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Two new FDA Warning Letters for API Manufacturers in China

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Two new FDA Warning Letters for API Manufacturers in China

In June 2016, two API manufacturers in China received a Warning Letter from the FDA. Both companies had major deficiencies regarding data integrity. For instance, manipulations were found in HPLC analyses as well as in GC analyses. You will find more information on the current FDA Warning Letters for Chongqing Lummy and Shanghai Desano here.,15484,Z-QCM_n.html
The Chinese Company Chongqing Lummy Pharmaceutical Co., Ltd. received a Warning Letter from the FDA on June 21, 2016. This Warning Letter referred to both the FDA inspection from March 14-16, 2016 and the response which the API manufacturer had sent to the FDA on March 31, 2016.

It was claimed that Chongqing Lummy Pharmaceuticals had no adequate control in place to prevent data manipulation or deletion. The FDA investigator’s review of the audit trail revealed that an analyst had manipulated the computerized gas chromatography (GC) system to falsify residual solvent results for several API batches.

The analyst had set back the clock of the GC computer to make it appear that the test had been done 7 months earlier. Then he analyzed 5 different injections in order to determine the 12-month value of the long-term stability test. Afterwards, the analyst deleted the original data and only reported the five new results that were conform. The FDA inspection revealed that this procedure of setting back the clock was conducted with at least five other API batches.

During the review of the HPLC system, the FDA inspector found that the HPLC system was configured in a way that analytical results were automatically deleted whenever a test was aborted prior to completion. The review of the audit trail for the Chemstation software indicated that during the analyses of content and impurities, the partial results of aborted tests were automatically deleted from the HPLC system’s records of these analyses. The clock was also set back on the computer for the HPLC analyses in order to retrospectively obtain “conform” results for stability tests.

The company’s response on March 31, 2016 wasn’t satisfactory for the FDA, either. In summary, the FDA writes: “Your response does not indicate how the software upgrades, the SOP revisions or trainings suggested by you can prevent data deletion in the future nor how your quality unit intends to guarantee that the data critical for approval are complete and correct. A response to the FDA is expected within 15 working days. And if you plan to discontinue the delivery of API to the U.S. altogether, FDA requests that you contact CDER’s Drug Shortages Staff immediately.”

Also with the second API manufacturer (Shanghai Desano Chemical Pharmaceutical Co., Ltd.), the data of the laboratory tests were targeted. Here, the main complaint was that laboratory staff performed “unofficial” tests without adequate documentation, justification or investigation:
The original, unofficial analyses were stored in a separate “test folder” and were not part of the official QC data. The inspection revealed that this company had performed about 8,400 of these unofficial chromatographic analyses between 2012 and 2014. According to their internal SOP, all these tests should have been documented. The volume of data in these auxiliary “test folders” suggests that performing unofficial analyses is a common practice at this facility.

You can open the two Warning Letters using these links:
Chongqing Lummy Pharmceutical Co., Ltd.
Shanghai Desano Chemical Pharmaceutical Co., Ltd.

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Is AQL Testing required within the 100% Visual Inspection?

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Is AQL Testing required within the 100% Visual Inspection?
One of the most frequently asked questions is whether an additional testing based on samples is required after the 100% visual inspection of parenterals. The answer is: basically, “yes”.,15484,Z-QCM_n.html

One of the most frequently asked questions is whether an additional AQL testing based on samples is required after the 100% visual inspection of parenterals. The background for that question is the probabilistic nature of visual inspection. It is known that the discovery of defects (like for example particulates) is a matter of detection probability. In other words, visual inspection cannot exclude that defective containers may still be in the batch which hasn’t been sorted out. This applies to manual, semi-automatic and also automatic visual inspection.

The American Pharmacopoeia has reacted to that and has integrated AQL testing in the monograph Visible Particulates in Injections. Here, the value 0.65 has been specifically added for particles testing. This also meets the requirement that injectables have to be essentially free of particles – which is not measurable in this form but with an AQL limit of 0.65. Depending on the batch size and using DIN/ISO tables, it can be determined how large the sample to be extracted has to be after the 100% inspection. It is also set in how many of these samples particles can still be found. Depending on the criticality defined priorly, other defects may required other respective AQL limits.

