INTRODUCTION:

The development and establishment of a robust manufacturing process for drug substances to deliver a product of consistent quality accounts for a significant proportion of manufacturer resources and efforts. For an organic chemist involved in bulk scale production and operating in today’s dynamic world of commerce, the challenge of bringing innovative and safe products to market is more daunting than ever. The rapid pace of change driven by new technologies, combined with unrelenting market demand for innovation, quality and value, requires that manufacturers rapidly develop and produce a steady stream of new products to meet the needs and wants of customers. When it comes to ensuring the polymorphic purity of ever increasing number of new products and their desired use in the pharmaceutical world, most reputable manufacturers design their products to comply with applicable regulatory standards. When required, they also subject new products to testing and certification by independent third-party testing laboratories. These steps are critical in gaining product acceptance from regulators, litigation-conscious wholesalers, distributors and retailers, and increasingly, quality conscious end users.

This paper will discuss the various risks and challenges that manufacturers face regarding the manufacturing of polymorphically pure products, and detail-specific risks during manufacturing in commercial plants and precautions to be taken during manufacturing unit and also during their product development efforts in R and D.

The manufacturing of polymorphically pure drug substance is a daunting task for an organic chemist involved in bulk scale production. Often large amount of quantities are required for FDF development, for submission of DMF and ANDA filings ( pre-exhibit and exhibit batches of FDF) to regulatory bodies and also to cater to sourcing activities of large size multinational organisations. The large scale production of such polymorphically pure substances has in built issues which are similar to scale up issues often encountered during commercial manufacturing of other drug substances.

A recent analysis by SSCI, the solid-state chemistry business of Aptuit (Greenwich, CT), showed that of 245 compounds it has screened, 89% had multiple solid forms (see Figure 1). Approximately 50% of the compounds showed polymorphism, 37% were hydrates, and 31 were solvates¹. Considering the enormous number of polymorphic drug substances being developed and manufactured worldwide at various stages of development, it is inevitable that manufacturing professionals have the sound scientific background of polymorphism related theoretical and practical aspects. Such an awareness would avoid the confusions and troubles during commercial activities.

Figure 1: Prevalence of multiple solid forms for 245 compounds screened for polymorphs.

Why different polymorphs are formed?

Ostwaldt's rule states that in general it is not the most stable but the least stable polymorph that crystallises first. Ostwald's rule is not a universal law but is only a possible tendency in nature. Thermodynamics govern everything we do in the pharmaceutical industry^.2-5

Polymorphs have different stabilities and may spontaneously convert from a metastable form (unstable form) to the stable form at a particular temperature. They also exhibit different melting points , solubilities (which affect the dissolution rate of drug and consequently its bioavailability in the body), X-ray crystal and diffraction patterns. Certain impurities inhibiting growth pattern and favour the growth of a metastable polymorphs. The level of supersaturation from which material is crystallised (in which generally the higher the concentration above the solubility, the more likelihood of metastable formation). Change in stirring conditions/ Stirring patterns/ Stirrer blades/ Reactor Surfaces can also induce crystallisation of undesired polymorph.

Metastable polymorph may convert to more stable polymorph. Metastable polymoph has lower melting point than the stable one and may be more soluble compared with most stable form. Metastable form may convert to stable polymorph under certain conditions of temperature or humidity or compression during table manufacturing. The most stable polymorph is having the least solubility hence it is the preferred form for development and large scale manufacturing e.g. Form I of Clopidogrel bisulphate. Thermodynamically most stable polymorph has higher melting point than metastable form. Form I of Sertraline HCl M.P. about 219°C and Form II of Sertraline HCl melts at about 246°C⁶

Many drugs receive regulatory approval for only a single crystal form or polymorph. However there are business opportunities for developing and commercialising the drug substances in metastable polymorphic form. Ritonavir being the most cited example in the literature of polymorphism and commercialising the metastable Form-I in the form of 100 mg Norvir® soft gel capsule. This formulation needs to be stored at 2-8°C in order to maintain the Form-I in the drug product and to avoid its conversion at ambient temperatures to Form-II, which is thermodynamically more stable and less soluble, hence may not be useful therapeutically to the end user/ customer i.e. the patient undergoing Anti-HIV treatment. (Table I)⁷

