The Chinese Ministry of Health has published revised GMP rules for drugs in the beginning of 2011. March 1, 2011 was specified as date for the entry into force. Now, an English translation is available. The following is a comprehensive assessment.
The document has 43 pages and is divided into 14 chapters with 313 paragraphs (sections in brackets):
1. General Provisions
2. Quality Management (Principle, Quality Assurance, Quality Control, Quality Risk Management)
3. Organization and Personnel (Principle, Key Personnel, Training, Personnel Hygiene)
4. Premises and Facilities (Principle, Production Area, Storage Areas, Quality Control Areas, Ancillary Areas)
5. Equipment (Principle, Design and Installation, Maintenance and Repair, Usage and Cleaning, Calibration, Water for Pharmaceutical Use)
6. Materials and Products (Principle, Starting Materials, Intermediate and Bulk Products, Packaging Materials, Finished Products, Controlled Materials and Products, Others)
7. Qualification and Validation
8. Documentation Management (Principle, Specifications, Master Manufacturing Documents, Batch Processing Records, Batch Packaging Record, Operation Procedures and Records)
9. Production Management (Principle, Prevention of Contamination and Cross-contamination in Production, Processing Operations, Packaging Operations)
10. Quality Control and Quality Assurance (Management of Quality Control Laboratories, Release of the Materials and Products, On-going Stability Program, Change Control, Deviation Handling, Corrective Actions and Preventive Actions, Supplier Assessment and Approval, Product Quality Review, Complaints and Adverse Drug Reaction Reports)
11. Contract Manufacture and Analysis (Principle, The Contract Giver, The Contract Acceptor, The Contract)
12. Product Distribution and Recalls (Principle, Distribution, Recalls)
13. Self Inspections (Principle, Self Inspections)
This breakdown already shows that the concept was mainly taken from EU GMP Guideline Part I. Many of the requirements are therefore comparable to those of EU GMP Guideline Part I. But in some parts the Chinese GMP rules are considerably stricter than those in EU GMP Guideline Part I. In the following the focus will be put mainly on these passages.
It is noticeable that falsifications and fraud are explicitly forbidden as in Chapter 1 (General Provisions).
The topic quality risk management is treated already in Chapter 2 as individual section. This is very modern indeed. The associated next steps (risk assessment, risk control, risk communication, risk review) are based very much on ICH Q9; however, without stating the tools listed in ICH Q9.
Chapter 3 (Organisation and Personnel) is very interesting since it quotes the key personnel. The Chinese GMP rules list the following functions as key personnel: the head of the manufacturer, the head of production management, the head of quality management and the Qualified Person. The heads of production and quality management must be independent from each other. The head of quality management and the Qualified Person can be the same person. The qualifications required for key personnel are also very interesting.
To be qualified for the post of head of production management you should, at a minimum, possess a college degree in pharmaceutical (or other) relevant specialities (there are stated some alternatives) with at least three years of practical experience in pharmaceutical production and quality management, among which at least one year in production management. Additionally, training relating to the products being manufactured is necessary.
To be qualified for the post of head of quality management you should, at a minimum, possess a college degree in pharmaceutical (or other) relevant specialities (there are stated some alternatives) with at least five years of practical experience in pharmaceutical production and quality management, among which at least one year in quality management. Additionally, training relating to the products being manufactured is also necessary.
To be qualified for the post of Qualified Person you should, at a minimum, possess a college degree in pharmaceutical (or other) relevant specialities (there are stated some alternatives) with at least five years of practical experience in pharmaceutical production and quality management. The Qualified Person should also have work experience in in-process control and in analyses for the determination of the product quality. He/she should be trained in product release and have the necessary theoretical knowledge.
Training activities should be carried out by the relevant department or the relevant persons.
Special features in Chapter 4 (Premises and Facilities) are the use of multi-purpose facilities and premises after having carried out a risk analyses and the statement that the air pressure differential between clean and non-clean areas should not be less than 10Pa. Oral liquid and solid preparations, suppositories, epidermal products and other non-sterile products should be manufactured in areas designed as Grade D (according to Annex 1). Dedicated air handling facilities are required for animal houses.
In Chapter 5 (Equipment) a separate paragraph (No. 78) is dedicated to production molds (purchase, check and acceptance, storage, maintenance, dispensing and discarding, documentation). It also contains a passage with very detailed information on the requirements for calibration equipment. Name, code, calibration validity date and the number of the accreditation certificate are required. A calibration label should be put on calibrated equipment. Lubricants are required to have food quality or an equivalent quality. Chapter 5 also contains a section on water for pharmaceutical use. Specifications should meet those of the Chinese Pharmacopoeia. Non-fiber releasing hydrophobic filters are required for storage tanks.
