Experimental Formulation Development : Experimental Formulation Development The formulation scientist in the generic industry has a demanding role when developing generic oral solid dosage forms which not only need to match innovator products within tight acceptance criteria but should also circumvent restrictive formulation patents which makes it extremely challenging to achieve the desired generic product.
As the innovator companies come under increasing pressure from generic competition, it becomes important that valuable aspects of intellectual property acquired during the development of a specific drug product be sufficiently detailed in order to file a formulation patent. Their primary goal is to prevent, as far as possible, generic drug products from entering the market until after the benefits of basic patent coverage and subsequent formulation patent protection have been suitably exploited
Innovator companies may also file additional patents related to the synthetic process employed to produce the active pharmaceutical ingredient (API) (1), the specific crystal form ( polymorph) (2), the formulation (3) and the combination of the drug with other active(s) which might provide synergistic benefits over the specific drug administered alone (4), specific ‘‘use’’ patents (5), and,of late, ‘‘paediatric exclusivity’’ (6). Experimental Formulation Development….. : Formulation scientists struggle in their quest to match the innovator
product from a bioequivalence point of view, resulting in failed biostudies.
Table 1 lists the effects of excipients on the pharmacokinetic parameters of oral drug products clearly indicating the effect that excipients may have on bioavailability and bioequivalence. Experimental Formulation Development….. Experimental Formulation Development….. : Experimental Formulation Development….. It is very important to characterize the active ingredient to be used with respect to polymorph, particle size and also from a morphological point of view.
Different crystal forms of the same chemical entity ( polymorphs), for example ibuprofen , can have varying solubilities, which could have significant implications with respect to bioequivalence if the incorrect form is used.
The morphology of APIs is of considerable importance especially in
direct-compression (dry-blending) formulations of drug products where the active content is less than 20% of the formula. Regulatory authorities the world over (especially the FDA) have become increasingly aware of variations in active content in ‘‘blend samples’’ drawn to confirm homogeneity of active distribution after blending. In a recent report , lack of adequate potency and or content uniformity was cited as the primary reason for the recall of solid dosage forms which, from a regulatory perspective, raises the issue of whether adequate process controls (including blend homogeneity testing) and release tests are in place. Formulation Development Strategies : Formulation Development Strategies Formulation Development Strategies….. : Formulation Development Strategies….. 1. Patent Search(es) : 1. Patent Search(es) In the early days of the generic industry, once the basic patent had expired, generic pharmaceutical companies were free to launch their version(s) of the drug product(s) into the market. However, over the last 20 or so years, the innovator drug companies have sought to extend their product(s) life, focusing initially on ‘‘Process Patents’’ (the route of synthesis whereby the API is produced, including any unique crystal forms which may have resulted). 1. Patent Search(es)…. : 1. Patent Search(es)…. 1.1 Formulation Patents
In certain instances, innovator drug companies have valid reasons for filing formulation patents, particularly where a specific excipient (or blend of excipients) lends a particular uniqueness in terms of release or stability.
However, some drug companies file patents which claim every excipient known, and such patents are clearly open to challenge. It is more difficult to file formulation patents in the arena of immediate release dosage forms than in the case of modified /controlled release formulations, where creative solutions have been applied to modify the invitro and in vivo release characteristics of active(s) so as to provide a dosage regimen which offers significant therapeutic advantages and improved patient compliance. 1. Patent Search(es)…. : 1. Patent Search(es)…. 1.2 Combination Patents
Combination Patents are those which pertain to more than one active ingredient combined together in a single drug product, the resultant product ideally displaying a synergistic pharmacological response compared with each active ingredient administered on their own.
One of the earliest examples of such a combination was co-trimoxazole, where sulfamethoxazole was combined with trimethoprim. More recent examples have focusedon decongestants in combination with antihistamines, for example loratidineand pseudoephedrine, antibiotic combinations such as amoxycillin and clavulanic acid. 1. Patent Search(es)…. : 1. Patent Search(es)…. 1.3. Use Patents
In certain instances, a drug substance has been found to be of benefit in treating disorders other than those first known and recognized, as for
example with omeprazole with its relatively new indication for use in Gastro-Esophageal Reflux Disease (GERD) and the amino-ketone antide- pressant, bupropion with the additional claim for use in smoking cessation.
New clinical studies are undertaken to provide the additional ‘‘use’’ which permits the innovator company to claim that particular new indication on both label and package insert. Use Patents prevent generic companies from
making the additional claim(s), but do not prevent the generic product from being prescribed to treat conditions originally claimed in the basic patent.
Consequently ‘‘Use Patents’’ do not carry the same impact as process and
formulation patents, but nevertheless cannot be ignored. 2. Literature Search : 2. Literature Search A comprehensive literature search should be performed that focuses on the API material in question and the proposed formulation.