Table 1. Solubility profile of Ritonavir API in various hydroalcoholic solvent systems at 5°C

Ethanol /Water	99/1	95/5	90/10	85/15	80/20	75/25
Form I	90 mg/ml	188	234	294	236	170
Form II	19 mg/ml	41	60	61	45	30

Regulatory perspectives:⁴

Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical stability, apparent solubility, dissolution rate, optical and mechanical properties like compressibility, vapor pressure and bulk density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability at various climatic conditions in the world, dissolution profile, and ultimately bioavailability to the patient undergoing treatment. Thus, changes in polymorphic purity of drug substance can affect the quality, safety, and efficacy of the drug product⁸

The solid-state properties of a drug substance can have a significant influence on the apparent solubility of the drug substance. Since polymorphic forms differ in their internal solid-state structure, a drug substance that exists in various polymorphic forms can have different aqueous solubilities and dissolution rates. When there are differences in the apparent solubilities of the various polymorphic forms,it is recommended that we focus on the potential effect such differences can have on drug product bioavailability (BA) and bioequivalence (BE).

Whether drug product BA/BE can be affected by the differences in apparent solubilities of the various polymorphic forms depends on the various physiological factors that govern the rate and extent of drug absorption including gastrointestinal motility, drug dissolution, and intestinal permeability. In this context, the Biopharmaceutics Classification System (BCS) provides a useful scientific framework for regulatory decisions regarding drug substance polymorphism.

For a drug whose absorption is only limited by its dissolution, large differences in the apparent solubilities of the various polymorphic forms are likely to affect BA/BE. On the other hand, for a drug whose absorption is only limited by its intestinal permeability, differences in the apparent solubilities of the various polymorphic forms are less likely to affect BA/BE. Furthermore, when the apparent solubilities of the polymorphic forms are sufficiently high and drug dissolution is rapid in relation to gastric emptying, differences in the solubilities of the polymorphic forms are unlikely to affect BA/BE.

Upon demonstration of in-vivo bioequivalence between the generic drug product and the reference listed drug (RLD), in-vitro dissolution testing is then used to assess the lot-to-lot quality of the generic drug product. Drug product dissolution testing frequently provides a suitable means to identify and control the quality of the product from both the bioavailability and physical (stability) perspectives. In particular, inadvertent changes to the polymorphic form that may affect drug product BA/BE can often be detected by drug product dissolution testing.

Regulatory agencies are more concerned about the polymorphism issues of APIs arising due to contamination of other polymorphic forms and such contaminations can also trigger patent infringement battles between a generic manufacturer and innovator of the same drug substance. Hence it is very much essential to ensure that drug substances are manufactured in most controlled way to avoid troubles arising in supply and distribution of drug substances. Formulation development and dissolution studies may not be successful, if drug substance is not polymophically pure and the entire efforts of developing and manufacturing drug substance may be futile. Such APIs may not be suitable for formulations.

Challenges encountered during manufacturing of polymorphic drug substance and precautions to be taken during manufacturing of polymorphically pure drug substances:

The drug substance i.e. API development efforts often focus towards the most stable polymorphs. However there are business opportunities in generic market to develop and commercialise the meta stable polymorphs. The patent infringement issues and para-IV opportunities are out of the scope of this paper. The process variables like temperature, time required for crystallisation and most importantly solvent or mixture of solvents, drying temperatures and particle size requirements for FDF development are studied in greater depth at research and development level. However, following are some of the issues often encountered during large scale manufacturing of polymorphic drug substances. It is necessary to mention that these issues are not limited to following aspects and can be different depending on the experimental observations of those working in this field.