Chapter 6 (Materials and Products) states that ink printed directly on a drug should meet food grade requirements. Imported starting materials should comply with importation regulations. A change of material suppliers, and procurement can only be carried out after the suppliers have been approved by the quality management department. Materials should be used according to the principle first-in-first-out and first-expiry-first-out. Where computerized storage systems are used, operation procedures should be in place to prevent mixups and errors in the case of a malfunction. Great importance is attached to the re-testing of starting materials. Each dispensed material and its weight or volume should be independently checked by another person. Procedures for the design, review and approval of printed packaging materials should be established to ensure compliance with the drug regulatory department. In dealing with narcotics, psychotropic and toxic drugs (including traditional Chinese medicinal products), radioactive drugs, pharmaceutical percursor chemicals, flammable and explosive materials and other dangerous materials, government regulations should strictly be followed. Introduction of material from one batch into another batch (recovery) should be carried out only after a thorough evaluation of the quality risks involved. The shelf life should start from the date when the earliest batch is produced. Reworking of finished preparations is prohibited explicitly. There are clear rules for reprocessing (no quality defects, specifications must be met, carried out according to predefined operating procedures after evaluating the risks involved). There are strict rules for the sale of returned products.
Chapter 7 (Qualification/Validation). The scope and extent of qualification or validation activities should be determined through risk assessment. A validation masterplan is required as well as a regular revalidation of critical manufacture processes. The classical approach to qualification with its four stages (design qualification, installation qualification, operational qualification and performance qualification) is also part of the Chinese GMP rules. Paragraph 143 regulates the requirements of a cleaning validation (sampling methods and locations, recovery rates, acceptance criteria, sensitivity of testing methods) at great length.
Chapter 8 (Documentation Management) expressly points out that superseded and outdated documents must not be used any more except for archiving. Data should be entered in documents truthfully. There are more requirements. Documents should be reviewed by the quality management department. Equipment printouts should be provided with product or sample name, batch number, equipment information and dated signature of the operator. In the case of transcription, the original record should not be destroyed, but be kept as attachment to the transcribed record. Batch records should be retained by the quality management department for at least one year after the product shelf life. Important documents (documents such as specifications, validation and qualification documents or reports of stability studies are mentioned) should be archived for the long term. If data is recorded by electronic processing systems or photographic techniques, the accuracy of the records should be checked. If documentation is handled by electronic data processing methods, only an authorized person should have access and be able to modify data. These changes or deletions should be recorded. Access should be restricted by passwords or other means and the entry of critical data should be independently checked. Master batch processing records should be reviewed and approved by the heads of production and quality management. In Chapter 8 much attention is devoted to topics such as shelf-life data and re-testing for starting materials, intermediate and finished products.
Chapter 9 Production Management. Unless stipulated in other regulations, the manufacturing date should be no later than the commencing date of the last blending operation. The packaging date of the product should not to be used as its manufacturing date. Measures to prevent contamination and cross-contamination should be checked regularly and evaluated for their suitability and effectiveness. The line clearance record should be incorporated into the batch documentation. Information printed by hand should be checked frequently. Printed and embossed information should be distinct and resistant to fading or erasing. There are high demands on repackaging.
Chapter 10 (Quality Control and Quality Assurance) requires that the head of quality control has appropriate qualifications and experience in managing a laboratory. He can also manage more laboratories of the same manufacturer. Testing technicians in laboratories should at least have a relevant technical school or high school education, have passed the exams and have received a job related practical training. For some data (e.g. testing results, environment monitoring data, microbiological monitoring data of the water system), it is recommended that records be kept in a manner permitting trend evaluation. Calculations carried out in connection with analyses should be checked critically. Reference samples should be checked visually at least once a year unless the examination could damage the sample. If drug manufacturing is ceased or a manufacturer closes down, the reference samples should be transferred to an authorized storage site. The competent authority must be informed accordingly. The size of reference samples of materials should be at least sufficient to perform the identification test. Detailed requirements are defined for the management of laboratory reagents, solutions, microbiological media and test microorganisms. The same applies for reference substances. In connection with the release procedure, release of materials (used) for finished products should be approved by a designated person with her/his signature. Prior to the final release, a lot release certificate should be applied for at the State Food and Drug Administration for vaccines, blood products, in-vitro diagnostic reagents used in blood screening, and for other biological products.
A specific section attaches great importance to on-going stability programs. It states e.g. that the number of batches and frequency of testing should provide a sufficient amount of data to allow trend analysis with the minimum number being one batch (each strength and each primary packaging type). Storage conditions should be adapted to the Chinese Pharmacopoeia. During on-going stability programs special attention should be attached to reworking, reprocessing or recovery batches. Results of on-going stability programs should be made available to key personnel and, in particular, to the Authorized Person(s) (translation error? Maybe Qualified Persons are meant). On-going stability programs which are carried out on behalf of a third party should be based on a contract and be available at both sites for review by the competent authority. Out-of-specification results or significant atypical trends during an on-going stability program should be investigated and the possible impact on the marketed product considered. If necessary, a recall should be carried out and be reported to the competent authority. A summary of the on-going stability program's data should be written and reviewed periodically.
