ICH Guidelines Show
This article focuses on ICH Q6A for testing new drugs—Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances—and considers pertinent sections, in order of their appearance within the guidance document. Where necessary, I have provided my comments after each excerpt. In some specific cases, the words of the Guidance are highlighted and underlined, followed immediately after by my related comments.
2.1 Periodic or Skip Testing
Periodic or skip testing is the performance of specified tests at release on pre-selected batches and/or at predetermined intervals, rather than on a batch-to-batch basis with the understanding that those batches not being tested still must meet all acceptance criteria established for that product. This represents a less than full schedule of testing and should therefore be justified and presented to and approved by the regulatory authority prior to implementation.
Author Comment: In a GMP-controlled process, the burden of testing every lot is time-consuming and expensive. Since end-product testing rarely identified process problems, 100% final testing of batches was deemed unnecessary. Under QbD/PAT, where the criterion of a set “design space” is to be met through feedback and feed-forward (continuous) testing, skip testing is an anathema. Perhaps this may be addressed in later attachments.
2.2 Release vs. Shelf-life Acceptance Criteria
The concept of different acceptance criteria for release vs. shelf-life specifications applies to drug products only; it pertains to the establishment of more restrictive criteria for the release of a drug product than are applied to the shelf-life.
Author Comment: There is much to be learned about an “ideal” from following stability samples more, not less closely. If a PAT paradigm is used to produce a product, wherein thousands of units are examined, it does not add to knowledge of the process to only examine six units for dissolution and (up to) ten for content uniformity. While it is necessary to show that a product remains potent and safe until the expiry date, merely taking small, non-statistical samples for stability tests reveals little about lot-to-lot variations over time.
Perhaps a monitoring system, utilizing techniques similar to process controls, could be in place to ascertain what percentage of units “change” over time. These “changes” could lead to testing of those units and, depending on how many outliers occur per lot, process conditions could be correlated (using multivariate algorithms) to help determine a design space which not only makes superior product for release, but has a longer shelf life. [This would be a financial benefit, since, with a longer shelf-life, fewer lots would be recalled or returned.]
2.3 In-process Tests
In-process tests, as presented in this guideline, are tests which may be performed during the manufacture of either the drug substance or drug product, rather than as part of the formal battery of tests which are conducted prior to release. In-process tests which are only used for the purpose of adjusting process parameters within an operating range, e.g., hardness and friability of tablet cores which will be coated and individual tablet weights, are not included in the specification.
Certain tests conducted during the manufacturing process, where the acceptance criterion is identical to or tighter than the release requirement, (e.g., pH of a solution) may be sufficient to satisfy specification requirements when the test is included in the specification. However, this approach should be validated to show that test results or product performance characteristics do not change from the in-process stage to finished product.
Author Comment: While this Guidance is only ten years old, the tests cited are ancient: hardness and friability are seldom telling about modern products. Certainly, they cannot be considered PAT/QbD tests of the 21st century. The reference to tests that are more stringent than release tests is a foreshadowing of “real-time” release testing…true QbD/PAT!
2.4 Design and Development Considerations
The experience and data accumulated during the development of a new drug substance or product should form the basis for the setting of specifications. [Author Comment: The learning curve may flatten as the product is made, but changes will become apparent as experience mounts. The “data accumulated” after product development should also be utilized to make a better product.] It may be possible to propose excluding or replacing certain tests on this basis. Some examples are:
- microbiological testing for drug substances and solid dosage forms which have been shown during development not to support microbial viability or growth (see Decision Trees #6 and #8); [Author Comment: Sounds logical, but a RMM could be used occasionally to be certain.]
- extractables from product containers where it has been reproducibly shown that either no extractables are found in the drug product or the levels meet accepted standards for safety; [Author Comment: The burden then may be shifted to a packaging control assay or vendor validation of the packaging supplier. Assuming that polymers are unchanging is very far from the reality of packaging.]
- particle size testing may fall into this category, may be performed as an in-process test, or may be performed as a release test, depending on its relevance to product performance; [Author Comment: Particle size has been demonstrated to be quite critical, especially in delayed/sustained release dosage forms. It should be tested prior to use on every lot! In addition, as we see in QbD, physical parameters of excipients should also be controlled.]
- dissolution testing for immediate release solid oral drug products made from highly water soluble drug substances may be replaced by disintegration testing, if these products have been demonstrated during development to have consistently rapid drug release characteristics (see Decision Trees #7(1) through #7(2)). [Author Comment: In the case of immediate release, this may be acceptable, but smacks of 1950s methodology.]
2.5 Limited Data Available at Filing
It is recognized that only a limited amount of data may be available at the time of filing, which can influence the process of setting acceptance criteria. As a result it may be necessary to propose revised acceptance criteria as additional experience is gained with the manufacture of a particular drug substance or drug product (example: acceptance limits for a specific impurity). The basis for the acceptance criteria at the time of filing should necessarily focus on safety and efficacy. [Author Comment: Yes! Could I suggest IVIVC or performance parameters of the finished product beyond mere dissolution as criteria? And acceptance criteria should focus on continued improvements, using those two criteria as a guideline.]
When only limited data are available, the initially approved tests and acceptance criteria should be reviewed as more information is collected, with a view towards possible modification. This could involve loosening, as well as tightening, acceptance criteria as appropriate. [Author Comment: Knowledge which comes from a working PAT program, not batch records of non-statistical testing.]
