Introduction
As a consultant I have received questions from colleagues as to whether the Chinese Pharmacopeia (ChP) microbial test methods are equivalent to the U.S. Pharmacopeia (USP) methods. Frankly, I was at a loss as how to answer this question. As all drugs marketed in China are expected to comply with the ChP, global pharmaceutical manufacturers using USP/Ph. Eur. /JP test methods would hope to obtain comparable results and make equivalent release/reject decisions for drug products destined for China. Some good news was the June 19, 2017 announcement that the International Council for Harmonization (ICH) has added China’s FDA (CFDA) as a new regulatory member so more harmonized approaches to regulatory submission can be expected from the Chinese. Founded in 1990 by the U.S., European and Japanese drug regulatory authorities to standardize regulatory submissions, now with the addition of the People’s Republic of China, the ICH has fourteen members. An important part of the Chinese Food and Drug Administration (CFDA) new drug submission process is that sufficient material from one batch to conduct three tests must be submitted to a Chinese testing institute to obtain approval. This exposes pharmaceutical manufacturers to the risk of discrepant results in the physical, chemical and microbiological testing that will stall the drug approval process. This risk is compounded by importation testing of each lot of the approved drug product. The ongoing revision to the ChP due in 2020 will offer the opportunity to bring the major pharmacopoeia closer together.
Scope of the Article
This analysis will be limited to a discussion of antimicrobial effectiveness, microbial limits and sterility testing. No attempt was made to review the Guiding Principle chapters. This article addresses the English translation of the 2015 ChP and can only speculate, after the review of recent public statements, as to the content of the 2020 ChP.
Brief History of the Chinese Pharmacopeia
The People’s Republic of China Ministry of Health founded the Chinese Pharmacopoeial Commission (ChPC) in 1950. Ten editions of the Chinese Pharmacopeia (ChP) have been published since the first in 1953, with a new edition published every 5 years since 1985. ChP 2015 was issued June 5, 2015 and the ChPC is currently working on ChP 2020. Of most interest to pharmaceutical microbiologists is ChP Volume IV that contains the microbial test methods and the guiding principle chapters. The stated developmental direction of ChP 2020 is to complete and standardize the test methods so where the current methods are similar to the tripartite compendial methods we may expect no major changes.
Contents of ChP 2015 Volume IV
Volume IV has four section: IV-1 General Requirements for Preparation, IV-2 Testing Methods, IV-3 Guidance Principles and IV-4 Pharmaceutical Excipients. There are thirteen biological test methods and twenty-four guiding principle chapters.
The pertinent chapters are:
Testing Methods
- 1101 Sterility tests
- 1105 Microbiological examination of non-sterile products: microbial enumeration tests
- 1106 Microbiological examination of non-sterile products: Tests for specified microorganisms
- 1107 Microbiological acceptance Criteria of Non-sterile Pharmaceutical Products
- 1121 Antimicrobial effectiveness testing
Guidance Principles
- 9201 Guiding principles of validation of alternative microbiological methods for pharmaceutical products
- 9202 Guiding principles of microbial limit tests in in non- sterile pharmaceutical products
- 9203 Guiding principles for quality control of microorganisms in non-sterile pharmaceutical products
- 9204 Guiding principles of microbiological assay
- 9205 Guiding principles for microorganism monitoring and control in a clean pharmaceutical product laboratory
- 9206 Guiding principles of isolated system verification used for a sterility test
Requirements for Sale of Pharmaceutical Drug Products in the Peoples Republic of China
ChP is prepared and promulgated according to the Drug Administration Law of the People’s Republic of China; it is official and compulsory quality standards for all medicinal products marketed in China.
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An important part of the new drug submission process is that sufficient material from one batch to conduct three tests must be submitted to a Chinese testing institute to obtain approval. Currently, only the National Institute for Food and Drug Control and its provincial counterparts can conduct these drug registration tests. Revisions allowing qualified private testing institutions to handle drug registration tests are under discussion. In limited cases, the Chinese testing institutes may lack the equipment and/or expertise to run specific tests. This requirement exposes pharmaceutical manufacturers to the risk of discrepant results in physical, chemical and microbiological testing that may stall the drug approval process.
The two other testing categories are importation testing which may be partial or full testing to meet the ChP requirements or surveillance testing to periodically verify compliance.
Garbe et al (2015) based on a 2014 industry survey of import testing of pharmaceutical products found that the testing had a limited safety benefit and delays the availability of the drug products to the Chinese people. Data was analyzed from six global pharmaceutical companies on their experience in 149 countries. The six companies reported 18,616 re-tests for importation, 23 out-of-specification investigations (0.34%), and one batch rejection (0.005%). The average supply chain delay ranged from 2 to 19 weeks. The survey determined that average global cost per re-test was €2950. The data strongly indicated that importation testing especially drug products from big pharma companies manufacturing, with their strict adherence to good manufacturing practices, has no impact on product quality and patient safety and should be discontinued.
