API Assessment: Common Deficiencies

API Assessment:Common Deficiencies Isabel Ortega and Antony Fake WHO Prequalification of Medicines Programme Assessors training, Copenhagen January 2012

Overview API information. What are we looking for. A summary of deficiencies found in APIMFs assessed within PQP. Common deficiencies. API Common Deficiencies January 2012

API Information • There are different options that can be used by applicants to submit API information. • Use of a prequalified API • Use of an EDQM CEP • Use of an APIMF • Provision of full API information in the product dossier. API Common Deficiencies January 2012

API Information • Regardless of the option chosen the same information is required. • The API information assessed within PQP is compiled in the Common Technical Document format (CTD). • This is regardless of whether the API is pharmacopoeial or not. API Common Deficiencies January 2012

API Information API Common Deficiencies January 2012

Is the starting point of the manufacturing process acceptable? API Common Deficiencies January 2012

Traditional manufacturing Raw materials Final API Traditionally, the API manufacturer manufactured the API from simple raw materials at their own facility. This meant it was safe to assume that the molecule used in the first step at the API manufacturer's factory was an appropriate API-SM. API Common Deficiencies January 2012 8

Contemporary manufacturing Intermediate API-SM API-SM Raw Material Final API Increasingly, intermediates late in the synthesis are being purchased. This means the API-SM can not be assumed to be the molecule used in the first step at the API manufacturer's factory. API Common Deficiencies January 2012 9

API Starting material Choice of API-SM ASSESSORS Simpler molecules Final API INDUSTRY API Common Deficiencies January 2012

API Starting material API manufacturers prefer to have the API-starting material (API-SM) defined as late in the synthesis as possible because: • It reflects the manufacturing steps undertaken at their factory under their control. • The API-SM is the point at which GMP applies to manufacture. • This can be financially advantageous when API manufacturers buy reaction intermediates from secondary manufacturers that do not operate under API GMP. API Common Deficiencies January 2012 11

API Starting material The problem for assessors is: • Information on the preparation of a complex API from one or two steps makes determination of impurities in the API very difficult. • If the SM is complex it is hard to judge the acceptability of the API-SM specifications. • The guarantee of quality API is the result of good manufacture and control throughout all the steps (GMP). Comprehensive testing of the final API does not replace this. API Common Deficiencies January 2012 12

Are the manufacturing process and process controls adequately described? API Common Deficiencies January 2012

Manufacturing Process API starting material A detailed and complete flow diagram is required API intermediate(s) A detailed narrative description is required. Final API intermediate Crude API Final API API Common Deficiencies January 2012

What are the potential impurities? API Common Deficiencies January 2012

Potential impurities API starting material API SM impurities Reagents Solvents Catalysts Reaction by-products API intermediate Reagents Solvents Catalysts Reaction by-products Crude API Crystallisation solvent Degradation products Final API API Common Deficiencies January 2012

Potential impurities • Residue of the SM • Residue of the intermediate • Impurities in the SM • Reagents • Solvents • Catalysts • Reaction by-products • Degradation products API Common Deficiencies January 2012

Can the potential impurities be carried over into the final API? API Common Deficiencies January 2012

Are the potential impurities detectable by the analytical procedure? API Common Deficiencies January 2012

Final API Specifications Analytical procedures Control Reference standards Stability Container/closure system API Common Deficiencies January 2012

Are the API specifications acceptable? API Common Deficiencies January 2012

Can a retest period and recommended storage conditions be established? API Common Deficiencies January 2012

Summary of deficiencies • I have started to investigate commonly observed deficiencies with APIMFs assessed by the PQ programme. API Common Deficiencies January 2012

Investigation overview • The initial assessment reports for 90 APIMFs were investigated (assessed between 2007-2011). • This includes 45 HIV, 24 MA, 19 TB and 2 IN APIMFs. • For more than 70% of the products, an official compendial monograph was available at that time. A total of 2828 deficiencies classified by CTD section API Common Deficiencies January 2012

Deficiencies by CTD section Number of deficiencies API Common Deficiencies January 2012

% of deficiencies by CTD section Common deficiencies API Common Deficiencies January 2012

Top 9 deficiencies (by CTD section) 1- Manufacturing process (3.2.S.2.2) 2- Starting material quality (3.2.S.2.3) 3- Quality of all other materials (3.2.S.2.3) 4- Control of intermediates (3.2.S.2.4) 5- Polymorphism (3.2.S.3.1) 6- Impurities (3.2.S.3.2) 7- Specifications (3.2.S.4.1 and 3.2.S.4.5) 8- Validation of analytical procedures 9- Stability deficiencies (3.2.S.7.1, 3.2.S.7.2 and 3.2.S.7.3) API Common Deficiencies January 2012

1- Manufacturing process (3.2.S.2.2) API Common Deficiencies January 2012

Information on the API preparation is not sufficiently detailed A detailed flow diagram of synthesis indicating chemical structures, molecular weights, solvents, reagents should be presented. When an APIMF is used this information should be provided in both the open and closed sections. A detailed narrative of each synthetic step should be presented, including: the types and quantities of reagents and solvents; reaction conditions; critical steps, in-process controls; and yields. • The description of the API manufacturing process represents the applicant’s commitment for the manufacture of the API. API Common Deficiencies January 2012

The proposed API SM is too complex • It is often observed that the proposed API SM is merely the molecule that is used in the first manufacturing step at the API manufacture site. • This is not a sufficient justification. • The API SM should be a relatively simple molecule. In general it should be one or more synthetic steps from the final intermediate. API Common Deficiencies January 2012