In Europe, there isn’t any explicit i.e. written requirement for AQL testing (yet). But it is already a state of the art in science and technology. GMP inspectors are also aware that a 100% inspection is “erroneous”, which means that a 100% sorting of defects is not always ensured. The ECA Visual Inspection Interset Group’s Best Practice Guide goes along with the same approach, too. Of course, there are other ways thinkable to optimise the quality of visual inspection, like for example a general second 100% inspection of all batches. This is already practised in many companies; however, only for charges destined to the Japanese market.
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FDA published generic user fee for 2017: for ANDA, DMF, and for Facility (API, FDF)

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Generic drugmakers submitting abbreviated new drug applications (ANDAs) and prior approval supplements (PAS) will see their US Food and Drug Administration (FDA) fee rates drop in 2017, though all other rates, including those for drug master files (DMF) and facility fees will increase when compared to 2016.

For FY 2017, the generic drug fee rates are: ANDA ($70,480, down from $76,030 in 2016), PAS ($35,240, down from $38,020 in 2016), DMF ($51,140, up from $42,170 in 2016), domestic active pharmaceutical ingredient (API) facility ($44,234, up from $40,867 in 2016), foreign API facility ($59,234, up from $55,867 in 2016), domestic finished dose formulation (FDF) facility ($258,646, up from $243,905), and foreign FDF facility ($273,646, up from $258,905 in 2016).

The new fees are effective 1 October 2016 and will remain in effect through 30 September 2017.

FDA explained the increases and decreases in fees, noting that for ANDA and PAS fees, the agency is expecting an increase in the number of submissions estimated to be submitted in FY 2017 when compared to 2016. For 2017, the agency estimates that approximately 891 new original ANDAs and 439 PASs will be submitted and incur filing fees.

Fees for DMFs will increase, meanwhile, because of an expected decrease in the number of submissions estimated to be submitted in 2017 (FDA is estimating 379 fee-paying DMFs for 2017), when compared to the estimated submissions from 2016.

And all facility fees will increase in 2017 when compared to the previous year because of a decrease in the number of facilities that self-identified (the total number of FDF facilities identified through self-identification was 675, of which 255 were domestic facilities and 420 foreign facilities; while the total number of API facilities self-identified was 789, of which 101 were domestic facilities and 688 were foreign facilities), FDA said.

How FDA Calculates the Fees

In order to calculate the ANDA fee, FDA estimated the number of full application equivalents (FAEs) that will be submitted in FY 2017, which is done by assuming ANDAs count as one FAE and PASs (supplements) count as one-half of an FAE, since the fee for a PAS is one half of the fee for an ANDA.

The Generic Drug User Fee Act (GDUFA) also requires that 75% of the fee paid for an ANDA or PAS filing be refunded if either application is refused due to issues other than a failure to pay the fees.

And since this is the last year of this iteration of GDUFA (the next version is still in the works), the agency is allowed to further increase the fee revenues and fees established if such an adjustment is necessary to provide for not more than three months of operating reserves for the first three months of FY 2018, though FDA estimates that the GDUFA program will have carryover balances for such activities in excess of three months of such operating reserves, so FDA will not be performing a final year adjustment.

To pay the fees, companies must complete a Generic Drug User Fee Cover Sheet, available at and generate a user fee identification (ID) number. Payment must be made in US currency drawn on a US bank by electronic check, check, bank draft, US postal money order or wire transfer.

Federal Register Notice

See more at:

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WHO Draft on Analytical Method Validation

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The World Health Organization (WHO) recently published a draft document on analytical method Validation for comment. Read more about the draft “Guidelines on Validation – Appendix 4 Analytical Method Validation“.,15438,Z-PDM_n.html

In June 2016 the World Health Organization (WHO) published a draft document “Guidelines on Validation – Appendix 4 Analytical Method Validation”. Comments on the text should be sent to WHO until July 30, 2016.