— Solvents: Various types of solvents are used during final crystallization of drug substance. Any changes in quality of solvent due to cross contaminations with other solvents while dispencing of solvents in warehouse may lead to changes in polymorphic purity. Hence there should be dedicated dispensing mechanism and equipments for dispensing non polar solvents like hydrocarbons and polar solvents belonging to class of esters, ketones, alcohols, amides, cyclic ueas and chlorinated solvents.

— Cross contamination: Cleaning of previous APIs and pH due to previous cleaning agents: Cleaning of reactor should be thorough and reactor and equipments should be cleaned properly to remove previous product/s. It is also important to ensure to remove cleaning agents like sodium hypochlorite completely from the reactor. The residual amount of such cleaning agents might change the pH during final recrystalisation and may change polymorphic form or inhibit the recrystallisation process partially or completely.

Contamination arising due to foreign particles also can interfere with the recrystallisation process thus inhibiting the process. This can be taken care by filtration of clear reaction mass in final recrystallisation solvent at ambient or hot temperaute through 0.25 to 1.0 micron candle filter.

Contamination in equipments like centrifuge and trays of VTD due to inadequate cleaning also gives rise to impurities which might induce polymorphic modifications during storage. Therefore meticulous cleaning of these equipments is necessary.

— Final API isolation solvent: Final API solvent used for recystallisation or isolation should be free of contamination due to mixing with other solvent while dispensing in warehouse. Warehouse personnel must be very careful while doing this dispensing activity and integrity of the solvent should be maintained in order to achieve successful recrystallisation and isolation of pure API in desired polymorphic form. QC personnel also should be more alert while doing the GC purity analysis and any other peak/signal observed in GC chromatograph should never be neglected and should be reported immediately during quality inspection of raw materials and solvents.

— Control: Seeding gives better control over the recrystallisation process since it provides the platform for crystal growth and ensures desired polymorph during large scale manufacturing. Seeding is preferred technique which assures the quality of drug substance in much more controlled fashion. Addition of seeds at the beginning of crystllisation or at later stage would be decided on experiments and identification of meta stable zone of the process. Addition of seed crystals into a supersaturated solution or reverse addition of supersaturated solution into suspension having seed crystals would be purely decided by the observations based on experiments in R and D.

— Solvent quantities-concentration: As per the Ostwald’s dilution law,in a saturated solvent, the metastable/ unstable polymophs will crystallize first. This type of situation might result when the solvent quantities are changed while charging into reactor. Due to lower quantities of solvents, a more concentrated solution or supersaturated solution might result, hence recrystallisation process might change drastically giving rise to metastable polymophs. Such metastable polymophs may contaminate completely or partially desired polymorph giving finally the mixture of polymorph. Contamination due to other polymorphic API could be a serious patent infringement issue leading to legal battles and prolonged court proceedings. Hence it is very much essential that charging operations are strictly monitored by senior production personnel to avoid complicated issues like contamination, impurity formation and deviations and investigations to address these issues later on.

— Temperature: Drifts? Excursions? Temperature during recrystallisation process plays a crucial role and it is the prime important variable from thermodynamic point of view. It is very essential that skin temperatures due to localised heating by steam should be avoided. Localised heating might induce crystallization of different polymorph due to higher energy being provided and this would contaminate partly or completely the batch of final API. Similar precautions also needs to be ensured while drying the API wet cakes /powders in Vaccum tray dryers and Rotary vaccum paddles dryers.

— Memory retention^[^9]: It is nothing but getting same polymorph after dissolving in solution during recrystallisations. It is also called as form memory. As it is well proven fact that all the crystal structure is lost when crystal is dissolved in a solvent^[^10]. There exists no polymorphism in solution stage. However, sometimes, a small particle remains undissolved, or there are some crystals sticking to the walls of the flask, reactor or baffles, which act as a seed and hence contaminate the solution. This gives back the same polymorphic form after recrystallisation. To avoid this, the solution of API should be filtered through 0.45 micron membrane or candle filter to remove any undissolved crystal. This is particularly necessary when a different polymorphic form is intended from an existing one. For example, it is known that in the case of Ritonovir, if there is any contamination of Form II, the product is always Form II even if it is seeded with Form I.

