DRU STAKEHOLDERS WORKSHOP 17 19 June 2009 Gaborone

DRU STAKEHOLDERS’ WORKSHOP 17 -19 June 2009 Gaborone, Botswana

Phone a friend!!

Thanks in the main to…. l l l Dr. Sinah Selelo, Principal Pharmacist and Head of Drug Regulatory Unit Seloi Mogatle, Principal Pharmacist 1, Drug Regulatory Unit Mrs Olawami Oladiran, Principal Pharmacist 1, Pharmacovigilance/Post-Marketing Surveillance (no longer head of DRU)

Need Identified by DRU l l l Large backlog necessitated revamping of DRU – increased efficiency (evaluation = 3 years, currently) Receipt of fully compliant, comprehensive dossiers – FASTER APPROVALS To provide guidance on DRU requirements Prevent current situation where submissions lie unresolved for months/years To prevent perpetuating backlog situation

Proposed Guidelines l 12 guidelines proposed for implementation in use with MH 2048 (retained) Ø DRU intends adopting some international guidelines based on ICH, EMEA or FDA DRU has developed some Botswana-specific guidelines (generally based on SADC harmonised guidelines) Ø

Proposed Guidelines (cont. ) l Stakeholders’ Workshop l Proposed changes discussed by DRU l Final guidelines presented to the Board, finalised for November Parliamentary session l Implementation – proposed January 2010

ICH Guidelines for adoption in Botswana l l Four ICH Guidelines to be adopted unaltered Minimal discussion was held on these guidelines 1. Validation of Analytical Procedures: Text and Methodology. ICH Q 2(R 1), version 4, dated November 1995 No points raised

ICH Guidelines for adoption in Botswana (cont. ) 2. Impurities in New Drug Substances Q 3 A(R 2), current step 4 version, dated 25 October 2006 If we submit CEP for API, they MUST be updated as E. P. is updated. Declaration that no changes have been made since EMEA approved the CEP. 3. Impurities in New Drug Substances Q 3 B(R 2), current step 4 version, dated 2 June 2006 Excludes biologicals, animal/plant extracts. No motivation accepted for impurity limits outside provisions of guideline. Generics to comply, different impurities limits will not be accepted. *

ICH Guidelines for adoption in Botswana (cont. ) 4. Pharmaceutical Development Q 8, current Step 4 version, dated 10 November 2005 l Include Pharmaceutical Development Report in Page 2 of 7 of MH 2048. Required for generics. Go to ICH website for Part II/Annexure to this guideline, for further explanation. l l

FDA Guideline for Implementation in Botswana l One FDA Guideline – Bioanalytical Method Validation, Guidance for Industry, CDER & CVM, dated May 2001 “A separate workshop will be arranged to discuss all aspects of biologicals, to do the subject justice. ”

Final Version of Annex 15 to the EU Guide to Good Manufacturing Practice July 2001 l l One EU Guideline Qualification and Validation – – – Adopted unchanged Does not cover distribution of fridge-line products Suggestion is DRU to adopt the distribution guideline of WHO with locally-specific changes Validation Protocol and Report to be submitted to DRU (DRU wants to see all deviations from protocol, minor or major) Read with Guideline on Good Manufacturing Practices

You still with me? ? ?

Proposed Botswana-specific Guidelines for discussion l Six Botswana-specific guidelines 1. 2. 3. 4. 5. 6. Drug Registration Applications Variations Stability Testing Bioavailability & Bioequivalence Good Manufacturing Practices Clinical Trials using Medicines in Humans

1. Guidelines on Drug Registration Applications in Botswana, Third Revised Edition Guideline 1 st revision 2000, 2 nd revision 2007, 3 rd revision June 2009 In line with harmonised SADC guideline, but local format MH 2048 I. III. IV. Intro & definitions Registration Guidelines Application Pre-registration/Evaluation Report Guidelines for Stability

1. Guidelines on Drug Registration Applications in Botswana, Third Revised Edition (cont. ) l Products addressing Botswana health priorities automatically fast-tracked (anti. HIV, anti-malarials, TB drugs) Completed “Application Pre. Registration/Evaluation Report” required for all submissions TOC to M 2048 to be submitted Dossiers bound in “dispot” clips; no lever arch files l l l