Based on the 2014 survey, there are three levels of lot release testing. They are merely reviewing the summary lot protocol and not testing, reviewing the summary with partial testing, and reviewing the summary with full testing. As shown in the survey many countries waiver the testing requirements.
How did China fare in this survey? At the time of the survey, the People’s Republic of China required full testing in government testing laboratories with no waiver possibilities. The long delays in import testing, reportedly from 18 to 22 weeks, increased inventory costs, and the seriously impacted available shelf life of the lots makes it more challenging to market drugs in China.
Do the Compendial Methods Give Equivalent Results and Decisions for an Individual Drug Product?
As stated in USP <1223> four options are available to establish the equivalence of a candidate alternative analytical method: (1) acceptable procedures (i.e., merely meeting a minimum performance or acceptance requirement without a need to demonstrate equivalence to the compendial method); (2) performance equivalence to the compendial method; (3) results equivalence to the compendial method; and (4) decision equivalence to the compendial method. How are these options applied to ChP methods?
When results equivalence is required as for USP <61> and ChP 1105, the hypothesis to be tested is that the two compendial test methods give equivalent numerical results. This contrasts with the evaluation of the validation parameters, as is done in performance equivalence. Because the same sample cannot be tested in microbiology, typically a tolerance interval is established when comparing the two methods, with the alternative method determined to be numerically superior or non-inferior.
A decision equivalence is similar to results equivalence but differs in that a numerical result is not generated; instead a pass/fail result is obtained. With this approach, the frequency of positive and negative results generated with the ChP 1106 method should be no worse than with the USP <62> method. This non-inferiority requirement is based on the long history of product quality tested by and released with the referee compendial test. For the purposes of qualification, laboratory studies involving spiking low levels of microorganisms may be considered.
What strategy should a U.S. manufacturer marketing their products in China pursue? The options are: 1) to qualify the USP <61>, <62> and <71> test method for each drug product and assume that the results will be equivalent to the ChP methods; 2) formally validated the USP method as equivalent to the ChP methods and routinely use the USP methods to release product for shipment to China; or 3) qualify the ChP 1101, 1105, and 1106 methods and routinely use the ChP methods to release product to the China market.
Options 1 through 3 range from the least conservative to the most conservative option. This author supports option two as it would demonstrate result and decision equivalency between the ChP and USP methods and avoids the compliance risk testing a batch with two tests that potentially exposes a released batch to an out-of- specification result. An example of this type of headache is testing a partial shipment to China with sterility testing performed by a contract-testing laboratory that botched the sterility test placing the entire batch at jeopardy.
Chinese Pharmacopoeial Standards for Pharmaceutical Excipients
The microbiological quality of excipients used in manufacturing drug product is critical. The ChPC has published the 2016 Standards Comparison of Pharmaceutical Excipients in Pharmacopoeias to help drug manufacturers comply with different compendial monographs. Table 1 demonstrates that the ChPC is progressively adding the monographs from the USP, Ph. Eur., and JP to the ChP. This will make it easier for Chinese manufacturers to sell drug products overseas and foreign manufacturers to sell drug products in China.
Plans for the Future Revisions to the Chinese Pharmacopeia
As reported by Haigney (2015) in their continuous efforts to harmonize standards, USP and the Chinese Pharmacopoeia Commission (ChP) jointly hosted the ChP and USP Science Symposium and 2014 ChP Science Annual Meeting on Nov. 13-14 in Chengdu, China. The theme of the meeting was “Strengthening cooperation, Harmonizing standards, Promoting mutual recognition” and focused on international coordination and mutual recognition of pharmaceutical standards in chemical medicine, biologics, traditional Chinese medicine, pharmaceutical excipients, packaging materials, and other related fields. According to a press release, “ChP and USP encouraged participants to engage with pharmacopoeias to explore ways of promoting international cooperation and harmonization, and mutual and multilateral recognition. USP and ChP also engaged in bilateral discussion about future opportunities to work together.”
A high level comparison of the USP and ChP microbial test methods is given in Table 2.
