At the end of the year, how to avoid those pits that have been stepped on by the annual quality review analysis of products?

Unconsciously, the time has reached December 2022, and there is less than a week left in 2022, how to carry out the annual quality review and analysis of drugs efficiently? This article sorts out the annual quality review of the product and analyzes the common defects and precautions and shares it with you in combination with their own interpretation.

1.
Relevant requirements of drug administration regulations

Product annual quality review analysis is an important part of drug production and quality management, is MAH's inherent responsibility and obligation, after review, China's current GMP body (2010) has a total of 6 articles involved, of which product annual quality review analysis Chapter 10 section 8 revised GMP a separate new chapter for "product quality review analysis", which clarifies the basic requirements, principles, content and purpose of drug manufacturers in carrying out product quality review analysis, The relevant requirements of China's current GMP body (2010) are summarized as follows:

1.
Article 23 One of the main responsibilities of the person in charge of quality management: 14.
Ensure the completion of product quality review and analysis
.

2.
Article 144 Confirmation and verification are not one-time acts
.
After the first confirmation or verification, it shall be reconfirmed or reverified
according to the product quality review and analysis.
Critical production processes and operating procedures should be periodically revalidated to ensure that they achieve the desired results
.

3.
Article 265 An enterprise shall establish a quality file for each material supplier, and the content of the file shall include the supplier's qualification certification documents, quality agreements, quality standards, sample inspection data and reports, suppliers' inspection reports, on-site quality audit reports, product stability inspection reports, regular quality review and analysis reports, etc
.

4.
Article 266 In accordance with the operating procedures, a review and analysis of the product quality of all drugs produced by variety shall be carried out every year to confirm the stability and reliability of the process, as well as the applicability of the current quality standards for raw and auxiliary materials and finished products, discover adverse trends in a timely manner, and determine the direction of
product and process improvement.
Historical data from previous retrospective analyses should be taken into account, and self-checks
should also be made for the validity of product quality retrospective analyses.
When there is a reasonable scientific basis, quality review can be carried out according to the dosage form classification of the product, such as solid preparation, liquid formulation and sterile preparation.

The retrospective analysis should be reported
.
At a minimum, enterprises should conduct a retrospective analysis of the following situations:

(a) all changes in raw and auxiliary materials used in the product, especially raw and auxiliary materials from new suppliers;

(2) Inspection results of key intermediate control points and finished products;

(3) all batches that do not meet the quality standards and their investigations;

(4) the effectiveness of all major deviations and related investigations, corrective measures and preventive measures taken;

(5) All changes in production processes or inspection methods;

(6) All changes in the registration of drugs that have been approved or recorded;

(7) the results of stability studies and any adverse trends;

(8) All returns, complaints, recalls and investigations caused by quality reasons;

(9) the implementation and effect of corrective measures related to product processes or equipment;

(10) The work that should be completed after marketing of newly approved and modified drugs in accordance with registration requirements;

(11) Confirmation status of relevant equipment and facilities, such as air conditioning purification systems, water systems, compressed air, etc.
;

(12) The performance of
technical contracts entrusted for production or inspection.

5.
Article 267 The results of the retrospective analysis shall be evaluated, and the assessment opinions and reasons for whether corrective and preventive measures need to be taken or reconfirmed or reverified shall be put forward, and rectification shall be completed in a timely and effective manner
.

6.
Article 268 When the production of drugs is commissioned, there shall be a written technical agreement between the entrusting party and the entrusted party, stipulating the responsibilities of all parties in the product quality review and analysis, and ensuring that the product quality review and analysis is carried out on time and meets the requirements
.

Second, product quality review and analysis of those pits

Every year, MAH shall conduct product quality review and analysis of the varieties of drugs produced by variety to confirm the continuous stability and reliability of the process, as well as the applicability of the current quality standards of raw and auxiliary materials and finished products, timely discover adverse trends, and put forward the direction of
product quality and process improvement.
Enterprises should focus on adopting appropriate analysis methods or software to analyze the trend of counting data, and should refer to historical data to analyze the quality changes of production varieties when doing trend analysis
.
The results of the product quality review and analysis are evaluated, and corrective and preventive measures such as deviations in the production process and changes in key process parameters are proposed and confirmed
.
This article combines the literature system to sort out the product quality review and analysis of those common pits, if there is an omission, welcome to leave a message to add, some pits need us to step on in person to have a deep experience, but the lessons of the past, the masters of the future, smart people can also learn from the defects of others
.

1.
Product quality review analysis SOP formulation those common pits

(1) SOP regulations are not perfect, unproduced products do not require quality review, and do not stipulate the collection, entry and review procedures
of quality review statistical analysis data.

(2) Failure to carry out product quality review
in accordance with the procedures.

(3) Failure to conduct trend analysis in accordance with the procedures
.

(4) Failure to stipulate
the time limit requirements for product quality review drafting, submission and approval in accordance with the procedural provisions.

2.
Product quality review and analysis content of those common pits

(1) The review content is not comprehensive, such as upstream process data and summary that does not include seed batch system, partial process data such as light inspection, partial control data such as bioload, unqualified semi-finished product batches and finished product batches, batches that have been produced but not yet released, individual exceeding events, medium simulation filling test, stability test result analysis, yield and yield, seed batch monitoring, key starting materials, analysis of test result trends, correction and prevention effectiveness evaluation, Review of the validity of technical agreements (including key starting materials, diluent suppliers), detailed analysis and explanation
of anomalous trends (including rejection rates, etc.
).

