GMP/Regulatory Environment in the

GMP/Regulatory Environment in the Latin America Irene Ortiz Barreal, Pharm. D., R.Ph. Pfizer International Affiliate Quality Compliance Regional Leader Latin America/Caribbean April 14, 2011

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Agenda Overview for the Latin America Region (selected topics) GMP Inspection Requirement/Mutual Recognition Product Stability Brazil Import Drug Product Quality Peru Regulatory Law Mexico Biotechnological Drugs Final Comments 3

GMP Inspection Requirement/Mutual Recognition 4

Current Environment Globalization required country regulators to evaluate current import requirement to protect public health. New regulations require inspections to manufacturing sites in countries globally. New requirements impose challenges to industry, regulator and patient, Industry - multiple l inspections, delay in product new/renewals, different inspection approaches, guidance's reference, optimize resources. Regulators multiple requests, timely completion, optimize resources. Patient therapy 5

Option - PIC/S Pharmaceutical Inspection Co-operation Scheme An informal arrangement between National Competent Authorities Exchange of information and experience on GMP Development of Quality Systems for Inspectorates Training of inspectors International harmonisation of GMP Presentation in Athens, Georgia Tor Gråberg - Chairman PIC/S, Head of Inspectorate t Medical Products Agency Sweden 6

PIC/S Goal To lead the international development, implementation and maintenance of harmonised GMP standards and quality systems of inspectorates in the field of medicinal products. PIC/S Goal to be achieved by: Developing and promoting harmonised GMP standards and guidance documents. Training competent authorities, in particular GMP inspectors. Assessing (and reassessing) GMP Inspectorates. Facilitating the co-operation and networking for competent authorities and international organisations. 7

Success view Collaborative activities such as API and medicinal product manufacturer inspections 37 + countries members January 1, 2011 recent members: US FDA and Ukraine LA -> Argentina, ANMAT member Applicants being assessed for membership: 6 LA -> Brazil 8

Challenges for the future LA Countries as Members Harmonization Technical development Optimize resources Communication Collaboration Trust 9

Product Stability 10

Product Stability Perspective Industry and Regulators have collaborated to streamline the registration process requirements gaining scientific consensus and the commitment of the regulatory (EMA) and WHO to implement guidelines and recommendations. Aim to remove redundancy and duplication of work in the development and review process to have a single registration documentation package for new medicinal products. Guidelines published, ICH Q1(R2) Stability Studies for New Drug Substances and Products. EMA: CPMP Guidelines on Stability Testing: Stability Testing of Existing Active Substances and Related Finished Products. WHO Technical Report Series, No. 953, 2009, Annex 2, Stability testing of active pharmaceutical ingredients and finished pharmaceutical. 11

Challenges in global registrations Local Stability Requirements and Marketing Application Stability (*NME s and PAC) Local shelf life confirmatory stability. Specific testing requirements (testing for parameters which do not change on stability). Formatting requirements, e.g. wet signature Product related data, e.g. batch related data for excipients, std. dev. for each time point, provision o of chromatograms, a requirements e e of product made with different API batches per strength, number of batches per strength/presentation for matrixing and bracketing. Unique stability study condition requirements. Harmonized stability requirements do not apply to PAC, requiring companies to consult country or region specific guidelines. Readiness and acceptance of innovative stability approaches e.g. statistical approaches in current guidelines. *NME = new molecular entities PAC = post-approval changes 12

Proposal Local Stability Requirements Suggested ICH/WHO recommendation be considered. Adopting these harmonized guidelines in lieu of local stability requirements. Use risk based approach on such issues as sitespecific stability data in countries were expectations made currently be divergent. Harmonize the concept of representative batches in alignment with ICH definitions. Have global scientific requirements leading to a great mutual acceptance of development data. 13

Proposal Marketing Application Stability (*NME s and PAC) Encourage the science and risk based approaches to support Marketing Applications and Post Approval CMC (e.g. bracketing and matrixing protocols and number of batches). Where applicable, use scientifically based predictive models to justify extrapolation of assigned use periods and retest. Reducing the need to submit regulatory use and retest t periods extensions and re-labeling. Use science based approach vs. standard check list for different dosage forms. Science based approach to allow changes in the process/route/formulation, post long term stability study commencement; if changes do not affect stability Critical Quality Attributes (CQA), then no further studies are required. If changes impact the CQA, use science and risk based to determined stability performance prior to the need of further long-term stability can a accepted as a viable approach. Use QbD to increase flexibility to operate prior to regulatory approval of changes. *NME = new molecular entities PAC = post-approval changes 14