1. Guidelines on Drug Registration Applications in Botswana, Third Revised Edition (cont. ) l Follow format of existing MH 2048, add extra pages to include extra information mandated by the guidelines State ATC pharmacological classification, but can motivate not to include in PI/PIL. Motivation to use ZA PI/PIL. Local agent currently not required but Act being revised & MAY be required in future l l

1. Guidelines on Drug Registration Applications in Botswana, Third Revised Edition (cont. ) l Declaration (affidavit) to be completed & signed by Applicant (not Agent) - SADC Addresses compliance of dossier vs master documents, GMP compliance, compliance with national requirements (batch release, adverse event reporting and batch recalls In line with SADC guidelines l l

1. l l Guidelines on Drug Registration Applications in Botswana, Third Revised Edition (cont. ) Copy of current RM pharmacopoeial monographs required, with statement to comply with latest edition Two COA’s for API’s, < two years old One COA required per IPI (not in this guideline) – DRU to revisit Batch production records for samples required – can arrange to view in DRU office

1. l l l Guidelines on Drug Registration Applications in Botswana, Third Revised Edition (cont. ) While biologicals are accepted, no “biosimilars” are currently accepted Extracts from standard references to be included as well as BA/BE studies Summaries only required for NCE’s – – l Pharmacotoxicology Clinical safety and efficacy, clinical pharmacology, etc. Stability data requirements: see separate guideline

1. l Guidelines on Drug Registration Applications in Botswana, Third Revised Edition (cont. ) Registration in other countries: – – – Include registration certificates from some ICH or PICs countries, and South Africa (not essential) DRU will accept submissions without CPP’s, with commitment to submit when available “Country of origin” = country of manufacture, not research/development

1. l Guidelines on Drug Registration Applications in Botswana, Third Revised Edition (cont. ) Labeling: – – Annexure I on page 46 of guideline = Warnings to be included on packages (problematic!!), different from Act 101 (1965) requirements – suggest applying for exemption Date of manufacture & manufacturer name & address required as per SADC TPM – suggest “Manufactured by…for…” Separate label for each manufacturer

1. l Guidelines on Drug Registration Applications in Botswana, Third Revised Edition (cont. ) Samples (cont. ): – – Big increase in number of samples required to facilitate analysis by Govt. laboratory Samples to be in “actual distribution pack” (“can do mock up of label provided it complies with DRU guideline”)

1. l Guidelines on Drug Registration Applications in Botswana, Third Revised Edition (cont. ) Promotional/advertising material – – Proposed materials to be attached to submission if available (otherwise apply for exemption) Guidelines to be discussed at a separate forum (watch this space!)

2. Guideline on Dossier Requirements for Variations l l Based largely on WHO Pre-Qualification Document 2007 & EU Document 2006 Adapted to suit local Botswana requirements & conditions Will determine the amount of “wiggle room” DRU will permit from Industry

2. Guideline on Dossier Requirements for Variations (cont. ) l l Guideline significantly changed from that emailed to industry – new version provided at Workshop Future intention for 5 year renewal period (cannot remove as in law, but the fact that products remain in “Blue Book List of Products Allowed into Botswana” means registrations can be regarded as current)

2. Guideline on Dossier Requirements for Variations (cont. ) l Requirements for Submission of Variations; – – l Application Form for Variations Table of Contents Specific Supporting Documents (amended pages of dossier always required) Payment Fee (not yet specified) Consult the Checklist for Variations Applications for Medicines

2. Guideline on Dossier Requirements for Variations (cont. ) l Generated LOTS of discussion !! – Guideline provided before Workshop – no resemblance to one provided at Workshop! – Checklist does not tie up with guideline! – Negotiated for maximum inclusion under “Minor Variations” – Practical issues eg. if prior approval required regarding continuity of stock, unique labels etc. – Discussion was not exhaustive – further feedback to DRU from ZA industry

