FDA Draft Guidance for Industry Contract Manufacturing Arrangements for Drugs: Quality Agreements (May 2013) Pfizer Comments General Comments:

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1 FDA Draft Guidance for Industry Contract Manufacturing Arrangements for Drugs: Quality Agreements (May 2013) Pfizer Comments General Comments: 1. The terms owner and product owner are new and may result in confusion regarding the holder of a regulatory filing or marketing authorization. 1.1 The definition used in the document is the party that introduces (or causes the introduction of) a drug into interstate commerce. This effectively establishes a new philosophy of holding accountable the last entity who has the product in their possession prior to introduction into the market for the entire supply chain. 1.2 As stated in the document and based on this definition, entities performing operations for the product Owner are considered contracted facilities which conflicts with the current industry accepted description of a contractor CFR states, The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company. The term owner could yield a lack of clarity as to the responsible party. No reference to owner is present in the CGMPs; yet the guidance states that 21 CFR (b) and 21 CFR (a)) hold the Owner s Quality Unit ultimately responsible for approving and rejecting drug product manufactured by the contract manufacturer. 21 CFR (b) statement, as well as the person who is responsible for the failure to comply, shall be subject to regulatory action. has applied to the Quality unit of the facility, not the new term and definition of owner. 2. Inconsistent or redundant use of the terms, manufacturing or manufacture. Line states, the term of manufacturing includes processing, packing, holding, labeling operations, testing, and operations of the quality unit. Throughout the document, manufacturing is used in combination with the terms included in the definition of manufacturing. 3. The ICHQ7 IWG (Implementation Working Group) is preparing a Q&A that will address much of the same concerns as outlined in this guidance (the first round of questions are loaded with expectations of contract manufacturing quality units, etc.). Suggest holding this guidance as draft to assure alignment and minimize confusion /implementation. Docket No. FDA 2013 D 0558 Page 1 of 8

2 Specific Comments: Relative Importance: C = A critical issue which we feel strongly about M = A minor point which we note but is less important E = An editorial point which could help to clarify the text or remove and error Line Number Relative Importance 35, 257 E 35 E Key Concerns with Explanation of Position It is not clear if it is the Agency s expectation for firms that manufacture Drug Substance/Drug Product (DS/DP) that they maintain quality agreements with raw material suppliers. This draft Guidance Document does not appear to include as contracted/outsourced activities the routine supply of raw materials to a firm that holds a BLA and internally performs all manufacturing activities for both DS and DP. If there is such an expectation, it is not clear how a firm s routine supplier management controls, such as on site supplier audits, supply channel surveys and periodic reassessment of supplier performance, would mitigate the potential need for quality agreements between a firm and a raw material supplier. And also it is not clear if there would be an expectation that a quality agreement is needed for other categories such as excipients, component such as filters used in manufacturing, sterile gowning, etc. Where a firm uses more than one location within its organization to perform activities for manufacture of a drug, it is unclear if it is Proposed change Add language stating when, if ever, a supplier quality agreement is required. Add clarifying language Docket No. FDA 2013 D 0558 Page 2 of 8

3 54 C E C the Agency s expectation that a quality agreement would be necessary between those sites. And if yes, how this would apply to all activities regardless of complexity and risk, e.g. (1) manufacture and supply by one site of a drug substance to another site which subsequently manufactures bulk drug product, (2) storage of raw materials by one site prior to their use by another site. All Contracted Facilities must assure compliance with applicable Current Good Manufacturing Practices for all manufacturing, testing or other support operations performed to make a drug(s) for the Owner. This contradicts ICH Q7 for steps of a synthesis prior to the starting material (Q7/Q11) testing is redundant as it is included in definition of manufacturing in line The statement, Under section 301(a) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 301(a)), manufacturers are liable for introducing or causing the introduction of adulterated or misbranded drugs into interstate commerce. seems to conflict with line 42 which defines the Owner as the party that introduces (or causes the introduction of) a drug into interstate commerce All Contracted Facilities must assure compliance with applicable Current Good Manufacturing Practices for all manufacturing steps performed within section S.2.2 of the CTD, testing or other support operations performed to make a drug(s) for the Owner. Suggestion to connect with the ICHQ7 IWG. There are multiple comments on this issue, such as what is expected prior to starting material...for all manufacturing or other support operations performed to make a drug(s) for the owner. Delete statement Docket No. FDA 2013 D 0558 Page 3 of 8