Detailed Comparison between the Microbial Test Method in the 2015 Chinese Pharmacopeia and U.S. Pharmacopeia 41
1101 Sterility tests
The formulation, preparation, sterility and growth-promotion testing of the fluid thioglycollate and soybean-casein digest media are essentially the same, with minor differences. The ChP method specified media water and not purified water as an ingredient, specifies five containers of sterilized media be incubated as a sterility test, likewise the volumes of each media subject to growth-promotion testing is specified. The ChP method recommends a storage time in sealed containers of up to one year and unsealed container for up to three months. Another difference is that the ChP method recommends the use of CMCC strains for growth-promotion and method suitability testing obtained from the Chinese National Center for Medical Culture Collection. The history of deposition of these ATCC equivalent cultures indicated that they came from the Soviet Union.
With respect to the actual test, issues are the number of units tested and the minimum quantity of product tested per media, the inclusion of negative and positive controls, and reasons for the invalidation of a failing test result. The number of units test for both the ChP and USP tests (Table 3 in USP <71>) is identical for parenteral preparations, large-volume parenterals, bulk solid products, and medical devices but the ChP lists requirements for freeze-dried blood products, ophthalmic injectable products, antibiotic raw materials bulk biologics and in vitro diagnostic products that are not addressed in the USP test. In terms of the minimum quantity of product per container to be tested (Table 2 in USP <71>) the requirements for aqueous solutions and solid products are identical but the ChP test has requirements for bulk biologics (undefined) and medical devices (different requirements). Pharmaceutical companies importing small volume parenterals will not have problems defining the test method but other products will need to be reviewed on a case-by-case basis with the Chinese authorities. The use of a positive control is not a part of the USP test so will require attention. The author believes that a test method for a specific product that has met the method suitability requirements should not have a positive control that is problematic when conducting a sterility test in highly controlled testing environment. The ChPC should eliminate this requirement.
1105 Microbiological examination of non-sterile products: microbial enumeration tests
There is little or no difference between the ChP and USP methods. Both tests recommend 10 g sample but the ChP chapter recommends that the sample be obtained from no less than two randomly selected packaging units and defines a negative control for the test.
1106 Microbiological examination of non-sterile products: Tests for specified microorganisms
There is little or no difference between the ChP and USP methods. Use of Triple sugar iron agar as indicative for Salmonella spp. and Candida chromogenic agar as indicative for C. albicans. Also tests for oxidase is added to aid the identification of P. aeruginosa and catalase is added to aid the identification of Clostridium spp. A positive control is routinely run with each test.
1107 Microbiological acceptance criteria of non-sterile pharmaceutical products
Differences in the ChP microbiological acceptance criteria include adding the absence of Salmonella spp. in 10 mL or 10 g for oral products, if they contain organic extracts, absence of E. coli in 1 mL or 1g for products of oromucosal, gingival, nasal and inhalation use, and absence of S. aureus and P. aeruginosa in 1 mL or 1 g for rectal products. These requirements will change the microbial specifications of many non-sterile dosage forms. The value of an absence of E. coli screening test for products other than oral dosage forms can be questioned. The ChPC should take the opportunity to harmonize the acceptance criteria with the USP/Eur. Ph. /JP chapter (see table 3).
121 Antimicrobial effectiveness testing
The ChP method recommends growing the inocula in liquid culture, harvesting the cells by centrifugation, washing the cells, and making a stock inoculation suspension. The acceptance criterion for validating the recovery of the challenge organisms is greater than 70% not between 50-200% as required in the USP method. The categories and acceptance criteria are comparable to the Ph. Eur. 5.1.3 but not USP <51> (See Tables 4.A, 4.B and 4.C). As the USP/Ph. Eur. /JP acceptance criteria are not harmonized, it may be expected that ChP will continue to follow the Ph. Eur. acceptance criteria.
Conclusions
The pharmaceutical industry can expect that ChP 2020 Volume IV Biological Tests will contain methods for microbial limit and sterility testing harmonized with the USP/Ph. Eur. /JP test methods. Other future regulatory changes may be the waiving of importation testing for foreign pharmaceutical manufacturers with good GMP compliance records and authorization to use Chinese contract testing laboratories when required. With the rapid changes in the biotechnology and pharmaceutical industries, the ChPC should consider moving from an every 5-year revision to an annual revision cycle.
References
- Garbe, J. H. O., K. Ennis et al, Import Testing of Pharmaceutical Products Has Limited Safety Benefits and Can Add Risk to Patients, Pharmaceutical Technology API, Excipients & Manufacturing Supplement 39 (9) s18–s26 (2015).
- S. Haigney, “Standards Organizations Update, ”Pharmaceutical Technology 39 (1) 2015
- Hong, X. X. 2016. Brief introduction of Chinese Pharmacopoeia 2015Volume IV Presentation at the Sino-Euro Pharmacopoeia Seminar, Strasbourg, France, October 17, 2016
- USP41/NF36 <1223> Validation of Alternative Microbiological Methods