2. Guideline on Dossier Requirements for Variations (cont. ) l Minor Variations (V 1 – V 37) (Annex I) – l Major Variations (Annex II) – – l Notification only, can be implemented after submission to DRU New dossier & prior approval required Proof required that quality of product unaffected Changes that make necessitate a New Application (Annex III)

2. Guideline on Dossier Requirements for Variations (cont. ) l l l No fee currently for minor variations Samples only required for packaging changes (labeling, 1° & 2° containers) Many changes requested to proposed Guideline

2. Guideline on Dossier Requirements for Variations (cont. ) l Minor Variations (V 1 – V 37) (Annex I) – – – Description of variation Conditions listed 1, 2, …. Documentation Changes exceeding the conditions of Minor Variations default to Major Variations or changes that require a new application – prior approval required

2. Guideline on Dossier Requirements for Variations (cont. ) V 1 - Change of Name &/or Address Applicant l l “Formal document” = letterhead of new applicant Points 2 & 3 deleted from “Documentation” required as not applicable V 2 - Change of Name &/or Address or Additional API Manufacturer l “Conditions” Add – Method of API manufacture unchanged

2. Guideline on Dossier Requirements for Variations (cont. ) V 4 – Change of name/address/site of manufacturer, 1°, 2° packer & “all manufacturing operations” l l Steriles excluded – requested reconsideration with adequate validation Stability data required, “or a commitment to carry out stability studies” to be considered

2. Guideline on Dossier Requirements for Variations (cont. ) V 7 – Minor change in manufacturing process of API l Route of synthesis to stay “essentially” (to be added) the same V 11 – Change in re-test period and/or storage conditions of API l No stability studies required if CEP submitted & states storage container & re-test period

2. Guideline on Dossier Requirements for Variations (cont. ) V 13 – Change in specification of IPI (limits tightened or additional parameter) l Documentation required point 4 – COA of minimum of two production batches “of product manufactured with updated excipient” (added) of concern to industry as not available at time of submission

2. Guideline on Dossier Requirements for Variations (cont. ) V 16 – Change to comply with major international pharmacopoeia, API/IPI l l DRU does not have access to all pharmacopoeias, so copies of all pharmacopoeial specs (& methods? ) MUST BE submitted Submit current monograph & state material will be tested according to latest version

2. Guideline on Dossier Requirements for Variations (cont. ) V 17 – Change in specifications of 1° pack l l Condition 3, “Any change should be within the range of approved limits, except for new parameters” (to be added) Documentation 4, COA’s of minimum of two batches of finished product in packaging materials with the new specifications (to be added)

2. Guideline on Dossier Requirements for Variations (cont. ) V 20 – Change in qualitative/quantitative composition of 1° pack material l Condition 1, sterile products excluded, to be reconsidered V 23 – Change in batch size of the finished product l Condition 2, sterile liquid products excluded, to be reconsidered

2. Guideline on Dossier Requirements for Variations (cont. ) V 24 – Change in colour/flavouring system of finished product l Documentation 2, “one sample of new product” (added) V 25 – Minor change in manufacture of finished product l Documentation 3 & 4, to be expanded & read in conjunction with Bioequivalence Guideline for changes to finished product

2. Guideline on Dossier Requirements for Variations (cont. ) V 26 – change in shape/dimensions of container or closure l Documentation 3, DRU wanted “Samples of the new container/closure” – to be changed to “One sample of product in the new container” V 27 – Change in specifications of finished product l Condition 3, “Any change should be within the range of approved limits, except for new parameters” (to be added)

2. Guideline on Dossier Requirements for Variations (cont. ) V 28 – Change (replacement/addition) in the test method of finished product l Condition 1, “method of analysis should remain the same” (to be reconsidered provided change adequately validated) V 30 – Change or inclusion of Score/Breakline of tablet l Documentation 4, “official letter of commitment to inform users of relevant changes, and that current stocks will be exhausted before new product is marketed”. DRU required “Dear Healthcare Professional” letters to be sent out – a database is available from DRU

2. Guideline on Dossier Requirements for Variations (cont. ) V 31 – Change in dimensions……. tablets, capsules, suppositories, pessaries l Documentation 4, sample of finished product – DRU increasing focus on counterfeits & moving towards Ugandan model of current samples available for importation approval by Customs officials