2.7 Alternative Procedures
Alternative procedures are those which may be used to measure an attribute when such procedures control the quality of the drug substance or drug product to an extent that is comparable or superior to the official procedure. Example: for tablets that have been shown not to degrade during manufacture, it may be permissible to use a spectrophotometric procedure for release as opposed to the official procedure, which is chromatographic. [Author Comment: This sentence sets the basis for PAT control of the product.] However, the chromatographic procedure should still be used to demonstrate compliance with the acceptance criteria during the shelf-life of the product. [Author Comment: This statement, however, is GMP-based. HPLC should be considered a reference method for QbD/PAT, not the only method. Consider that, in the early 1970s, HPLC as a release method was not accepted by the FDA. Its inclusion in an NDA would trigger immediate rejection.]
2.9 Evolving Technologies
New analytical technologies, and modifications to existing technology, are continually being developed. Such technologies should be used when they are considered to offer additional assurance of quality, or are otherwise justified.
Author Comment: This is the largest opening to PAT in the entire document and can lead to Q8, Q9, and Q10 in the minds of development scientists.
3.1.2 Justification of Specifications
When a specification is first proposed, justification should be presented for each procedure and each acceptance criterion included. The justification should refer to relevant development data, pharmacopoeial standards, test data for drug substances and drug products used in toxicology and clinical studies, and results from accelerated and long term stability studies, as appropriate. Additionally, a reasonable range of expected analytical and manufacturing variability should be considered. It is important to consider all of this information.
Author Comment: While not meant to refer to PAT and physical parameter control, it opens the door. This one section lays the foundation for PAT, years before PAT was considered.
3.3.2 New Drug Products
Additional tests and acceptance criteria generally should be included for particular new drug products…. Application of the concepts in this guideline to other dosage forms is encouraged.
The following tests are applicable to tablets (coated and uncoated) and hard capsules. One or more of these tests may also be applicable to soft capsules and granules.
a) Dissolution: The specification for solid oral dosage forms normally includes a test to measure release of drug substance from the drug product. Single-point measurements are normally considered to be suitable for immediate-release dosage forms. For modified-release dosage forms, appropriate test conditions and sampling procedures should be established. For example, multiple time point sampling should be performed for extended-release dosage forms, and two-stage testing (using different media in succession or in parallel, as appropriate) may be appropriate for delayed-release dosage forms…
For immediate-release drug products where changes in dissolution rate have been demonstrated to significantly affect bioavailability, it is desirable to develop test conditions which can distinguish batches with unacceptable bioavailability. If changes in formulation or process variables significantly affect dissolution and such changes are not controlled by another aspect of the specification, it may also be appropriate to adopt dissolution test conditions which can distinguish these changes (see Decision Tree #7(2)).
Where dissolution significantly affects bioavailability, the acceptance criteria should be set to reject batches with unacceptable bioavailability. Otherwise, test conditions and acceptance criteria should be established which pass clinically acceptable batches (see Decision Tree #7(2)).
For extended-release drug products, in vitro / in vivo correlation may be used to establish acceptance criteria when human bioavailability data are available for formulations exhibiting different release rates. Where such data are not available, and drug release cannot be shown to be independent of in vitro test conditions, then acceptance criteria should be established on the basis of available batch data. Normally, the permitted variability in mean release rate at any given time point should not exceed a total numerical difference of +/-10% of the labeled content of drug substance (i.e., a total variability of 20%: a requirement of 50 +/- 10% thus means an acceptable range from 40% to 60%), unless a wider range is supported by a bioequivalency study (see Decision Tree #7(3)).
Author Comment: While dissolution is a complex and, sometimes, controversial test method, it is still a fact of pharmaceutical life. When IVIVC data is established, there may be some correlation potential of dissolution rate with spectral data. I would suggest that this correlation be used to monitor, not release, the product. The process of continuous/sustained/delayed release products is quite complex and, barring many, many lots experience, a mere NIR correlation may not reliably always predict dissolution behavior. It is, however, quite possibly the perfest tool for monitoring (non-destructively) vast numbers of stability samples for changes in dissolution profile post-production.
b) Disintegration: For rapidly dissolving (dissolution >80% in 15 minutes at pH 1.2, 4.0 and 6.8) products containing drugs which are highly soluble throughout the physiological range (dose/solubility volume < 250 mL from pH 1.2 to 6.8), disintegration may be substituted for dissolution.
Author Comment: This is probably alright as written. Barring extreme changes to the drug or unexpected binding with the matrix (usually excluded in formulation and early production work), it is effective for immediate release products.
c) Hardness/friability: It is normally appropriate to perform hardness and/or friability testing as an in-process control (see section 2.3).
Author Comment: This property was important when sugar coating tablets with a water matrix. There is no specific reason not to perform this test, although it probably may be correlated spectrally.
d) Uniformity of dosage units: This term includes both the mass of the dosage form and the content of the active substance in the dosage form; a pharmacopoeial procedure should be used. …. If appropriate, these tests may be performed in-process;
Author Comment: The highlighted portion of the paragraph speaks for itself. While not explicitly advocating on-line testing, it certainly allows it.
e) Water content: A test for water content should be included when appropriate. … a Loss on Drying procedure may be considered adequate; however, a detection procedure which is specific for water (e.g., Karl Fischer titration) is preferred.
Author Comment: No, a spectrophotometric procedure is preferred; a KF or LOD makes a good reference tool to calibrate, i.e., a near-infrared spectrometer.
f) Microbial limits: Microbial limit testing is seen as an attribute of Good Manufacturing Practice, as well as of quality assurance. …
Author Comment: Until rapid, specific microbial methods are validated, the criteria in this guidance will need to be followed.
There are a number of sections and subsections in this guidance which may be interpreted as encouraging PAT. However, the wording, by and large, still relates to wet chemical and HPLC testing of intermediates and products. There is a definite need to either refer to or harmonize with later (Q8, Q9, Q10, and soon Q11) guidances.