common deficiencies in submissions for prequalification (quality part) hua yin prequalification of...

Common Deficiencies in submissions for Prequalification

(Quality part)

HUA YINPrequalification of Medicines Programme

QSM / EMP / HSS

WHO prequalification programme: Training workshop March 2010, Beijing

WHO prequalification programme: Training workshop March 2010, Beijing2 |

DocumentationDocumentation

1. The product submitted for prequalification is NOT in the latest EOI (should be the same API and strength)

2. The cover letter from the applicant did not clearly indicate that the information submitted is true and correct.

3. The PQIF and BTIF are NOT submitted or submitted but Not in word document.

4. The dossier submitted does NOT have (clear) table of contents and the numbering of dossier pages does not follow one sequence.

5. The FPP applicant has made reference to the APIMF, but a copy of the Letter of Access from the APIMF holder is not submitted.


Common DeficienciesCommon Deficiencies

Active Pharmaceutical Ingredient

(API)


S.1.3 General PropertiesS.1.3 General Properties

Water solubility of the API is not characterized:

– Quantitatively (over the physiological pH range 1.2-

6.8)*

– For a low-solubility API, particle size, polymorphism,

should be characterized

(based on the lot used in clinical or bioequivalence studies)

See decision tree #3, #4 in ICHQ6A


S.2 Manufacture S.2 Manufacture

Description of the manufacturing process is not sufficiently Flow chart and detailed description of the manufacturing of API, operating

conditions and materials used, typical batch size should be provided.

Specifications of materials used are not complete When the starting material (SM) is not available commercially or is only one

or two steps from the final API, or is not of simple structure, the synthetic route of the SM should be provided, as well as the detailed specifications especially regarding the impurity profile including residual solvents.

solvents, reagents and catalysts used in the process and their specifications, should include as a minimum an identification test and an assay.specification of recovered solvents should be provide


S.3 CharacterisationS.3 Characterisation

Discussion on potential impurities is not sufficient

The following information should be provided:

– List of impurities including chemical name, structure, and origin (e.g., starting materials, by-products, intermediates, chiral impurities, degradations)

– All potential residual solvents should be discussed, and controlled in specifications unless adequately justified.

– If catalysts are used in the synthesis, these should be controlled in specifications unless adequate justified

– Data on observed impurities in batches used in clinical or BE study

– Impurity limits must be suitably qualified (ICHQ3A)


S.4 Control of Drug SubstanceS.4 Control of Drug Substance

Copy of the compendial monograph is not considered as sufficient

The specifications should have tests/limits meeting existing compendial monographs—as minimum requirement. However,

– The suitability of the monograph method to determine new impurities due to a new route of synthesis must be demonstrated. If not, propose a new validated method and a qualified limit.

– The purity and potency methods should be verified for specificity, precision and accuracy.

– The API specification from the manufacturer of the FPP should be provided, including the parameters related to the specific product. It should be dated and signed by authorized personnel.


S.5 Reference Standards S.5 Reference Standards

Information on reference standard is missing

– Where a compendial reference standard (RS) exists, this should be the primary standard against which all house standards are qualified.

– Where no compendial RS exists, the primary standard should be highly purified and fully characterized. Potency should be based on mass balance.

– Whether any additional purification solvents used for the reference standard could result in modified properties (e.g. polymorphism).


S.6 Container Closure System S.6 Container Closure System

Identification of container-closure/packaging of the API is not done

– Identity of materials of construction of primary packaging

– Specifications for components in contact with the API should include a specific test (eg IR) for identity.

– Container specifications should be provided by API packager, not the packaging supplier.

– The packaging should be food and/or pharmaceutical grade


Common DeficienciesCommon Deficiencies

Finished Pharmaceutical Product

(FPP)


FPP Description and CompositionFPP Description and Composition

Description of the FPP is incomplete.

Good example:

White to off white coloured capsule shaped biconvex uncoated tablets with central breakline on one side and debossed with ‘A’ on other side

Description of the Packaging is incomplete.

Good example:

The primary packs are cylindrical, white, opaque, induction-sealed HDPE bottle fitted with a white Non CRC Screw Cap and containing 1 gm Silica gel bag and Rayon Sani coil.


FPP Description and CompositionFPP Description and Composition

The composition has errors:– Not in agreement with the master production records– Solvents should be listed in the table, but amounts per unit

should not be included or added to the totals– All components used in manufacture should be listed, eg

Nitrogen

The qualitative composition of mixtures, such as Opadry colourants, capsule shells, printing ink, is not provided.


3.2. Pharmaceutical development3.2. Pharmaceutical development

Pharmaceutical development is absent or not complete.

Lack of information on physico-chemical characteristics of the API which may have an impact on the manufacturing and performance of the product. such as particle size distribution, bulk/tapped density, polymorphic form

Compatibility of the API with excipients and in case of FDCs compatibility between APIs are not studied or at least not shown in the dossier.– Compatibility studies often report appearance only. Studies should include

chromatographic results (potency and impurity). e.g. Rifampicin/Isoniazid

Rationale behind choice of manufacturing process, overages (if any), not given. e.g. Rifampicin


3.2. Pharmaceutical development3.2. Pharmaceutical development

Lack of comparative dissolution testing with the innovator/comparator

Comparative dissolution testing is a tool

Help in selection of the formulation– compare formulation(s) with innovator product,– a basic strategy in development to maximize the chances of bioequivalence

Comparison of dissolution properties of pivotal batches with future commercial batches, post-approval changes

Setting of dissolution specification

For solid dosage forms, it is a requirement to submit comparative dissolution data for the biobatch and innovator/comparator batch used in the bioequivalence. These data can be included in both part quality and bioequivalence study of the dossier.