— Milling : To reduce the particle size of API to micron level, usually milling is done. During milling operations especially in ball mill extended time cycles should be avoided. During such extended milling, API powder gets energy and polymorphic conversion may take place. More milder techniques like micronisation should be preferred to achieve desired particle size. Cryomilling is also an option for temperature sensitive materials.

— Solubility changes : During quality inspections, any changes in solubility should be observed and noted down critically. The observation of turbidity or insoluble matter could be due to other polymorphic form and hence this simple test of solubility can give very valuable feedback about the quality of the drug substance in very short time.

— Melting Points : The melting point of drug substance should be also observed very critically. Any deviations from the specified melting range should be reported in quality inspection reports and investigated systematically. The drifts in melting points are an indication of polymorphic modifications or impurities. Melting point alone is not sufficient to identify any particular form. Melting points can be very close. Hence more advanced instrumental techniques like high resolution XRD and ATR IR are necessary for conclusive decisions.

— XRD Patterns: It is necessary to maintain humidity levels low inside instrument chamber while scanning samples. Higher humidity converts unhydrous material to hydrates and different XRD pattern is obtained after analysis. XRPD diffractograms should be matched exactly with the standard Form^[11]. Each of the peak in XRPD diffractogram must be matched peak by peak. Only matching of certain characteristic 2θ values is not sufficient to ensure purity of polymorphic form. Any additional 2θ values/signals than the standard polymorph diffractogram could be contamination due to other polymorph. In case of doubt, API should be analysed using quantification methods to ensure that polymorphic purity is within specified limits.

— Thermal Analysis and IR: DSC can be used to ensure the exact melting points and generate more authentic analytical data than melting point. TGA technique also can give confirmation about hydrate or solvate and also give authentic analytical data about the loss upon heating of API. IR spectra also can give qualitative data about polymorphic form. However it is not more reliable tool as it lacks quantification and also peak /signals intensity depends on how properly sample preparation (KBr pellet) is done. Advanced IR instruments like Golden Gate ^TM ATR IR can give more reliable information using quantification tools to detect other polymorph contamination.

— Packaging of drug substance: Anhydrous APIs may get converted to hydrates or water induced polymorphic conversion upon slight exposure to humidity. To avoid exposure to moisture and conversion to other hydrates or polymorphic form due to exposure to moisture, it is often necessary to include dehydrating materials like silica bags/ pouch, to control moisture level in containers especially in high humidity coastal areas. Unhydrous materials absorb moisture in the containers, so keep inside material protected from moisture. Packing under Nitrogen is highly recommended using three bags systems i.e. inner LDPE bag flushed with Nitrogen after filing of API, followed by Black LDPE bag and tied with nylon fastener and then placed in suitable HDPE container and silica bags kept around and finally sealing the lid of the container. Printed labels also need to be fixed properly for inside bag and outside the container. Such type of packing will maintain the integrity of the material and also avoid any cross contamination during storage and transportation to other locations whenever required.

— Process safety: It is also necessary to share the common physical properties like melting points and sensitivity to moisture to FDF collegues. If the drug substance is sensitive to water, such precautionary notes should be communicated to FDF to avoid wet granulation. Safety precautions about powder handling, dust explosion etc. should also be studied and shared with cross functional team members of HSE, Production, QC and FDF. Such Process safety services are provided by earstwhile CiBa expert services (now Inertek) in Mumbai, India. Exposures to dust of highly potent drug substances during micronisation or milling should be also avoided using proper personal protective equipments i.e pressure suits, face masks to avoid inhalation of dust particles.

— Training: Adequate training of shop floor employees is necessary to increase their awareness about new product requirements and latest trends in manufacturing technologies. Training sessions with respect to basic knowledge of polymorphs technology, process safety and regulatory aspects should be conducted on regular basis by competent professionals.

— Maximize the number of observations: It is very much essential that manufacturing processes are very closely observed to avoid unpleasant surprises due to quality issues. The bitterness of poor quality remains for long, after the initial satisfaction of quick delivery. Such issues also raise the concerns of stake holders and regulatory agencies. There has to be a mechanism to prevent occurrence of unplanned deviations and investigations. This type of issues increases the time spent on such unproductive activities and also increase the paper work in the entire process of manufacturing activities.