Summary Benefit from the existing stability package guidelines. Have a single registration documentation package for new medicinal products. Increase opportunities for industry and regulators dialogue and collaboration through out the lifecycle of the product to discuss science and risk based approaches to stability. 15

Brazil Import Drug Product Quality 16

Regulation History Regulation require the importing company own lab located in the national territory is responsible for conducting complete quality control assays, in compliance with the drug product registration at ANVISA, for each received shipment, batch by batch, for all imported drug products. Contracting third party services to conduct quality control assays is not allowed, except for cases anticipated by the law in effect. This Regulation aims at ensuring imported drug products quality. RESOLUTION - RDC No. 10 dated March 21, 2011 provided changes 17

Changes The importing company is exempted to conduct complete quality control assays provided, and shall conduct, for each shipment received, batch by batch, at least tests registered for content and degradation products, as long as complying with the following requirements: drug products are imported as a finished product and in their original package. the importing company shall have a valid Certificate of Good Manufacturing Practices or Good Distribution and Storage Practices, as the case, issued by ANVISA. companies involved in the productive process shall have a valid Good Manufacturing Practice Certificate, issued by ANVISA, by requesting importing company, for the productive line at issue. temperature and humidity conditions during each transport operation should be continuously recorded, by a calibrated equipment, with supporting information that the drug product was kept within storage conditions established by the drug product registration at ANVISA. Humidity may not be monitored, except in specific situations technically justified. 18

Changes Transport conditions shall be validated for drug products under refrigeration; The importing company shall ensure the exporting company has standard operating procedures specifying details regarding transport operations, including storage and shipment size, number of temperature and humidity recorders and their position, in order to ensure representativeness regarding g the shipment; The importing company Quality Assurance system shall be capable of verifying records and technically evaluate documents concerning the imported drug product batch, which includes, not limited to, physical conditions of received shipment, temperature and humidity temperature proving the drug product was kept within conditions anticipated in the registration, so as to ensure quality, efficacy and safety; and The importing company Quality Assurance department shall conduct all complete analysis, in compliance with the drug product registration, for at least two batches a year, in case of imports over eight shipments/year for each drug product. For imports of less than or equal to eight shipments/year received for each drug product, all complete analysis shall be conducted for, at least, two batches every two years. 19

Changes Requirement is considered to be met when companies involved in the productive process have already been previously certified by ANVISA and when companies requesting inspection file the Good Manufacturing Practices Certification order within at least 120 days before the current certificates expire. Records generated shall identify the drug product name (s), batch number (s), time and shipment date by exporting company and receipt at importing company warehouse. In case of temperature and/or humidity deviations, the exemption provided for in this article shall be applied only after the formal investigation process, by Quality Assurance, concluding the absence of impact on drug product quality, efficacy and safety. This investigation shall consider technical information, including completed accelerated and long term stability trials, as per the specific health law. The company responsible s e for importing shall issue a Batch Release ease Certificate together with its analytical batch, under the Responsible Pharmacist responsibility. Documents proving compliance with requirements provided for in this article, shall be available whenever required by health surveillance entities and during health inspection to check compliance with Good Practices. 20

Summary RDC 10 provides an option Industry with comprehensive systems in place to ensure that product meets rigorous quality standards will benefit from the exemption. The regulation aims ensuring imported drug products quality and patient t safety is met. 21

Peru Regulatory Law 22

Peru Regulatory Law Changes Globalization required country regulators to evaluate current import requirement to protect public health. DIGEMID (BoH) 2009 Law revision with new guidelines for medicinal products, January 2009 (Art 50 Law 26842) Registration new requirements to align with international requirements. November 2009 - new law 29459, focus on administrative details,,published for public consultation on October 2010. 23

Challenges Recognized the intend to respond to globalization, challenges are, Procedures not well understood by industry and reviewers. Inconsistently applied by evaluators. Delays in new registrations, renewals and modifications to medicinal products. Regulatory approval is delay due to Administrative i ti procedures. Non acceptance of GMP inspection certification. Patient suffers availability of medications. 24

Challenges - Administrative Details Wet ink signature requirements on Quality documents (e.g. analytical validation reports for API and DP, specifications for API and DP, stability reports). Misunderstanding of the WHO Certification scheme, e.g. CPP address and company names with minimal differences vs. prior documentation, ti obvious to be the same. Request of identical information without scientific rationale, e.g. Ampoule formula specifies Nitrogen not in CPP. Is an accepted practice to exclude gases. Statement/declarations to explain self-explanatory items included in dossiers, e.g. shelf-life statements, explanations for pharmacopoeia monographs. Non-acceptance of reference to pharmacopoeia for excipients. Information transpose into specification sheets and signed. Documentation in specific format. 25