2. Guideline on Dossier Requirements for Variations (cont. ) V 33 – Change in pack size of finished product l Condition 3, volume of sterile injectables to remain unchanged (to be added) – becomes a new product if volume changes V 35 – Addition/replacement/deletion of measuring or administration device not being an integrated part of primary packaging (spacer devices for metered dose inhalers are excluded) (clarification required regarding bracketed text - mouthpiece or true secondary spacer device? )

2. Guideline on Dossier Requirements for Variations (cont. ) V 37 – Change in Package Inserts w. r. t. indications, new dosage regimen, deletion of CI’s, warnings, side-effects, precautions, drug interactions etc. l Documentation 3, requires legalised copy of approval in country of origin (raised the problem of Urgent Safety Restriction Notices as we won’t get timeous response from MCC – submit stamped proof of submission in ZA & Botswana, & do Dear Healthcare Professional letter in Botswana)

2. Guideline on Dossier Requirements for Variations (cont. ) l Major Variations (Annex II) “ Includes changes like…. . ” 1. ∆ Manufacturing method of API ◄ 2. ∆ Composition of Finished Product 3. ∆ Immediate packaging of Finished Product ◄ ◄ DRU to reconsider

Guideline on Dossier Requirements for Variations (cont. ) l Changes that make necessitate a New Application (Annex III) 1. Changes to API (change to different API, additional API/ removal of API in multi-component product) 2. Changes to Pharmaceutical Dosage Form (immediate release → slow release; Liquid → powder for reconstitution; Change in dose of one or more API’s) 3. Change in Route of Administration

Still there……. are you sure?

3. Guideline on Stability Testing of Pharmaceutical Products l Adaptation & adoption of……. . 1. SADC Guidelines for Stability Studies ICH Guidance on Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products (Q 1 D) WHO Classification of Climatic Zones DRU local requirements 2. 3. 4.

3. Guideline on Stability Testing of Pharmaceutical Products (cont. ) l WHO / ICH Climatic Zones: Zone I: Temperate v Zone II: Subtropical with possible high humidity v Zone III: Hot and dry v Zone IV: Hot and humid v Botswana is classified as Zone III – stability studies to be appropriately designed STORE BELOW 30°C

3. Guideline on Stability Testing of Pharmaceutical Products (cont. ) l API: – – Stress testing SADC = 1 primary batch, DRU wants 2 primary batches Accelerated and long term studies on 3 primary batches of API Long term stability studies at 30°C/35%RH (SADC allows 25°C/65 RH) 12 months data at submission infers max. SL of 24 months; 24 months data at submission infers max. SL of 36 months

3. Guideline on Stability Testing of Pharmaceutical Products (cont. ) l Finished Product: – – – Accelerated and long term studies on 3 batches of product (min of 2 x pilot, 1 x production), using different batches of API where possible Long term stability studies at 30°C/65%RH (SADC allows 25°C/65%RH) 12 months data at submission infers max. SL of 24 months; 24 months data at submission infers max. SL of 36 months

3. Guideline on Stability Testing of Pharmaceutical Products (cont. ) l l Lively discussion regarding products already registered with “Store below 25°C” storage conditions – how should DRU proceed? Possibility is to provide a proposal to DRU as to how each applicant will commit to achieve compliance with Climatic Zone III requirements, with stated timelines per product eg. Annual batches for GMP compliance to be tested on stability at 30°C/65%RH. DRU to respond individually.