The formulation patent(s) filed and information on the innovator’s New Drug Application (NDA) can be obtained by requesting the Summary Basis of Approval(SBA) from the FDA and provides an excellent source of background information.
It is essential that such a literature search be embarked upon as early in the development process as possible. http://www.fda.gov/cder/foi/anda/index 3. Regulatory Strategy : 3. Regulatory Strategy Once all of the patents have been comprehensively analyzed, a regulatory strategy must be formulated to establish when the ‘‘earliest date of sale’’ of the generic drug product can legally be made.
In this respect, the Approved Drug Products (Orange Book) provides useful information relating to the expiration date of appropriate patents of drug products that are the subject of approved applications but excludes process patents.
Once patent hurdles have been fully investigated, and regulatory strategies put in place, it is up to the formulation scientist to ensure that a non-patent infringing raw material can be incorporated into a non-patent infringing formulation which will be at least as stable as the innovator drug product and also bioequivalent. 4.Sourcing of the Active Raw Material(s) : 4.Sourcing of the Active Raw Material(s) Data bases are consulted as to which manufacturers have the required material available and once the potential vendors are identified, each is requested to furnish the following information:
The detailed synthetic pathway whereby the API is produce including all solvents, catalysts, materials, etc. utilized at every step.
A statement indicating that the process pathway does not infringe any patent(s) that may be in force and must be verified by the generic company’s patent lawyers
A statement indicating the possible polymorphic nature of the active drug in question, where relevant.
The batch size(s) of API which have been manufactured to-date
Any validation data which may be available to provide some degree of assurance that the synthetic process has been evaluated/controlled
Fifty to one hundred gram samples from three discrete batches of material manufactured according to the synthetic pathway provided. In each case, the batch-size should be made available. 4.Sourcing of the Active Raw Material(s)…. : 4.Sourcing of the Active Raw Material(s)…. A complete list of synthetic impurities and potential degradation products which may be used to fingerprint the API, together with full chemical characterization of each as well as50/100 mg samples of each synthetic impurity degradation product alluded to. Appropriate methodologies such as mass spectroscopy, high performance liquid chromatography(HPLC), X-ray diffraction (where polymorphs may be present), nuclear magnetic resonance (NMR), electron spin resonance(ESR), amongst others are generally used for the characterization
A complete list of solvents used in the synthetic process (which should relate to those claimed in the detailed synthetic pathway)together with those which should be monitored in the API. Where appropriate, a statement must be made by the API manufacturer claiming that none of the organic volatile impurities(OVIs) listed in the USP are present.
Specifications pertinent to raw material particle size, which may become better defined as the drug-product manufacturer closes in on a final formulation.
A Technical Package, which embraces the information requested, plus stability data to confirm suitability of the raw material in question and validated analytical methods pertinent to assay, related substances degradation products and residual solvents.
A commitment by the API manufacturer to undertake the necessary validation of the synthetic process, and the batch-size envisaged for future commercial production. 4.Sourcing of the Active Raw Material(s)…. : 4.Sourcing of the Active Raw Material(s)…. The vast amount of data required (not to mention the sensitivity of the information requested) will necessitate the signing of Confidentiality Secrecy Agreements between the API manufacturer(s) and the generic pharmaceutical company. Once the information has been received and reviewed, the choice can be made as to which raw material supplier to select.
The reader is referred to the Drug Information Association and the subsequent publication of several relevant articles in the Drug Information Journal.
Although the strength of the Drug Master File (DMF) or Technical Package supplied by the vendor may be the most important criterion on which to base the selection, past experiences with the bulk drug manufacturer( promptness of supply, quality, working relationships, ability to respond to competitive pricing) should enter into the decision-making process as well. , it is important to maintain a close liaison with the API manufacturerto ensure that any change in API manufacture is promptly communicated.
4.1 Alternate Vendor Sourcing
It is useful to secure approval of an alternate API manufacturer. How ever, different API manufacturers may have applied different strategies to overcome process patents. In such cases, there is a high probability that the impurity and residual solvent profiles will vary significantly, necessitating full analytical methods re-validation. 5. Formulation Development : 5. Formulation Development Formulation development should only commence once the following issues
have been suitably addressed :
1. relevant patents have been accessed and investigated,
2. the appropriate literature search has been undertaken,
3. regulatory and formulation strategies have been established, and
4. the desired API(s) have been ordered and received.