— Minimize the number of variables: The processes transferred from R and D to Manufacturing plants for commercialization should have minimum variables. The more the number of variables like solvent quantity, moles equivalent ratio of reagents , temperature, reaction maintenance time, drying time, there is likelihood that quality of final drug substance may vary. It is often said that processes should be robust enough so that minor variations in operating parameters as mentioned above is taken care by the work up and or isolation procedure and quality of drug substance is assured. However in reality often R and D gets the blame for not developing robust process and Production gets blame for not being able to reproduce the results of R and D. However, it is a fact, in generic industry, whatever quality results are achieved by other generic manufacturers; same should be reproducible at any location on the globe.

CONCLUSION:

We have discussed the challenges faced during the manufacturing of drug substances on large scale. These challenges may arise from raw materials including solvents, warehouse activities and cross contamination. Troubles can be originating from manual errors of operators during cleaning of equipments or during quality inspections in QC. However, a conscious approach of all personnel involved in manufacturing teams towards ensuring the polymorphic purity of the drug substance is very much essential element for regulated markets and for business continuity of a generic firm.

ABBREVIATIONS USED:

FDF: Finished Dosage Forms, Drug Product, ANDA: Abbreviated New Drug Application, BA: Bioavailability, BE: Bioequivalence, API: Active pharmaceutical ingredient, Drug substance, QC: Quality control unit, GC: Gas Chromatography, XRD/ XRPD: X-ray powder, diffraction pattern, DSC: Differential Scanning Calorimeter, TGA: Thermogravimetric analysis, LDPE: Low density polyethylene bag, HDPE: High density polyethylene container

ACKNOWLEDGEMENTS:

The Authors are grateful to Principal, Ismail Yusuf College, Gogeshwari East, Mumbai for valuable guidance and constant encouragement during preparation of this article.

REFERENCES:

1. Advancing Approaches in Detecting Polymorphism ,Patricia Van Arnum CPhI Focus: Pharmaceutical Ingredients

2. H. G. Brittain, Polymorphism in Pharmaceutical Solids 1999 Informa Healthcare.

3. Yu et al. Physical Characterization of Polymorphic Drugs PSST vo1. 1(3) 1998.

4. H.G. Brittain, Physical Characterization of Pharmaceutical Solids 1995, M. Dekker.

5. Rolf Hilfiker, Polymorphism in Pharmaceutical Industry, 2006, Wiley-VCH.

6. Sertraline acid addition salts, its preparation and its use in the preparation of Sertraline Hydrochloride Form II , Ramana Venkata Kintali, Johannes Ludescher, Raji Nair and Sudhir Sawant US Patent no. US 2007/0054960 A1.

7. Ritonavir: An Extraordinary Example of Conformational Polymorphism , John Bauer et al , Pharmaceutical Research, Vol. 18, No. 6, 2001.

8. Guidance for Industry ANDAs: Pharmaceutical Solid Polymorphism Chemistry, Manufacturing, and Controls Information U.S. Department of Health and Human Services Food and Drug Administration,Center for Drug Evaluation and Research (CDER) July 2007.

9. Dealing with the impact of Ritonavir polymorphs on the late stages of bulk drug process development, Sanjay R. Chemburkar et al, Organic Process Research and Development, 2000, 4, 413-417.

10. Osol A. Remington’s Pharmaceutical Sciences; Mack Publishing Co.,Easton, PA, 1980; p 1358.

11. The process for synthesis of Bazedoxifene acetate and intermediates thereof, Joshi Shreerang, Bhuta Sachin, Talukdar Sanjay, Sawant Sudhir and Venkataraman Deepak, PCT Patent application No. WO2010 118997A1.

Received on 01.07.2011 Accepted on 01.08.2011

Asian J. Res. Pharm. Sci. 1(3): July-Sept. 2011; Page 63-68