The proposed API SM is too complex There are exceptions to this rule. For instance • Artemisinin is accepted as a API SM despite it’s complexity because it is derived from a plant. • Aminobutanol is accepted as the API SM for ethambutol, despite being a one step synthesis, because both the API SM and AP are simple molecules. API Common Deficiencies January 2012

The proposed API SM is too complex The point at which the API SM is introduced is the starting point of the application of GMP requirements. The API SM itself needs to be proposed and justified by the manufacturer and accepted as such by assessors. • In these cases, the applicant is requested to redefine the API-SM as a synthetic precursor one or more synthetic steps prior to the final key intermediate. • The manufacturer of the key intermediate should be included as an API intermediate manufacturing site and should be GMP compliant. API Common Deficiencies January 2012

The information on reprocessing is not sufficiently detailed Steps where reprocessing may occur should be identified and justified. • Reprocessing is the repetition of a step of manufacture for a batch of API or intermediate that is considered substandard. • The frequency of reprocessing should be stated because excessive reprocessing indicates the manufacturing process is not under control. This is not in line with GMP. API Common Deficiencies January 2012

The maximum batch size is not clearly stated The description of the process should indicate the scale of manufacture and the range for which the considered process may be used. It may be helpful to indicate the yield or yield range produced at each stage. • Often the intended scale (or range) of manufacture is not categorically stated. • The applicant should be able to provide evidence of manufacture at this scale (at a minimum batch data). API Common Deficiencies January 2012

The maximum batch size is not clearly stated • We need to know what is the maximum batch size for which the applicant has experience with the defined method. • Also, if blending occurs it has to be confirmed that each batch incorporated into the blend is individually tested and found to meet specifications set for the final API prior to blending. API Common Deficiencies January 2012

Solvents used are not clearly identified in the process All solvents used in the manufacture (including purification and/or crystallization step(s)) should be clearly identified. Quantities of solvents reflecting the representative batch scale for commercial manufacture should be stated. Solvents used in the final steps should be of high purity. • Specifications should be provided for all solvents. • The carry-over of all solvents into the final API needs to be assessed. API Common Deficiencies January 2012

The information on recovery of solvents is not sufficiently detailed The recovery of materials, if any, should be described includingthe step they are taken and re-introduced into the process. Use of recovered solvents in the final steps of purification and/or crystallization is not recommended. • Often no comment is made as to whether the recovery of materials occurs or not. • The recovery of solvents is very common. • The use of multiple solvents and reagents for different purposes within a process leads to the formation of solvent mixtures. • The potential for cross contamination needs to be assessed (the impurity profile of the API should remain unaffected). API Common Deficiencies January 2012

2- Starting material quality (3.2.S.2.3) API Common Deficiencies January 2012

The information on API SM preparation is not sufficiently detailed or is missing. • Information on the API SM preparation is needed to determine the appropriateness of the specifications. • Detailed information is usually not required, because the SM should be relatively simple. • This information is often supplied in form of a flow-chart (synthetic transformation, reagents, and solvents). • If there are two or more suppliers of the API SM, information on the preparation of the SM from each supplier should be provided. API Common Deficiencies January 2012

Information on the API SM manufacturer is missing For each SM, the name and manufacturing site address of the manufacturer should be indicated. If there are several manufacturers, it should be clarified whether the SM obtained from different sources is prepared by the same route of synthesis or if different routes are used. API Common Deficiencies January 2012

The API SM specification is not satisfactory The SM specifications should include among others an identity test and tests and limits for assay and for specified, unspecified and total impurities. • The API SM impurity limits should be justified by the demonstrated ability to manufacture API from batches of SM with similar impurity levels. API Common Deficiencies January 2012

The API SM specification is not satisfactory • Each API SM supplier does not have to have the same specifications but a singleSM specifications should be defined by the API manufacturer and applied to all sources of SM. • The carry-over of impurities into the final API should be considered and discussed. The same applies for solvents, reagents, and catalysts used in the SM preparation, as needed. API Common Deficiencies January 2012

3- Quality of all other materials (3.2.S.2.3) API Common Deficiencies January 2012

The specifications for raw materials, solvents, reagents, catalysts are unsatisfactory. Information of the quality and control of these materials should be provided. Information demonstrating that materials meet standards appropriate for their intended use should be provided. • The specifications for all materials used should be provided. • They should include at least an identification test and assay limit. • Limits for benzene in toluene, methanol, ethanol and acetone are commonly requested as this can be an impurity. API Common Deficiencies January 2012

The specifications for recovered solvents are not satisfactory. Recovery operations should be adequately controlled such that impurity levels do not increase over time. Use of recovered solvents in the final steps of purification and/or crystallization is not recommended. • Their specifications should include appropriate limits for assay, impurities and non-volatile matter (0.1%). • Any lessening of quality of the recovered solvent limits needs to be justified. • It should be demonstrated that recovered solvents with impurity levels approaching the limits proposed affords API of an acceptable quality. API Common Deficiencies January 2012

4- Control of intermediates (3.2.S.2.4) API Common Deficiencies January 2012

The specifications for isolated intermediates are not satisfactory. Information on the quality and control of intermediates isolated during the process should be provided. The specifications should include tests and acceptance criteria for identity, purity (individual and total impurity limits) and assay, where applicable. • The limits chosen should be justified and demonstrated to be acceptable (in terms of carry-over into the final API). • Often the proposed limit for total impurities is too high. • Control of certain impurities in the intermediate may eliminate the need to control this impurity in the final API. API Common Deficiencies January 2012

5- Polymorphism (3.2.S.3.1) API Common Deficiencies January 2012

API Assessment: Common Deficiencies