Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products - Quality Considerations
2013-289 Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products - Quality Considerations
2018-06-13 2018-06-20 2018-06-20 2018-06-20 2018-05-11 2021-09-17 2018-05-29 2018-05-29 2018-05-03 2020-11-30
FDA-2018-D-1098-0011 FDA-2018-D-1098-0013 FDA-2018-D-1098-0023 FDA-2018-D-1098-0014 FDA-2018-D-1098-0007 FDA-2018-D-1098-0032 FDA-2018-D-1098-0010 FDA-2018-D-1098-0009 FDA-2018-D-1098-0004 FDA-2018-D-1098-0030
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https://api.regulations.gov/v4/comments/FDA-2018-D-1098-0011 https://api.regulations.gov/v4/comments/FDA-2018-D-1098-0013 https://api.regulations.gov/v4/comments/FDA-2018-D-1098-0023 https://api.regulations.gov/v4/comments/FDA-2018-D-1098-0014 https://api.regulations.gov/v4/comments/FDA-2018-D-1098-0007 https://api.regulations.gov/v4/comments/FDA-2018-D-1098-0032 https://api.regulations.gov/v4/comments/FDA-2018-D-1098-0010 https://api.regulations.gov/v4/comments/FDA-2018-D-1098-0009 https://api.regulations.gov/v4/comments/FDA-2018-D-1098-0004 https://api.regulations.gov/v4/comments/FDA-2018-D-1098-0030
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Comment - 1-How many serial analyzes are recommended for acceptance criteria in validation studies to be performed for APSD preliminary routine analysis on line 918-919. Can we use the 10 percent limit as the change in the stability study on line 1417-1418 as the batch to batch limit in routine analysis?Comment - 2 - Lne 978 and line 1035 have the same table number. At line 1027 you are directed to table 8,but table 8 does not exist. Please correct your error. Line 1035 should be typed as table 8 correctly Comments from SRF Limited are enclosed. Comments from The Association for Accessible Medicines (AAM) on behalf of our member companies, regarding Docket FDA-2018-D-1098: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products - Quality Considerations. 1- Does Other organic impurities in Table 4 refer to individual impurity in HFA-134a?2- What would constitute a good justification for not using PTIT approach for measuring Delivered Dosage uniformity (DDU)?3-  Lines 865 and 866 state that the volume of collection for Delivered Dosage Uniformity (DDU) should not exceed 2 L at a constant flow rate. Can the agency explain why is there a limit to the volume of collection for DDU analysis?4- Can Effect of Patient Use study be performed on samples from PK study for generic developers?   Cipla has following Comments on section IV. A. of the guidance:Comment no. 1:We understand, to obtained consistent physical attribute of micronised drug substance, it is critical to have consistent physical attribute (i.e. morphology, Polymorph, particle size  amorphous content) of in-put non-micronised drug substance.  Hence, we propose to include requirement for demonstrating consistent physical characterisation in three consecutive non-micronised batches and corresponding micronised batches.Comment no. 2:Guidance specify Morphology tests should be part of release and stability specifications. Under Morphology, guidance specify examples like  shape, crystal habit, texture, surface area, and rugosity. Different techniques are used to determine above listed characteristics. For e.g. Shape and crystal habit is determined by using G3 morphology and/or SEM techniquesIGC-SEA or BET technique is used for Surface area determination.Cipla believe, above characteristics studies can be part of one time characterisation requirement in three consecutive micronised and non-micronised batches along with stability of three micronised. Once consistency is demonstrated, Industry need not be including these tests as part of routine release and stability specifications.  Comment 3:We request Agency to provide guidance to Agency on  preferred Analytical method to be used for above characteristics test like rugosity, Texture etc. In Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products - Quality ConsiderationsGuidance for Industry, there is likely an type error. In the page 44, the talbe D is named One-sided Tolerance Interval Factors (k1) for 95 Percent Confidence Level and 90 Percent Coverage37. When search 2.566 in the reference 37 (Hahn and Meeker, Statistical Intervals  A Guide for Practitioners, John Wiley and Sons, Inc), this number appear in the Table A.12d named Facters for calculating Normal distribution one-sided 100(1-)% Tolerance Bounds and the corresponding P is 95% and corresponding Confidence level is 95%，but the talbe D is labeled with 95% Confidence Level and 90 Percent Coverage. This is a discrepancy. please clarify it. Thanks. IDD-Xpert has following comments :Comment n1 : line 853 - typo comment - replace Dosage by Dose to be consistent with Table 6 terminology (line 823).Comment n2 : line 924 - the following part of the sentence the mass balance (i.e the amount of drug substance deposited on all surfaces from the VALVE to the equipment filter)... involves to calculate the total ex-valve. However the mass balance is compared to the range between 85 and 115 percent of TDD. TDD according to line 655 corresponds to  the mass of drug delivered from the mouthpiece per actuation, i.e the total ex-device. Please could you specifiy if mass balance needs to be calculated from the total ex-valve or the total ex-device? This QC Draft Guidance makes no reference as to how combination products, both MDIs and DPIs, such as LABA/LAMAs, LABA/ICS and LABA/LAMA/ICS are to be assessed in vitro. One could assume that for combination products, each API should be assessed individually, but in my view, these requirements should be defined in the guidance document rather than leave it to interpretation.  There is also no reference to other non-COPD, asthma indications and the QC assessment for inhaled drugs, MDI, DPI, nebulizer) prescribed for their treatment. 1) The scope should be extended to also include spacers - plastic parts used as an accessory in conjunction with MDI to assist the administration of the drug to elderly and young children who have difficulty in breathing. These components are potentially changing the DDU and also influence potential leachables from the plastics.  The plastics used in these spacers can contain both pigments and / or dyes to impart color and additives to provide anti-static properties to the surface.2) Controls for incoming materials. (line 528)  Since USP has defined a risk based strategy of how to assess drug contacting materials in the recent publication USP661.1 materials of construction  reference should be given to this standard. This sets out a logical approach to materials design and control.  Table 6 and Table 7 should also make reference to this standard.3) Line 959  - same as point 2.4) Reference in addition to ICH-Q3D elemental impurities should be considered. The limitation of USP661.1 is that it only looks for extractable metals that you expect to find in the plastics as carry-over of catalyst from the polymerization process. However immediately the plastic is colored ( as is the case in most of the MDI and DPI), there are many more possible metals that should be considered, and appear in the list in the ICH-Q3D and USP232.  Recommend that specific reference should be made to both standards.  5) There is no reference to change control. The industry seems to think that providing they carry out a qualification test on final parts and 3 batches, then nothing changes. They are quite surprised to understand that a polymer and / or color can change in its ingredients, still have the CAS Nr and % but have an effect  on DDU or leachables.   It should be clearly stated that the materials used in the plastic parts should have documented evidence of change control being implemented. Ideally these materials should have a DMF conforming to latest FDA standard.  Dear sirPrimimg and reprimg Drug product characterization studies needs to be done only at single time point