3.5 Manufacturing Process 3.5 Manufacturing Process

Missing of typical commercial batch size

Batch manufacturing records are not included

Poor description of manufacturing process

– In-process testing should be specified. – granulations: moisture (range), blend uniformity, as necessary: bulk and

tapped densities, particle size distribution; – tablet cores: average weight, weight variation, hardness, thickness,

friability, disintegration– coated tablets: weight gain during coating;

– Equipment should, at minimum, be identified by type (e.g., tumble blender, in-line homogeniser) and working capacity

– process parameters such as time, temperature, speed should be indicated


3.7 Process Validation and Evaluation3.7 Process Validation and Evaluation

Process validation protocol is not adequacy

– Description of the manufacturing process & Flow diagram

– identification of critical steps and process parameters to be monitored

– equipments to be used in the process

– sampling plans i.e. location, time and method

– Proposed in-process controls with acceptance criteria

– The frequency of in-process testing

– Finished product release specification

– Evaluation of results

Confirmation/commitment that three consecutive, production-scale batches of this drug product will be subjected to prospective validation.


3.9. Control of the FPP3.9. Control of the FPP

– The specification should include a reference number, version, date, and appropriate standard, (e.g. Int.Ph+ In-house)

– The specification should be dated and signed by authorized personnel

– Details of specifications and test methods should be provided

sufficiently.

– information for reference standard

– justification of specifications


3.9. Control of the FPP3.9. Control of the FPP

– Validation of analytical methods and/or demonstration of applicability for pharmacopoeial methods

– The FPP is a pharmacopoeial product and the pharmacopoeial method is used but a minimum validation is not performed.

– The pharmacopoeial monograph cannot cover all the formulations for a FPP. As a minimum, the selectivity of the pharmacopoeial method towards a specific formulation should be demonstrated, in terms of specificity, precision and accuracy.

– If the tablet contains a score (justified), a one-time study of uniformity of tablet halves should be provided. refer to TABLETS,

Subdivision of tablets (EP, 5.5, p. 4166)


3.11 Stability testing3.11 Stability testing

Incomplete stability to meet the requirements as stimulated in the regulations & guidelines

– three batches, at least pilot scale. Batch No., B.size

– in the claimed commercial packaging– 6 months accelerate (40°C / 75% RH) + 12 months long term

data + commitment to continue

Unless otherwise justified, 30°C / 75% RH is the recommended storage condition for Prequalification



Lack of discussion and evaluation of the results Variation in analytical results,

Example

– Stability specificaiton limit of API : 92.5-105.0%

– Stability data: 102.0% at initial→95.0% at end of 24 months (Within spec), But, loss in potency: 7.0%

– Disscuss: is it a real trend of decrease in assay or due to method variability? Investigation of the Out of Specification (OOS) results. Investigation of known/unknown degradation products Justification of the shelf life specification

– widening of the acceptance criteria at the end of shelf-life is possible for some parameters with justification, such as degradants and assay

– but unacceptable for some other, such as dissolution



In-use stability testing is not provided

– To provide information for the labelling on the preparation, storage conditions and utilization period of multidose products after opening, reconstitution or dilution of a solution, such as powder for oral solution/suspension

– The test should be designed to simulate the use of the FPP in practice,

– Monitor the physical, chemical and microbial properties of the FPP susceptible to change during storage. Although there is no control of impurities in monograph, degradation should be monitored in stability studies—products contain rifampicin.

– A minimum of two batches, at least pilot-scale

– At least one of these batches should be chosen towards the endof its shelf-life, or at the final point of the submitted stability studies


Documentation in EnglishDocumentation in English

Original documents to be submitted with translation

– Certificates, Manufacturing license, MA, GMP, TSE

– Manufacturing process documentation

Batch manufacturing record

Validation reports

Specifications and CoAs


Documentation in EnglishDocumentation in English

Terms of specification: essential to be correct.

Example:

IR/UV absorption chromatogram does not exist. it should be spectrum

Moisture: is not equal to Water in a molecule with two moles of water of crystallization. It should be water content

Calculated on “dehydrated products” is not an acceptable term for “anhydrous basis.”

Tips: use pharmacopoeia Int Ph/USP/BP terms


Other sources of information: refer to the drug information of innorvators, approved generics for SmPC, FPP description, packaging information, etc.

WHOPARs: http://healthtech.who.int/pq/WHOPAR/WHOPARPRODUCTS/WHOPAR_Index.htm

EPARs: http://www.emea.europa.eu/htms/human/epar/a.htm

FDA approved drug products: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm


Thank youThank you

common deficiencies in submissions for prequalification (quality part) hua yin prequalification of...

Documents

prequalification programme

beijing slide

training workshop

prequalification quality

specifications of materials

manufacturing of api

ichq6a slide

detailed specifications