4. Guideline on Bioavailability & Bioequivalence l l l Based on SADC BE Guideline Biowaver Application Form (supplied at the Workshop) WHO Prequalification of Medicines Programme If innovator product not registered in Botswana, DRU is not in favour of registering a generic/generics (as they have no clinical data on file for the drug product)

4. Guideline on Bioavailability & Bioequivalence (cont. ) l BA/BE studies performed previously may not comply with latest requirements – motivation for acceptance will be looked at on individual basis depending on: – – Therapeutic window of drug Medical condition being treated Lack of AE’s (must just be under-reported) Lack of efficacy (may just be under-reported)

4. Guideline on Bioavailability & Bioequivalence (cont. ) l Reference Product: If the innovator product is not being used, the market leader can be used as long as: l It is authorised for marketing in SADC region (PROOF TO BE SUBMITTED) l PRIOR approval has been obtained from DRU

4. Guideline on Bioavailability & Bioequivalence (cont. ) l Biowavers: l Applicant to provide justification and proof of safety, efficacy & quality – submit copies of entries from standard reference books showing linear kinetics over dose range & that API is not a pro-drug (DRU does not have access to these) Biowaver Application Form to be used to PREAPPLY for a Biowaver for in-vitro testing. Applicant to provide evidence of BCS class and that excipients will not affect absorption of active. l

4. Guideline on Bioavailability & Bioequivalence (cont. ) l Biowavers (cont. ): l Biopharmaceutics Classification System – – Class 1: High solubility – high permeability Class 2: Low solubility – high permeability etc. SADC & FDA accept ONLY BSC Class 1 drug substances for biowavers Developing countries need access to innovator products whose API is not BCS Class 1 (in-vitro BE studies are much cheaper than in-vivo BE studies; research is underway on BSC Class II drug substances w. r. t. proof of BE)

4. Guideline on Bioavailability & Bioequivalence (cont. ) l Bioequivalence Studies: – – If measurements of concentration of active/inactive metabolites used instead of parent compound, this must be stated in the protocol, not after the study is complete. Acceptance Criteria (AUCt, Cmax & Cmin (ss)): 0, 8 – 1, 25 (80 – 125%), based on FDA, EU, SADC & Canadian criteria – wider limits may be accepted if stated “a priori” & justified in protocol

4. Guideline on Bioavailability & Bioequivalence (cont. ) l Bioequivalence Studies (cont. ): l Similarity factors F 1 & F 2: – l Submit F 2 comparison as well as F 1 Aerosols for inhalation require bioequivalence/clinical testing, not in-vitro testing

4. Guideline on Bioavailability & Bioequivalence (cont. ) l Bioequivalence Studies (cont. ): – – “Adequate wash-out periods” = 5 -8 t½’s (as per FDA) Number of subjects to be calculated statistically to provide at least 80% power of meeting acceptance criteria – minimum is n=12 subjects (immediate release oral dosage forms) & n=20 (modified release oral dosage forms) (“South African companies tend to submit smaller subject numbers & no account is taken of drop-outs”)

4. Guideline on Bioavailability & Bioequivalence (cont. ) l Bioequivalence Reports – – – Full studies to be submitted, not just summaries Refer to FDA Guideline on Bioanalytical Method Validation, for validation required for BA/BE studies Lower limit of quantitation, detection & recovery to be stated in protocol

5. Guideline on Good Manufacturing Practices l Developed & adapted from WHO GMP Guideline and “other countries” l Inspections: – only on a prioritised basis (eg. If BMR’s show problems, if products in the Public Health arena if any concerns are raised)

5. Guideline on Good Manufacturing Practices (cont. ) l Complaints: – – – DRU wanted all complaints to be reported on all products from all sites……… Discussion followed & DRU acknowledges they lack resource to manage complaint reports and even Annual Product Reviews, as well as SMF’s (for further discussion within DRU) DRU to be advised regarding all recalls & incidents of counterfeiting

5. Guideline on Good Manufacturing Practices (cont. ) l Responsible Person: – – – Currently law does not define a “Responsible Person” within Botswana Amendment to law in process to include local “Responsible Person” (local competent person), expected by end 2009 Implementation date to be specified

5. Guideline on Good Manufacturing Practices (cont. ) l Batch Manufacturing Records (MBR): – – – DRU will not waive requirement to see BMR’s If parent companies do not want them submitted, Applicant can arrange appointment to take them to DRU offices for inspection Packing Record to contain outer container label in compliance with Botswana requirements (problem for new products)

Almost time for lunch!

