PHARMACEUTICAL SCIENCES - QUESTIONS AND ANSWERS

Transcription

1 PHARMACEUTICAL SCIENCES - QUESTIONS AND ANSWERS The document PHARMACEUTICAL SCIENCES - QUESTIONS AND ANSWERS is intended to provide clarification on a number of issues that relate to Quality (e.g., Chemistry and Manufacturing) and Biopharmaceutics (e.g., Bioequivalence/Bioavailability) information of human drug submissions for pharmaceutical-type products. It is based on the current thinking on the topic. They are indented to briefly communicate in easily understood and comprehensible manner, requirements and practices or interpretations responding to the relevant questions in specific areas of Pharmaceutical Sciences. To facilitate the review of this Q&A Document, the format and structure is based on ICH's Common Technical Document (CTD). It is acknowledged that not all modules of the CTD have been included (e.g., Module 4 has been omitted). The Q&A Document only includes those modules and sections that have questions related to Quality or Biopharmaceutics issues. It is our intent to update the Q&A Document on a quarterly basis. For any further clarification on any Q&A please contact bps_enquiries@hc-sc.gc.ca. Sultan Ghani, Director Bureau of Pharmaceutical Sciences Therapeutic Products Directorate, HPFB, 101 Tunney's Pasture Driveway, Tunney's Pasture (A.L. 0201D) Ottawa, Ontario K1A 0K9 Telephone: (613) Facsimile: (613) bps_enquiries@hc-sc.gc.ca This and other guidance documents are available on the web site.

2 TABLE OF CONTENTS MODULE 1: ADMINISTRATIVE INFORMATION AND PRESCRIBING INFORMATION Summaries Certified Product Information Document (CPID)...1 MODULE 2: COMMON TECHNICAL DOCUMENT SUMMARIES Quality Overall Summary (QOS)...1 MODULE 3: QUALITY S Drug Substance S.2 Manufacture S.4 Control of Drug Substance S.5 Reference Standards or Materials P Drug Product P.2 Pharmaceutical Development P.3 Manufacture P.4 Control of Excipients P.5 Control of Drug Product P.8 Stability...8 MODULE 5: CLINICAL STUDY REPORTS...8 Created: 2007/05/23 i

3 MODULE 1: ADMINISTRATIVE INFORMATION AND PRESCRIBING INFORMATION 1.4 Summaries Certified Product Information Document (CPID) Q): When filing a post-approval change (e.g., Supplement, NC), can previously fulfilled commitments (e.g., process validation, stability studies for a commitment batches) be removed from the CPID? A): Yes, in order to maintain a concise document, previously fulfilled commitments should be removed from the CPID. However, if a commitment for new stability studies is warranted by the proposed change a summary of the protocol for the commitment batches should be included in the CPID. A summary of the protocol for the ongoing stability studies should be retained. In addition, for process validation studies a protocol number or study report number (for a completed study) with a brief summary, should continue to be recorded in the CPID. MODULE 2: COMMON TECHNICAL DOCUMENT SUMMARIES 2.3 Quality Overall Summary (QOS) Q): Is the filing of 's Quality Overall Summary - Chemical Entities (QOS-CE) required? A): A drug submission containing either 's QOS-CE or one prepared in accordance with ICH's CTD guideline for the Quality Overall Summary would be considered acceptable upon screening. However, due to anticipated benefits in promoting an efficient review of the submitted information, sponsors are encouraged to file 's QOS-CE. MODULE 3: QUALITY 3.2.S Drug Substance 3.2.S.2 Manufacture Q): What level of detail for submission purposes is required on the starting material of an API prepared by chemical synthesis? A): It is acknowledged that ICH Q7A provides a definition for API Starting Material, which may be distinct from the concept of starting material for synthesis discussed in this Q&A document. These are considered complementary definitions, since Q7A defines the point at which GMP requirements apply to the synthetic process in some jurisdictions, while requirements for starting material for synthesis defines the starting point in the synthetic Created: 2007/05/23 1

