1 TG Dekker – WHO, MalaysiaFeb 2005 Experience with Prequalification of Dossiers (quality part) Workshop on GMP and Quality Assurance of Multisource Tuberculosis

1 TG Dekker – WHO, MalaysiaFeb 2005

Experience with Prequalification of Dossiers (quality part)

Workshop on GMP and Quality Assurance of

Multisource Tuberculosis MedicinesKuala Lumpur – Malaysia

21-25 February 2005

Theo Dekker, D.Sc., consultant to WHOResearch Institute for Industrial Pharmacy

North-West University, Potchefstroom, South [email protected]


Abbreviations

API Active pharmaceutical ingredientBP British PharmacopoeiaCEP EU certificate of suitabilityEOI Expression of interestFDC Fixed dose combinationFPP Finished pharmaceutical productGMP Good manufacturing practicesICH International Conference on HarmonizationInt.Ph. International PharmacopoeiaPh.Eur. European PharmacopoeiaSmPC Summary of product characteristicsTB TuberculosisUSP United States Pharmacopeia


Assessment procedures

1. Assessment according to the guidelines2. Two assessors per quality (first & second)3. Assessment outcome letter to applicant

(manufacturer)4. Applicant’s response, assessment of

additional data. Repeat this step if necessary:5. Approval of quality, with storage requirements

and shelf-life6. Approval safety/efficacy/CRO and GMP7. Listing as prequalified on website


Well-established FPPs (Blue Book):

Have been marketed for at least five years in countries that undertake active post-marketing monitoring,

Have been widely used to permit the assumption that safety and efficacy are well known &

Have the same route of administration and strength, and the same or similar indications as in those countries

All the FPPs on the 5th Invitation of EOI conforms to requirements, though innovator products are not always identifiable


General remarks

Encouragement Since the 1st invitation for EOI (Jan 2002) the

quality of the dossiers (including DMFs) have notable increased (quality section)

DMFs accepted: 14 Valid CEPs presented: 5 One product registered via the route of

registration in an ICH country


General remarks (2)

Concerns Supportive literature information absent in

most dossiers (other than compendial data) Literature information not professionally analysed

& discussed in terms of the situation Photocopies and/or full reference particulars of

literature used in dossier are not presented

Responses to assessment reports not comprehensive Resulting in multiple assessment/responses


General remarks (3)

Concerns (continued) FPPs not registered in country of origin Marketing authorisation issued without

assessment by national DRA Only a small number of TB products appear on

the prequalification list: 8 anti-TB products by September 2004

(85 HIV/AIDS products by Nov. 2004) (2 antimalarial products by April 2004)

4 suppliers/manufacturers


PQ list of TB products (09/2004) - tablets

Ref INN Strength Supplier

008 Ethambutol (Eth) 400 mg Cadila

015 Pyrazinamide (Py) 400 mg Cadila

024 Rif/INH/Py/Eth 150/75/400/275 Wyeth Pak

068 Rifampicin/Isoniazid 150/75 mg Lupin

070 Rif/INH/Py/Eth 150/75/400/275 Lupin

084 Rifampicin/Isoniazid 300/150 mg Sandoz

085 Rifampicin/Isoniazid 150/75 mg Sandoz

090 Rif/INH/Py/Eth 150/75/400/275 Sandoz


Approach to deficiency discussion

Deficiencies experienced with dossier (and additional data) assessments are discussed according to the points set out in the prequalification guideline (session 1):

Guideline on Submission of Documentationfor Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs)

used in the Treatment of HIV/AIDS, Malaria and Tuberculosis (hand-out)


Administrative 1/33

Poor organisation of the dossiers hampers the assessment. Examples: Files are sometimes poorly bound (or not securely

packed in the courier parcels) Absence of table of contents Absence of page numbers throughout dossier It is recommended that sections be clearly

indicted with securely fixed tags to assist cross-checking by assessors


Section 1. Characteristics of FPP 2/33

Samples of FPPs are not always submitted

• This is quite frustrating, since the samples are needed for instance: To verify the description of the product To inspect the packaging materials To check correctness of the label To check the data in the SmPC & PIL For laboratory testing


Section 2. API deficiencies 3/33

Full description of the reactions/steps used in the API synthesis not presented, including the purification step. Specifications of chemicals, catalysts & solvents used also absent. Possible impurities cannot be established Benzene (class 1 solvent, ≤ 2 ppm) in toluene

1,2-dichloroethane used in the synthesis of ethambutol 2HCl not specified in API specs. This is a class 1 solvent, ≤ 5 ppm (ICH) Class 1 solvents acceptable only when

unavoidable


Section 2. API deficiencies (2)

The open part of the DMF of the API is often incomplete and lacks information such as Solubility properties (solubility in water, buffers at different

pH values & organic solvents and partition coefficient) Solid state properties (existence/absence of

polymorphism, hygroscopicity, particle size, flowability, etc.)

