does not in accordance with the quality standard, in order to in accordance with the intending quality standard.

8.    Bulk product

Product with no package but have finished all other processing procedures.

9.    Quarantine

The status of raw material, wrapper, semifinished product, bulk product or finished product, use physics method or other effective method to isolate or distinguish them, and it is stored, waited for taking the decision of delivering before it is allowed to manufacture or come into market.

10.  Extending

A series of operations done in the enterprise, such as the operations of material, semifinished product, bulk product, document, mould used for manufacturing.

11.  Period of double examination

After the raw material, wrapper is stored for certain time, for ensuring it is still applicable to intending purpose, the double examined date decided by enterprise.

12.  Delivering

It means a series of operations done from enterprise to dealer or consumer, such as matching goods, transportation and so on.

13.  Renew process

For a batch of semifinished products or bulk products, part of finished products or all products which certain production technology is not in accordance with the quality standard, return the products to the previous procedure, re-process with the same production technology, in order to be accordance with the intending quality standard.

14.    Discharging

Take quality evaluation to a batch of material or product, and take decision of approval for using or approval to come into market, or other decisions.

15.    Senior administrator

It means the person with the power and responsibility of directing and controlling enterprise in the enterprise, and has the power of adjusting resources.

16.    Production technology: A document or set of documents setting for manufacturing specified quantity of finished products, including manufacturing prescription, processing instructions (including middle control), notice items and so on.

17.    Supplier

Supplier for material, equipment, apparatus, reagent, service, such as manufacturer, dealer and so on.

18.    Callback

In certain manufacturing stage, add a previous batch or several previous batches of products, partial or whole, which in accordance with quality requirements to the operation of another batch of products.

19.    Computer system

It means the integration system for reporting or auto controlling, including data input, electric disposal and information output.

20.    Cross pollution

Pollution happens between different raw materials, excipient and products.

21.    Adjustment

Confirm a series of activities between the value (especially metage) of measuring, recording, control apparatus or system, or the represented value of practicality measure and corresponding contrast standard measuring value under prescribed condition.

22.    Stage manufacturing method

In common manufacturing area, concentrated manufacturing a kind of product in a period of time, and then completely clean corresponding common manufacturing area, establishment, equipment, apparatus, and change to manufacture another kind of product.

23.    Clean Room: A room (area) with defined environmental control of particulates and microbilogical contamination, constructed and used in such a way as to reduce the introduction, generation, and retention of contaminants within the area.

24.    Alarm limit

It means the limit standard when the key parameter of system is above the normal scope, but not achieving the correction limit, the limit shall be alarmed, and may take correction measures.

25.    Correction limit

It means the limit standard when the key parameter of system is above the accepted standard, and needs to investigate and take correction measures.

26.    Inspection result exceeding standard

All situations when inspection result exceeds the legal standard and standard set up by enterprise.

27.    Batch

It means a certain amount of raw material, wrapper or finished product of same intended quality and characteristic by one or several processing procedures. In order to finish some manufacturing operation proceduress, a batch of products may need to divide into several batches, and finally combine into one batch. When the products are manufactured in series, batch of product shall correspond to the specific amount of products of same intended characteristic. Batch amount means the amount of products which could fix amount or time when manufacturing.

Such as: oral or external used solid, semisolid preparation use one combined equipment before moulding or discharging, the manufactured products in same quality are one batch of products; oral or external used liquid preparation combine by medicine liquid before filling load (envelop) in same quality are one batch of products.

28.  Batch number: A distinctive combination of numbers and/or letters by which one is able to identify a special batch.

29.  Batch production record: All documents and records associated with the manufacture, all history information related to finished products’ quality could be traced.

30.  Ventilator

The ventilator shall set between isolated space with two or more doors of two or more rooms (such as between the rooms with different clean level). The aim of setting ventilator is to control air current when person or material is coming in and out of the room. Ventilator divides into person ventilator and material ventilator.

31.    Enterprise

Enterprise means pharmaceutical goods’ manufacturing enterprise if there is no special indication in this Regulation.

32.    Confirmation

A series activities confirm workshop, establishment, equipment could run correctly and could achieve intended result.

33.    Withdraw of goods

It means the activity of returning the pharmaceutical goods to enterprise.

34.    Document

The document means in this Regulation include quality standard, technique procedure, operation procedures, record, report and so on.

35.    Material

It means raw material, excipient, packaging materials, and so on.

Such as: raw material of chemical pharmaceutical goods preparation means raw drug; raw material of biology preparation means raw material; raw material of Chinese tradition medicine means Chinese medicinal plant, Chinese traditional medicine tea and outsourcing Chinese traditional medicine extractive matter; raw material of raw drug means other material in raw drug manufacturing besides wrapper.

36.  Reconciliation

A comparison, making due allowance for normal variation, between the amount actually produced or used and the amount of product or materials theoretically produced or used.

37.  Pollution

Raw material, semifinished product, bulk product, finished product is adversely influenced by impurity or foreign matter with chemistry or microorganism characteristics, during the process of manufacturing, sampling, packaging or re-packaging, storage or transportation.

38.  Validation: The documented act of proving that any operation procedures (or method), production technology, or system actually leads to the expected results.

39.    Printing wrapper

It means that the wrapper with special pattern and printing content, such as working aluminum foil, label, instruction, paper box and so on.

40.  Raw material

Any material used in the process of pharmaceutical goods’ manufacturing except wrapper.

41.    Semifinished product

Product with part processing procedures finished, and shall take further process to become bulk product.

42.    Middle control

Also named as process control, it means to monitor to production technology during manufacturing, and adjust to take each inspection so that to ensure the product is in accordance with the related standard. Environment or equipment control shall regard as a part of middle control.

Article 313   This Regulation shall be effective from March 1, 2011. According to Article 9 prescribed in "Drug Administration Law of The People's Republic of China", the detailed implement method and implement procedure shall prescribe by State Food and Drug Administration.

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