4 process for an API which should be provided to to permit the evaluation of the safety and quality of the API. In many cases, the starting material for synthesis may precede the ICH API Starting Material by several steps in the synthetic process. The level of details required concerning reaction conditions and controls will increase as synthetic steps get closer to the final API. In general, the starting material for synthesis in drug submissions should: be a synthetic precursor one or more synthetic steps prior to the final API intermediate, be a well characterised, isolated and purified substance with structure fully elucidated, have well defined specifications which include one or more specific identity tests, and tests and limits for potency, specified and unspecified impurities and total impurities. Acids, bases, salts, esters and similar derivatives of the API, and the racemate of a single enantiomeric API are not considered final intermediates. The selection of a particular compound as the starting material for synthesis and its specifications should be justified. In order to assess the presence of all potential impurities, including regioisomeric and stereoisomeric impurities, toxic impurities, residual solvents and residues of catalysts in the starting material, a brief narrative description of the synthesis including an outline leading to the starting material beginning with simpler molecules with all the reagents, solvents, and intermediates specified and the flow chart of the synthesis should be provided. Potential for the presence of adventitious agents, including viral and bacterial agents, residual proteins and TSE agents in the starting material selected should be discussed. A more detailed description of the synthetic process should be provided for steps leading from the starting material to the final drug substance. The additional details should include quantities of raw materials, description of equipment, reaction conditions, in-process controls, percent yields, etc. 3.2.S.4 Control of Drug Substance Q): When qualifying a limit for an impurity in a generic product based on levels found in the Canadian Reference Product (CRP), what evidence should be submitted to show that it is the same impurity that is being analysed? A): Generally, having the same retention time in an HPLC run using a single method, would not be considered sufficient to show the same impurity is being analysed. As such, it is recommended that samples of both the test and reference materials be spiked with the same impurity reference standard to show increased concentrations. For unidentified impurities, confirmation by another technique should be utilised, e.g., retention time comparison using a different chromatographic method, diode array spectroscopic detection. Created: 2007/05/23 2

5 Q): What is meant by the terms professed, house and compendial standards? A): Compendial standard claim is used for a drug substance and/or product claiming conformance to Schedule B compendial standards (e.g., USP, BP, Ph. Eur.). may require additional tests, to ensure the quality, and safety of the drug substance and or product even for products claiming a compendial standard. Professed standard claim is used for a drug substance and/or product where an official standard (i.e., Canadian Standard Drug (Part C, Division 6), Schedule B compendia) is not available. House or Manufacturer s standard claim is used for a drug substance and/or product that is listed in at least one of the Schedule B compendia, but the Sponsor chooses to use different standards and test methods. In accordance with C , drugs for which a manufacturer s standard is claimed must meet the most stringent limits for potency and purity among any of the Schedule B monographs. This applies to assay, content uniformity, impurities (related and process) but does not include performance tests such as dissolution/drug release. Q): Are signed and dated specifications and certificates of analyses for drug substance and drug product required? A): Submissions are expected to have copies of the drug substance and drug product specifications signed and dated by the Quality Control manager or designate. Electronic signatures are also considered acceptable if certified in accordance with an acceptable standard (e.g., FDA s 21CFR, Part 11). The specifications should include tests, acceptance criteria, and reference to analytical methods, and a version number. Signed and dated Certificates of Analyses should also be provided for batches used in pivotal clinical and bioavailability studies or those used to establish the pharmaceutical equivalence where a request for a biowaiver has been included in the submission. However, in situations where a significant number of batches have been used in pivotal clinical studies, a tabulated summary of the testing results would be considered acceptable if accompanied by copies of representative CofA s of batches used in pivotal clinical studies. 3.2.S.5 Reference Standards or Materials Q): What information should be submitted to validate primary and secondary reference standards? A): A primary reference standard other than a compendial standard should be highly purified and fully characterized. All data supporting structure elucidation, strength and purity should be submitted. A certificate of analysis should also be submitted with purity assigned based on mass balance. Created: 2007/05/23 3

6 Secondary reference standards [working standards, house standards] should be prepared similarly to the primary reference material and standardized against the compendial reference standard or primary reference standard. Secondary reference standard should be fully characterized as to identity (IR and UV spectra should be submitted for both the primary and secondary reference standards run concomitantly) and purity, and copies of CofA should be provided. In all cases, all purification steps used to further purify samples taken from a pilot or commercial batch for the purpose of generating a reference standard should be described. 3.2.P Drug Product 3.2.P.2 Pharmaceutical Development Q): What are the requirements for a scored tablet with respect to uniformity of fractions resulting from breaking it? A): For immediate-release, uncoated and coated tablets manufactured with a score (e.g., bisected or quadrisected), data is required to ensure that the divided portions provide uniform dosing for the patients. In other words, split tablets are considered dosage units and their uniformity needs to be established. This is applicable irrespective of the labelled dosage regimen due to the possibility of the tablets being broken for lower dosing by the user by virtue of the tablet design with a score line. The requirements for scored modified-release tablets will be evaluated on a case-by-case basis, and additional tests, e.g., comparative dissolution (release) test results of split halves may be required. The data provided should include uniformity of dosage units on each split portion from a minimum of 10 randomly selected whole tablets. At least one lot of each proposed strength should be tested, performed in a manner that would be representative of that used by the consumer (e.g., manually split by hand). The uniformity test on split portions should be demonstrated with the results reported in the submission. The data should include a description of the test method, individual values, mean, and standard deviation. The acceptance criteria (range and variation) for the split portions should be as described in the USP General Chapter <905> Uniformity of Dosage Units for whole tablets. The scoring configuration for a subsequent entry product (e.g., generic) should match that of the innovator s product. Q): What is the significance of f 2 while comparing dissolution test results? A): Calculation of similarity factor, f 2, is recommended to compare dissolution profiles from solid dosage forms (e.g., tablets, capsules) to establish in vitro similarity between different test samples of the same product. This comparison could be used to support a request for waiver of performing bioequivalence study. Created: 2007/05/23 4