API specifications lack attributes additional to compendial monograph, e.g. Residual solvents (OVIs), particle size USP OVIs (organic volatile impurities) not always covering

specific synthesis OVIs



The limits for assay in the API specifications not given to one decimal place, e.g. Must be 98.0-101.0% (instead of 98-101%) The same applies for the FPP specifications

Potency determination & CoAs not presented for secondary/working standards Applies to both API and FPP manufacturer Official standards available for all TB APIs, except

moxifloxacin Copies of API CoAs and stability data sheets

not QA certified, signed or dated



Degradation information not presented- through forced degradation studies and/or- from relevant literature / CEP To identify possible degradants for stability

studies To verify specificity of stability assay method

- Diode array detection for API peak purity not demonstrated in stability indicating assay validation!


Section 3. FPP deficiencies 8/33

Pharmaceutical development reports are seldom included (done?) – a major problem When provided often incomplete Result: changes requested during assessment,

for instance due to stability problems

Pivotal batches (BE, validation, stability) Lack of table for comparison of formulas &

discussion Lack of comparative dissolution testing

(f2 similarity calculations)


Section 3. FPP deficiencies (2)

The purpose of excipients not indicated in the unit and batch formula table

Overages not justified Especially in case of rifampicin containing FPPs

Commercial colorant mixtures (e.g. Opadry) Composition not indicated Test methods not included

Microbial limit and colorants (skip-testing) not included in FPP specifications



Documentation not in English, e.g. in Manufacturing process documentation Validation reports

Statements on adventitious agents not presented, e.g. TSE/BSE (e.g. Mg-stearate from animal origin) Asbestos in talc

Lack of validation data/reports on pilot and first 3 commercial batches



Release/stability specifications & test methods of rifampicin containing FDC products are of MAJOR CONCERN:1. Main degradant (> 5.0%?) not specified or tested

► 3-(isonicotinoylhydrazinomethyl)rifamycin

2. API peak purity (DAD) not demonstrated in stability indicating HPLC assay validation studies

3. USP monographs do not include degradants

4. Specificity of USP assay method for 4FDC must still be demonstrated (found specific for products tested on equipment in our laboratory)



Stability specifications lack parameters that may be variables, e.g. Tablet strength, friability & water content These variables are interrelated, also with

dissolution, and may show meaningful trends Testing of these variables is inexpensive

Stability data presented in tables lack e.g. Discussion of each parameter Statistical analysis where required Full details of batches tested



Real-time stability studies carried out under Zone II conditions (25ºC / 60% RH)1. Yet storage requirements indicated on labels, in

SmPC & PIL often 30ºC !!2. Storage requirements must be supported by

stability studies3. Zone IV strongly recommended for

procurement purposes (currently: 30ºC / 65% RH).- A large portion of medicines distributed to Zone IV areas



Summary of product characteristics (SmPC): Not included Essential for FPP Essential for WHOPAR

(1) Identification of dosage form and(2) presentation (packaging description) not given in detail in SmPC and PIL Important in fighting counterfeit


Major conclusions

Expansion of the number of products and type of products in the prequalification list is of high priority for WHO

Development pharmaceutics studies (experimental and literature) will reduce the problems and increase the quality of the products / dossiers

API-API interactions in FDCs should be studied and resulting degradants identified and included in stability testing Degradant analytical methods to be developed/validated


The mission

The joint efforts of manufacturers & WHO should cover all activities aimed at ensuring that

the patient receives a product that meets established specifications and standards of quality, safety and efficacy.

It concerns both the quality of the products themselves and anything that might affect quality, including information supplied with the product.

(derived from Health Action International (Africa) definition for QA)

Documents

1 TG Dekker – WHO, MalaysiaFeb 2005 Experience with Prequalification of Dossiers (quality part) Workshop on GMP and Quality Assurance of Multisource Tuberculosis