Requirements on change control, deviation handling, corrective actions and preventive actions (CAPA) are also regulated at length in the respective sections. The required content of a standard operating procedure describing a change control procedure is listed. The quality management department should assign a person responsible for the change control procedure. The manufacturer should classify the changes according to their impact and extent (e.g major or minor). Changes that might affect the product quality are to be proposed by an application department (translation error?), be identified by means of a risk analysis and then be implemented within an implementation plan with defined responsibilities and after final approval by the quality management department. The implementation of a change should be recorded. If changes involve key quality factors (starting materials, packaging materials with product contact, manufacturing process, major equipment) the quality of the first three batches produced after the change should be reviewed. If the change has a potential impact on the shelf life, stability studies should be conducted. When implementing changes, measures should be taken to ensure that all documents affected by the change are revised. Documents related to changes should be archived by the quality management department. The manufacturer should classify deviations according to their impact and extent (e.g. major or minor). Deviation reports should be reviewed and approved by a designated person from the quality management department. Preventive actions after the occurrence of a deviation are required explicitly. The quality management department is responsible for classifying deviations and for archiving the relevant documents. The required content of a standard operating procedure concerning the CAPA-management is listed. Documents concerning CAPA should be archived by the quality management department.
A whole section is dedicated to supplier assessment and approval. In conjunction with other departments, the quality management department should perform a quality assessment of all suppliers of production materials. Suppliers of key materials (especially the producers) should be audited on-site. The quality management department should exercise its veto against any suppliers who fail to meet the requirements of quality assessment. The legal representative of the manufacturer, the head of the manufacturer and other personnel should not interfere with the quality assessment performed by the quality management department. Auditors should be appointed by the quality management department. The responsibilities between a supplier of key material and the producer should be regulated in a quality agreement. This agreement is signed by the quality management department. A quality archive, including at least the relevant documentation (e.g. supplier's certificates of analysis, periodic review reports etc.) is required for each supplier of materials.
One section is dedicated to product quality review. This section requires, inter alia, self-inspection of the results of product quality reviews. A grouping of product quality reviews by dosage forms is accepted, if scientifically justified. The product quality review should contain 12 points. These points have been reproduced in almost identical terms from the EU GMP Guideline. If necessary, the evaluation of the results of the product quality review should induce the relevant measures (e.g. CAPA, revalidation, etc.) to be completed in time and effectively. In the case of contract manufacturing the contract should define the party responsible for carrying out the product quality review.
The last section is dedicated to complaints and adverse drug reaction reports. Monitoring and reporting of adverse drug reaction reports should be carried out by a specific organization with specialized personnel. Adverse drug reaction reports should be reported to the competent authority as required. There should be designated person(s), supported by sufficient staff for investigating and handling the quality complaints. The Qualified Person should be made aware of any complaints and investigations. Complaint records should be reviewed regularly.
Chapter 11 on contract manufacture and analysis requires the contract giver to carry out an on-site audit of the contract acceptor. Much importance is attached to the contract between contract giver and contract acceptor, especially concerning the release by the Qualified Person and the responsibilities (such as purchase of starting material, sampling etc.). The contract should define that processing, testing and distribution records and samples are kept by the contract acceptor.
One special feature can be found in Chapter 12, Product Distribution and Recalls: Only two batches of remnant products are allowed in one shared package. Both batch numbers must be indicated on the outside of the package. A person should be designated to carry out and coordinate recalls. This person should be supported accordingly by staff. He/she should be independent from the sales and marketing organization. If this person is not the Authorized Person (translation error? Qualified Person might be meant), the latter should be made aware of any recall activity.
Chapter 13 (Self Inspections) stipulates that self inspections should be organized by the quality management department. The self inspection status should be reported to the senior management.
Chapter 14 (Supplementary Provisions) points out that manufacturers may use validated alternative approaches to meet the requirements of the Provisions. It also indicates that the Provisions are basic requirements and that there are special requirements for sterile products, biological products and blood products. The Chapter finishes with a comprehensive glossary.
Conclusions: The new Chinese GMP rules are very comprehensive (43 pages). They mainly follow EU GMP Guideline Part I, but are more detailed in many points. This is partly due to the fact, that the Chinese have included topics (such as requirements on water systems) in the general rules which the EU GMP Guidelines treat in annexes. The extent is also due to duplication. Remarkable points are the high requirements on key personnel and that oral liquid and solid preparations, suppositories, epidermal products and other non-sterile products should be manufactured in areas designed as Grade D. Modern GMP elements such as quality risk management, inclusion of the senior management and CAPA are included in the Guideline. Many tasks are directly aimed at the quality management department. The topic qualification/validation is treated in a rather classical way. Four stages of qualification are required (design qualification, installation qualification, operational qualification and performance qualification). Even the magic number three appears, although in connection with the assessment of changes which should be reviewed in three batches.
Please see the complete document "Good Manufacturing Practice for Drugs" for further details.
CONCEPT HEIDELBERG (a service provider entrusted by the ECA Foundation)