7 An f 2 value between 50 and 100 suggests the two dissolution profiles are considered similar. If the f 2 values are below 50, an investigation should be initiated to determine the cause of apparent dissimilarity. Scientific explanation and alternative data may be considered on a case by case basis. 3.2.P.3 Manufacture Q): Is it necessary for analytical testing facilities to meet GMP requirements? A): Yes. Analytical tests performed by any facility must be compliant with Good Manufacturing Practices (GMP) requirements of Division 2 under the Food and Drug Regulations. This requirement is applicable to all Canadian distributors and importers engaged in the sale of a drug (as described in C ) who either have their own testing facility or rely upon the services of another testing facility for evaluation of raw material (C ), packaging material (C ) finished product (C ), and stability (C ). Q): What is the requirement in the pre-approval stage, in the way of data to support transportation of drug product intermediates and bulk dosage forms from one facility to another for final processing and/or packaging in the market container? A): It should be noted that the HPFB Inspectorate s GMP Guideline and Guidelines for Temperature Control of Drug Products during Storage and Transportation provides guidance for transportation requirements for drug product in its final market container. However, at the pre-approval stage an assessment is needed of the transportation conditions of drug product intermediates (e.g., granules, coated pellets) and bulk dosage forms (e.g., bulk tablets, bulk solutions), which are transported from one manufacturing facility to another for additional processing and/or packaging in the final market containers. Data required to support transportation of finished product intermediates and bulk dosage forms will vary, depending on the nature of the intermediate or bulk product and the mode of transportation. Transportation studies should consider conditions likely to be encountered during transportation, including exposure to elevated and depressed temperature and humidity, and reduced atmospheric pressure (such as might be encountered during air transportation), and physical stresses associated with vibration and impact. The pre-market submission should include results of, or a detailed protocol for, transportation studies, and may include tests conducted on actual shipped samples, or on samples subjected to simulated transportation conditions. Product characteristics which should be considered include, but are not limited to the following: assay and degradation products (all intermediates and bulk drug products) precipitation of dissolved solutes for solutions phase separation of multi-phase (disperse) systems Created: 2007/05/23 5

8 settling of fines in powders and granules friability of tablets or granules container/closure integrity (e.g., liquid preparations subjected to reduced pressure). any other stability/performance indicating test specific to the particular drug product type The transportation studies should be adequate to support conclusions regarding selection of appropriate bulk packaging materials, mode(s) of transportation, necessary controls on shipping conditions, and maximum hold times. Q): What are the criteria for using matrix or family approach for product process validation of tablets? A): Use of matrix or family approach may be possible and acceptable in particular circumstances for a manufacturer that uses the same process for several related products to develop a scientifically sound validation plan. For tablets use of matrix approach is limited to certain process steps, depending on the composition and manufacturing process. It is recognized that the matrix approach has limitations when there are concerns with respect to physical characteristics such as flow properties, particle size distribution, homogeneity that could influence the quality and performance of the tablet. Generally speaking, for common granules of different tablet strengths (i.e., same composition of granules for all strengths), the granulation steps could be validated using a matix approach. However, discrete manufacturing steps such as compression, and coating that involve different tools, equipment, and process conditions for the different strengths can not be validated using the matrix approach. For these steps the manufacturing process for each tablet strength has to be validated individually. The Sponsor may submit data from pharmaceutical development based on design of experiment (DOE) to establish design space for manufacturing steps such as compression, in which case matrixing approach of process validation would be considered. 3.2.P.4 Control of Excipients Q): What are the requirements for use of gelatin from animal origin? A): The following are the requirements for acceptance of gelatin manufactured from animal origin materials from countries which are classified either as low- or high-risk for Transmissible Spongiform Encephalopathy (TSE) disease such as Bovine Spongiform Encephalopathy (BSE). information on the country of origin is provided, all Specified Risk Materials and the vertebral column are removed from bones used for the production of gelatin, appropriate production methods are used to ensure TSE inactivation, information on the manufacturer of gelatin product (e.g., capsule shells) is provided, the gelatin used for production has a recent EDQM Certificate of Suitability for TSE risk products. The above information could also be provided in the form of a Drug Master File. Created: 2007/05/23 6