Challenges Quality items Import testing, e.g. Biotech products methodology. COA additional testing requirements not aligned to ICH. Lack of variation procedures MAAs for commercialize products with years in market. Full lldossiers required, e.g. clinical i lti trials for simple variations; change of secondary packaging site. Stability reports in specific format, not aligned with ICH. 26

Proposal Follow ICH guidelines of Technical Requirements for Registration of Pharmaceutical for Human Use (e.g. Wet signature not required under ICH). Acceptance of GMP inspection certificate BoH for high vigilance markets (e.g. FDA, EMA, ANVISA), and risk based inspection every 3 years for non vigilance markets aligned with ICH. Accept application form signed by MAH/distributor attesting to the accuracy of documents submitted. One responsible person attesting for overall quality of the dossier. 27

Proposal cont. Allow alternatives pathways e.g. whom it may concern letter/affidavit certifying specifications and test method in dossiers, approved by the company based on compliance with International ti guidelines and standards. d If manufacturing site in located in reference countries, accept testing from site of origin. Or ensure product Quality by supply chain controls. Establish timeline for review process. Closer collaboration with PANDRH/ICH/GCG (Global Cooperation Group). 28

Summary Well recognized effort to strengthen regulations. Benefit from mutual cooperation with other regulatory agencies. Adopt International guidelines for global consistency. Maximize submission and approval process to provide product availability to patient. 29

Mexico Biotechnological Drugs 30

Regulation COFEPRIS In June 2009 Congress approved the bill that regulates biotechnological drugs, sent to the Executive Power and publisher in the Official Gazette for its enactment on September 2009. The project approved in Congress legally defines biotechnological and biocomparable products and regulates their marketing authorizations (requirements and clinical trials), labeling and acquisitions. The bill creates an entity called Subcommittee for the evaluation of Biotechnological Products within the Mexican regulatory agency (COFEPRIS) to oversee such procedures. Currently the regulatory process which consists of specifying conditions applicable for biotechnological products in the Health Supplies Ruling has not concluded. 31

Definitions Biotechnological drug Innovative biotech drugs Non-innovative biotech drugs, The identification of these drugs will be determined by the Health Regulation. 32

Registration requirements All biotechnological presented to the New Molecules committee. Biocomparable Pre clinical and clinical studies of innovative or reference conducted in Mexico (mfr in Mexico) or as determine by secretariat, with subcommittee input, if mfr abroad. Includes comparability tests, immunogenicity studies and adverse events. Pharmacovigilance program. Labeling requirements. Validation report of the manufacturing process Analytical methods (non pharmacopoeia methods) for raw material and biopharmaceuticals Process controls Flowchart of the manufacturing process Free sale certificate, Health license Requirements similar to biologicals for registration requirements for Biopharmaceutical Art. 177. BoH time to resolve registration ti in NMT 235 business days. 33

Changes - Others Health Manager Responsable Sanitario Obligation, Supervise storage, release and transport. Presence during verification visit by Secretariat. Authorize in written procedures. Comply with regulation for referred establishments. Possible to request the registration of as generic or biocomparable Biotechnological for a drug product whose active substance or ingredient is protected by patent within the validity of time of the patent. t Health registry awarded d at the end of the validity of the patent. Import products release (COA, Import testing). 34

Summary Submitted project stands in acceptable terms for industry. Changes to the ruling are needed to describe procedural details and requirements to be met for guaranteeing the quality, safety and efficacy of all biotechnological products. Guidance for Pre clinical and clinical for FOB s. Clarity on the operating rules for the New Molecules Committee Health law to separate innovator and FOB s in national formularies. Changes to the ruling were submitted by COFEPRIS (Regulatory Agency) to COFEMER (Regulatory Improvement Commission). COFEMER issued its report in December 2010. COFEPRIS must respond so it can be sent to the legal council for the President s office for publication in the Official Gazette. Industry yprovided feedback to COFEPRIS in points requested. Process expected to conclude during 2011 35

Final Comments Globalization required country regulators to evaluate current regulations, registration and import requirement to protect public health. Well recognized effort to strengthen regulations. New requirements impose a challenges to industry, regulator and patient. Industry and Regulators collaboration work to streamline the registration process requirements, Harmonisation and Mutual Acceptance processes. Benefit from work completed by ICH, WHO, PIC s Use Science and Risk Base approach. Actively participate i t in International ti committees to influence and benefit for Technical development and Optimize resources e.g. PIC s, ICH, WHO. Increase the opportunities to dialogue and collaboration between industry and regulators to achieve harmonization. 36

Conclusion The Patient is the winner 37

GRACIAS OBRIGADA THANK YOU FOR YOUR ATTENTION 38