The appendix 4 of the published Supplementary guidelines on good manufacturing practices: validation (WHO Technical Report Series, No. 937, 2006, Annex 4) has been revised in view of current trends in validation. The appendix presents some information on the characteristics that should be considered during validation of analytical methods. Approaches other than those specified in the Appendix may be followed and may be acceptable.

The new Appendix 4 is structured as follows (New and revised):

1. Principle (revised):

  • 1.5 The recommendations as provided for in good laboratory practices and guidelines for transfer of technology (WHO Technical Report Series, No. 961, 2011, Annex 7) should be considered, where applicable, when analytical method validation is organized and planned.

2. General (revised):

  • 2.6 The procedure should become part of a continuous verification procedure to demonstrate that it meets the predefined criteria over the life of the procedure.
  • 2.7 Trend analysis and risk assessments should be considered at intervals to ensure that the method is appropriate for its intended application.
  • 2.8 Changes to methods should be managed in accordance with the authorized change control procedure.
  • 2.9 The scope of verification or degree of revalidation depend on the nature of the change(s) and the outcome of risk assessment.
  • 2.11 The data obtained during method validation and verification should be considered covered by good anything practices (GxP) requirements and are expected to follow the principles of good data and record management practices. Their associated metadata are also expected to be retained and subjected to good data and record management practices (WHO Technical Report Series, No. 996, 2016, Annex 5).
  • 2.12 When computerized systems are used to obtain and process data relating to method validation and verification, they should comply to the principles enunciated in Appendix 5 – Validation of computerized systems.
  • 2.13 Adequate attention should be paid to the method of sample preparation.
  • (…)

3. Pharmacopoeial methods
4. Non-pharmacopoeial methods
5. Method validation
6. Method verification (New):

  • 6.1 Method verification should be performed for already validated analytical methods, for example, when it is used on a product for the first time (e.g. in case of a change in API supplier, change in method of synthesis or after reformulation of a drug product).
  • 6.2 Method verification may include only the validation characteristics of relevance to the particular change.
  • (…)

7. Method revalidation (New):

  • 7.1 Methods should be maintained in a validated state over the life of the method. Revalidation (see also ICH Q2) should be considered whenever there are changes made to the analytical method (e.g. changes to mobile phase, column, column temperature, detector).
  • 7.2 In case of repeated SST failures or when obtaining of doubtful results. In such cases an investigation of the root cause should be performed, the appropriate changes made and the method revalidated.
  • 7.3 Periodic revalidation of analytical methods should be considered according to a period that is scientifically justifiable.
  • (…)

8. Method transfer  (New)

  • 8.1 During method transfer, documented evidence should be established to prove that a method has equivalent performance when used in a laboratory different from that where it has been originally validated.
  • (…)
  • 8.3 The two sets of results should be statistically compared and the differences between the two sets of test results should be within an acceptable range.
  • 8.4 Method transfer should be performed before testing of samples for obtaining critical data for a dossier, such as process validation or stability studies or applied for routine use.
  • (…)

9. Characteristics of analytical procedures (revised), 9.3 System suitability testing:

  • 9.3.1 The suitability of the entire system should be confirmed prior to and during method validation tests as well as during the test of samples.
  • 9.3.2 System suitability runs should include only established standards or reference materials of known concentration to provide an appropriate comparator for the potential variability of the instrument.
  • 9.3.3 Where a sample is used for system suitability or a trial run, written procedures should be established and followed and the results of all such trial runs be included in the results and data review process. A sample can be used only if it is a well characterized material. Characterization in such a case should be performed prior to the use of this sample as part of system suitability testing. The sample material or product under test should not be used for trial run purposes or to evaluate suitability of the system (see WHO guidelines on good data and record management practices).

The revised version of appendix 4 parallels certain considerations of the current USP lifecycle approach for analytical method validation. However, QbD concepts and the Analytical Target Profile (ATP) – which is equivalent to the Quality Target Product Profile (QTPP) – have not yet been introduced in the WHO draft.

According to WHO the draft of Appendix 4 will also be placed on the WHO Medicines website under “Current projects“.

Members of the ECA Academy are able to access the new WHO Guidelines on Validation – Appendix 4 Analytical Method Validation in the ECA Members Area.


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