9 3.2.P.5 Control of Drug Product Q): What is the requirement with respect to the assay limit of drug substance in the drug product specifications? A): The assay limit of ±10.0% ( %) described in the regulations and some Schedule B compendia indicates the minimum and maximum potencies of the medicinal ingredient in a drug product until the end of its shelf life. This would mean at release a more stringent limit, e.g., ±5.0%, needs to be maintained to ensure the above expectation of ±10.0% is met until the end of shelf life. Typically, an assay limit of % at release and % at the end of shelf life of the medicinal ingredient in the drug product is considered acceptable. It is acknowledged that there are exceptions to this recommendation (e.g., vitamins, some antibiotics). Q): What are the recommendations for developing a discriminatory dissolution/drug release method? A): The proposed dissolution/drug release method is intended to ensure the entire drug present in the dosage form is available for release, and that quality and/or manufacturing anomalies can be detected. To demonstrate the discriminatory power, the Sponsor may use formulations prepared during the pharmaceutical development that have differences. Examples include qualitative and/or quantitative difference in excipients, drug substance particle size, process parameters or have different in-process test specifications for hardness, coating thickness etc. Inability to demonstrate the discriminatory power for the dissolution/drug release would mean the proposed test method has limited utility as a quality control test to verify lot-to-lot similarity, and would be of minimal value for supporting significant post-approval changes. Q): What is the recommended development data for a dissolution/drug release method? A): The method development information should include a rationale for choosing the particular apparatus type (paddle, basket, peak vessel etc.), dissolution medium (volume, temperature, ph), operating conditions (rotation speed), and should establish sink condition (i.e. dissolves > 3 times the amount of drug). When a surfactant is used in the dissolution medium a rationale should be provided to justify the choice of the surfactant and its concentration. Evidence that the method is discriminatory (refer to the Q&A on discriminatory method) could also be included in the method validation section. The RSD at time points beyond the initial time point should be less than 10%. The general chapters of the USP and Ph. Eur. provide additional information on this subject. Created: 2007/05/23 7

10 3.2.P.8 Stability Q): An NDS is proposed which is a combination of two previously approved drug substances. Which stability guideline would apply (i.e., Stability Testing for New Drug Substances and Products or Stability Testing for Existing Drug Substances and Products)? A): If the new drug submission contains active ingredients that have been previously approved by, they would be considered existing drugs and therefore the recommendations outlined in the Stability Testing for Existing Drug Substances and Products guideline would apply. Q): In deleting a test or time point from the approved stability protocol, does the revised protocol have to be submitted via a Level 2 - NC? A): Yes, a relaxation in previously approved information (e.g., deletion of a test or time point in an approved stability protocol) would generally be filed as a Level 2 - NC. The deletion of certain tests (e.g., deleting a sterility test and replacing it with process parametric release) would be filed as a Level 1 - Supplement. MODULE 5: CLINICAL STUDY REPORTS Q): With respect to filing an Abbreviated New Drug Submission (ANDS) do the criteria for comparative bioavailability/bioequivalence outlined in the Therapeutic Products Directorate guideline Conduct and Analysis of Bioavailability and Bioequivalence Studies Part B: Oral Modified Release Formulations, 1996 (Guideline B) apply for a drug product that displays complicated pharmacokinetic characteristics (e.g. critical dose drug, etc.) and is an oral modified release dosage form. A): Yes, the criteria outlined in the Therapeutic Products Directorate Guideline B applies to oral modified release drug products filed as an ANDS, in addition to the criteria outlined in other applicable guidelines and policies (e.g., TPD guideline Bioequivalence Requirements: Critical Dose Drugs, 2006). Q): With respect to filing an Abbreviated New Drug Submission (ANDS) do the criteria for comparative bioavailability/bioequivalence outlined in the Therapeutic Products Directorate guideline Conduct and Analysis of Bioavailability and Bioequivalence Studies Part A: Oral Dosage Forms Used for Systemic Effects, 1992 (Guideline A) apply for a drug product that displays complicated pharmacokinetic characteristics (e.g., drug for which an early time to onset of action is important) and is an oral immediate release dosage form? A): Yes, the criteria outlined in the Therapeutic Products Directorate Guideline A applies to oral immediate release drug products filed as an ANDS, in addition to the criteria outlined in other applicable guidelines, policies and notices to industry (e.g., Notice to Industry: Bioequivalence Requirements for Drugs for Which an Early Time of Onset or Rapid Rate of Absorption is Important (rapid onset drugs), 2005). Created: 2007/05/23 8