4 76-78 M 121 E E 135 C The statement, Because the Agency considers contractors an extension of the manufacturer s own facility, both Owners and Contracted Facilities are responsible for ensuring that their products are not adulterated or misbranded (21 CFR ). makes the term manufacturer synonymous with Owner. This is not necessarily consistent with the definition of Owner stated as, the party that introduces (or causes the introduction of) a drug into interstate commerce manufacturing operations is not clear as manufacturing includes all processing, testing, and support operations Statement is redundant as manufacturing is defined in line as including all other processes mentioned (i.e., processing, packing, holding, labeling operations, testing, and operations of the Quality Unit). The statement, CGMP regulations (i.e., 21 CFR (b) and 21 CFR (a)) hold the Owner s Quality Unit ultimately responsible for approving and rejecting drug Delete statement or clarify definition of owner All parties performing manufacturing operations should monitor incoming ingredients and materials, if applicable to their function in the supply chain, to ensure they are from approved sources using the agreed supply chain. Alternatively, as the section is delineating the responsibilities of Owner and Contracted Facilities, the following may be more appropriate: All Contracted Facilities performing manufacturing should monitor incoming ingredients and materials to ensure they are from approved sources using the agreed supply chain.to perform all or part of processing, packing, holding, or testing of a drug product OR..to perform all or part of the manufacturing of a drug product Delete statement or clarify definition of owner Docket No. FDA 2013 D 0558 Page 4 of 8

5 M M product manufactured by the contract manufacturer. Per definition of owner provided above, the owner may be an entity only involved in the final distribution of the drug product The 21 CFR (b) statement, as well as the person who is responsible for the failure to comply, shall be subject to regulatory action. has applied to the Quality unit of the manufacturing facility, not the new term and definition of owner. Owners are ultimately responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company. 1. This wording is not clear as to final release to market and could conflict with the responsibilities of the regulatory filing holder, specifically if the owner is only distributing product. 2. Does this require all finished products to USA to be released by the import company? The statement.,.reporting information about objectionable conditions observed during inspections and audits of the contracted facility, regardless of which products were covered on inspection. is good in concept but may be challenging to implement due to confidentiality agreements across multiple partners of the contractor. Clarify definition of owner.reporting information about objectionable conditions observed during inspections and audits of the contracted facility, regardless of which products were covered on inspection, if the observations are systemic or have the potential to impact the Quality System. Docket No. FDA 2013 D 0558 Page 5 of 8

6 C 257 E M 289 M The statement, The Quality Agreement should also indicate how the parties will communicate information about preventing cross-contamination and maintaining traceability when a Contracted Facility processes or tests drugs for multiple product Owners. is too prescriptive as it requires the means of communication to be included in the Quality Agreement. In addition, it should not only be applicable when there are multiple product owners. If there were a quality agreement between a manufacturer and a material/component supplier, it is unclear if it is expected that a complete description of the supply channel for each material be contained in the agreement. If the firm captures the supply channel in an independent, validated software system that would mitigate the need to capture the entire supply channel in a quality agreement. Component/product specifications should not need to be included/maintained in the Quality Agreement but should be available upon request. Specifications, and product specific information, should be shared but it does not need to be included in the Quality Agreement. The statement, The Quality Unit of each participating party to a Quality Agreement should have adequate laboratory facilities available to them for testing and approval (or rejection) of drug products (see 21 CFR The Quality Agreement should also indicate how that the parties will communicate information about preventing cross-contamination and maintaining traceability for all products within the scope of the agreement. when a Contracted Facility processes or tests drugs for multiple product Owners. Add clarifying langage Recommend removing this requirement and stating who is responsible for maintaining applicable specifications and that these would be available upon request..the Quality Unit of each participating party to a Quality Agreement should have adequate laboratory facilities available to them for testing and approval (or rejection) of drug products (see 21 Docket No. FDA 2013 D 0558 Page 6 of 8

7 M 314 M (b)). may not be applicable to one or more parties in a Quality Agremeent. Regarding the statement, The Quality Agreement should indicate procedures for the Owner to review and approve documents and any changes thereto, such as Standard Operating Procedures, manufacturing records, specifications., Contract Facilities typically do not allow owners to approve their SOP s as this is applicable to their Quality System. Additionally, situations where a significant number of Owners are using the same services of the Contractor (and the same documents are impacted validation, SOP, etc.) could result in numerous and possibly conflicting changes. The parties should also specify how records and documentation required by the applicable CGMP regulations will be made available for immediate retrieval, and how copies will be made and maintained under a certification or controlled copy procedure (21 CFR ). 1. This statement is too restrictive in requiring agreement of how records are stored. It should suffice that records are available for immediate retrieval; CFR neither specifies or requires a certification or controlled copy procedure. CFR (b)), if applicable to their function in the supply chain.the Quality Agreement should indicate procedures and responsibilities for the Owner to review and approval of documents and any changes thereto, such as Standard Operating Procedures, manufacturing records,. The parties should also specify that records and documentation required by the applicable CGMP regulations will be made available for immediate retrieval, and how original documents or copies will be made and maintained under a certification or controlled copy procedure in accordance with CGMPs (21 CFR ). Docket No. FDA 2013 D 0558 Page 7 of 8

8 322 M Section title as well as the Table of Contents includes Subcontractors however, no further reference is made to subcontractors. Typographical/grammatic errors regarding colons and semicolons Include within the list in lines , subcontracted operations or activities E Comments: Five : (colons) should be changed to ; (semicolons) 372 E Typographical/grammatical Delete the word, and after but in the statement Docket No. FDA 2013 D 0558 Page 8 of 8