(2) The relevant data of air conditioning and water systems were not summarized and trend analysis was carried out in the 20XX annual quality review and analysis
report of indapamide sustained-release tablets.

(3) Failure to identify key quality parameters and key quality attributes
based on risk principles.
No quality review of pharmaceutical water systems, air conditioning systems, pure steam systems, etc
.
was conducted.

(4) In the "**** Product Annual Quality Review" (review period: April 20XX - March 201XX, approval date: May 23, 20XX), the quality assessment conclusion of **** suppliers **** is that the supply crystal form is unqualified and temporarily not listed in the qualified supplier directory, but it has not timely issued a "suspension of supplier purchase notice" to the marketing department in accordance with the provisions of "Supplier Confirmation and Audit" (SOP-QA-002), to the "Supplier Register Directory" (SOP-QATP-003) will be classified as "Suppliers of Raw Materials Temporarily No Purchase" (R-SOP-QATP-003-01)
when the upgraded version takes effect.

(5) The product quality retrospective analysis of albumin injection at the original production address was carried out, and the key parameter control of the bottle washing, filling, capping and other processes was not reviewed
.

(6) The purified water and water for injection system are reconfirmed as retrospective confirmation, and the water system process distribution chart, the corresponding table of each point of use, and the summary table of the test data of each point of use are missing in the report and record; The retrospective trend analysis items of water for injection quality were incomplete, and the items such as TOC, conductivity, pH, bacterial endotoxin and other items were not retrospectively analyzed; Performance confirmation data
is missing in the vacuum freeze dryer reconfirmation report.

(7) The use of raw materials is not confirmed in the annual quality review report of
the product.

(8) In the supplier audit data, the < quality assurance agreement signed with Ningxia BMW Chemical Group Co.
, Ltd.
, a dicyandiamide supplier, has expired >; The supplier of morpholine is Jihua Liaoyuan Chemical Co.
, Ltd.
Longteng Branch, its organization code has expired, the "Supplier Annual Quality Review Analysis Report" provided in the information is a review of Jihua Liaoyuan Chemical Co.
, Ltd.
rather than the quality review of Longteng Branch, safety production license and other qualification materials are Jihua Liaoyuan Chemical Co.
, Ltd.
, and all expired
.

(9) The inspection data of intermediate products is not included in the annual quality review
.

3.
Product quality review analysis statistical analysis methods those common pits

(1) The statistical analysis methods used are unscientific and unreasonable, and it is difficult to effectively identify quality trends and abnormalities
.

(2) The key indicators are not analyzed by the process capability index, and the calculation method and standard
of the process capability index are not stipulated.

(3) Use Excel to calculate the warning limit and action limit and the calculation situation cannot be recorded, and the calculation table is not verified
.

(4) The statistical methods used are not applicable to the data analyzed (involving the amount of data and data distribution).

(5) Product quality review analysis adopts data from different operations for trend analysis of dust particles and floating bacteria; Moisture and content analysis does not set correction limits and warning lines
.

(6) The procedural provisions require the calculation of the process capability index, but lack procedures
on how to calculate the process capability index.

(7) The trend was not analyzed statistically in the quality review of sodium chloride injection
.

(8) Compound licorice tablets, golden lotus clear heat granules, ammonia huangmin capsules, gentian diarrhea liver pills (water pills) did not analyze
the data exceeding 3δ (UCL) in this year's product annual quality review report.

(9) In the annual product quality review report of danshen drip infusion, although the total ash, alcohol-soluble extractable, water-soluble extract, and protocatecaldehyde content of different batches of danshen medicinal materials are within the correction limit, they vary greatly between batches, and the report does not analyze its possible impact on the quality of the finished product, which cannot guide the future improvement of the quality of the product
.

(10) There is an undesirable trend in the disintegration time limit item in the product quality review and analysis report of Huanglian supernatant tablets this year, and the reasons for the trend are not analyzed to guide production
.

(11) The internal control standard of the process regulations of the finished product yield of metformin hydrochloride is 66.
0%-92.
0%, which is too broad and is not conducive to controlling product quality
.
This year's product annual quality review analysis report shows that 17 batches of metformin finished product yield is close to the low limit of yield, and there is no analysis of the reasons in the
report.

4.
Product quality review and analysis report review and management of those common pits

(1) Insufficient resources for report writing and review (such as multiple report reviewers completing the review and signing within one day), it is difficult to ensure the consistency of key information, unable to effectively analyze trends, and difficult to identify process and product improvement content
.

(2) There are errors in the content of the product quality review report (such as conflicts before and after the content of the review report, inconsistent conclusions with data trends, errors in individual key process parameters and key quality attributes), such as a product described in a certain annual quality review a total of 8 over-standard results, but 28 over-standard results are listed in the annex, a total of 6 complaints are described in the report, but only 5 complaints
are in the annex.

(3) The product quality review report is not a controlled document, and lacks the report number and effective control method
.

References

[1] Key points analysis and research of GMP and product quality review[J], NMPA official website, etc