6. Draft Guideline – Clinical Trials using Medicines in Human Participants l Adapted from: – – – 1. 2. 3. SADC guideline (approved 3 -4 years ago) ICH & RSA guidelines for Clinical Trials TGA & FDA guidelines Lays out requirements for regulatory evaluation of CT applications by DRU (scientific & ethical review done by HRU) – reviews the investigational drug (SECTION 9 of guideline) HRDC does scientific & ethical review of CTA – must assist in capacity-building within the country Submit 1 & 2 in parallel

6. Draft Guideline – Clinical Trials using Medicines in Human Participants (cont. ) l Much more detail is required on the investigational drug review by DRU than is found in Investigators’ Brochure → a slightly abbreviated pharmaceutical dossier required: – NCE’s, therefore DRU has no information on its chemical nature or safety in humans l eg. API: physico-chemical properties, method of synthesis, impurities, specifications & test methods, stability. Drug Product: formulation, method of manufacture/packaging, specifications & test methods, stability, labelling of investigational product is specified, etc.

6. Draft Guideline – Clinical Trials using Medicines in Human Participants (cont. ) l Clinical Trial Application: – – Section 1 – Checklist of Required Information Section 2 – Administrative and Supplementary Details l Applicant details, Investigational Product control details, Trialists’ & Trial Sites’ details, Trial subjects’ details, Other details, Ethics, Applicants’ Report/Presentation (summary of planned trial conduct)

6. Draft Guideline – Clinical Trials using Medicines in Human Participants (cont. ) l Appendices 1 – 8: – – – Clinical trial application form Format for Investigators’ CV Joint Financial Declaration – Sponsor & PI Declaration by PI; Co-investigator; Regional Monitor; Clinical Trial Protocol Amendment Form Application Form for Additional Investigators & Sites

6. Draft Guideline – Clinical Trials using Medicines in Human Participants (cont. ) l l Separate guidance for the application made to HRDC (www. MOH. gov. bw) HRDC gives final approval for CT when DRU evaluation is complete Secretary to HRDC: Mary Kasule Marykasule@gmail. com Tel: 3632466 (office) +267 71862559 (cell)

General Q & A Session l l l Pharmacovigilance: draft available, based on TDA/SADC guidelines, due to be finalised by end 2009 PSUR’S: no infrastructure to handle now at DRU, may be required in the future Renewals & retention fees: will be phased in some time in the future (proposal: DRU to include in guideline that currently renewal is automatic unless DRU contacts Applicant)

General Q & A Session (cont. ) l Safety Updates: DRU wants to approve safety updates – sometimes disagree with MCC’s requirements – For products coming from RSA, DRU will consider proposal of i) Dear Healthcare Professional letter for serious AE’s and ii) submit to MCC & then to DRU (to be revisited)

General Q & A Session (cont. ) l Section 21 Approvals: – – – require a prescription from a Doctor registered in Botswana Motivation for use (no effective alternatives) DRU Application Form “Exemption from Registration”

General Q & A Session (cont. ) l Blue Book Updates? – – Currently have Blue Book plus Addenda No update to Blue Book is planned Must buy Blue Book & check with DRU as to latest Addenda listed by generic name instead of brand names – Customs cannot use this, requested lists to be stated by trade name

General Q & A Session (cont. ) l Interaction between DRU & Customs Control? – – – l Currently very little communication Increasing Hope to follow Ugandan model in the future due to increasing threat of counterfeits Registration Certificates? – Due to be supplied by end 2009

DRU Structure (‘work in progress’) Principal Pharmacist Head of DRU DR SINAH SELELO Principal Pharmacist 1 Medicine Registration Unit MS SELOI MOGATLE Principal Pharmacist 1 Control Habit-Forming Drugs Principal Pharmacist 1 Post-Marketing Surveillance MRS OLAWAMI OLADIRAN

General l New Botswana banking details: Government of Botswana Bank Swift code is BBOTBWGX Account No. 0101000016620000 Bank of Botswana Credit Vote: 1108 23251 - Drug Registration and licensing Department of Clinical Services, Ministry of Health

Where to from here? è Study the draft guidelines è Provide feedback & comment on areas of concern to: – SAPRAA or SAAPI or directly to Seloi Mogatle at DRU

THANK YOU…. …. . for your attention!