A beneficial approach to formulation development is to critically evaluate and, where possible, to characterize the innovator product with respect to composition, type of granulation (wet granulation or direct compression) and any other qualitative and/or quantitative analyses which may be practical or feasible. Additional useful information relating to the innovator product may be gleaned by measuring in vitro drug release over a range of pHs and rotational speeds used in dissolution testing as well as inspection of brand labeling for stability information. Conventional microscopy and visual observation may well provide useful information regarding the granulation method used although caution should be exercised since the results may prove inconclusive and possibly erroneous. 5.Formulation Development…. : 5.Formulation Development…. A simple and very useful approach is to determine the pH of the innovator drug product dispersed in a small volume of pH adjusted Purified Water, and then to compare the result with that yielded by a similar dispersion of the trial formulation. This approach is based on the premise that if the two dispersions provide comparable pHs, the excipient compositions of both innovator and generic formulations are probably similar. Once again circumspection is necessary since this simple test may sometimes not be sufficiently discriminatory.
Initial trials should be undertaken employing the identical excipients referenced in texts such as the Physicians’ Desk Reference ,Compendium of Pharmaceuticals and Specialties
Selection of appropriate quantities of key excipients such as binders, disintegrants, dissolution enhancers compressibility aids ,glidants, lubricants, anti-adherents, and surface-active agents is an important consideration for the formulation scientist. In this regard, a valuable reference that should be consulted is The Handbook of Pharmaceutical Excipients 5.Formulation Development…. : 5.Formulation Development…. It would be reasonable to presume that provided the same excipients, as outlined in referenced texts, are used, possible instability/incompatibility issues may be circumvented.
The need to optimize tablet punch design and even consider the nature of the stainless steel used is often overlooked at the formulation stage. The fifth edition of the Tablet Speciﬁcation Manual..
Relatively small changes in the amount of such key excipients can dramatically alter the appearance and physical attributes of tablets, whereas the impact of such changes on drug product stability and dissolution profiles can be significant. 5.Formulation Development…. : 5.Formulation Development…. Finally, all formulation trials should be compressed on a high-speed,rotary tablet-press that is preferably instrumented to provide the scientist valuable information relating to pre-compression, main compression, ejection, and take-o¡ff forces. During the initial formulation process, it is extremely important to validate/characterize each key process, such as:
1. screen-sizes and milling rates ( pre-granulation),
2. dry blend mixing times ( pre-granulation),
3. the quantity and rate of addition of the granulating vehicle,
4. the specific granulating time(s),
5. the temperature and air flows employed during the drying process,
6. loss on drying of the granules,
7. screen-sizes and milling rates ( post-granulation), as well as granulometry assessment ( pre-blending),
8. times and speeds used during all blending operations where the
active granule is blended with the inter-granular=extra-granular phase(s), and
9. all coating parameters and conditions.
When the formulation scientist is satisfied with the compressibility characteristics of the formulation, aesthetic appearance and disintegration profile of the tablets/capsules produced, samples should be submitted to the laboratory for dissolution profile testing.
The use of dissolution profile testing at the formulation development stage is extremely important, and consequently it is essential that time and effort be devoted to developing discriminatory dissolution methods, which are sufficiently sensitive to highlight differences between innovator and test products 6. Equipment Selection for Formulation Development : 6. Equipment Selection for Formulation Development During the early era of generic drug-product manufacture, formulation development was often commenced using different equipment to that used for pilot production, exhibit batch and=or in the commercial scale manufacturing facility.
Of all the processes that need to be controlled, the most critical is wet granulation since it is particularly vulnerable with respect to consistency using different types of equipment. Careful monitoring of (a) mixer and chopper speeds, (b) rate of addition of the granulating vehicle, (c) the quantity of granulating vehicle, and (d) the processing time necessary to yield an evenly textured granulate in order to result in satisfactory granules after subsequent drying.
Drying of wet granulate can be undertaken effectively using either a fluid-bed dryer or a circulating air oven, the most noticeable difference between the two techniques manifesting itself in the granulometry of the dried granule, since the fluid-bed technique tends to provide a ‘‘finer’’(less dense) granule than an oven .
Wet-granulation formulations tend to suffer less from non-homogeneity of (active) distribution than do direct-compression formulations
The selection of blender and blending times can also impact the final granule with respect to active/excipient homogeneity and compressibility
In the case of direct-compression formulations, over-blending can result in de-mixing of active 6.Equipment Selection for Formulation Development…. : 6.Equipment Selection for Formulation Development…. scientist must optimize the blending conditions during formulation development, with the realization that these may well vary from product to product.
Many pharmaceutical companies employ a perforated pan (for example Accela-Cota) coating system to film coat tablets. Sugar-coating has almost entirely been eclipsed by ¢lm-coating. Once again, it would be in the company’s best interests to ensure that the formulation scientist is provided with a smaller version (12 or 24 in. pans)) of the same equipment used in the production facility. In addition, environmental, safety, and cost concerns have necessitated the change to aqueous based ¢lm-coating dispersions or water soluble polymers from organic solvent based coating solutions. However, the use of organic solvents may in certain cases be unavoidable. 7.Assessment of the Final Formulation and Exhibit-Batch Production : 7.Assessment of the Final Formulation and Exhibit-Batch Production The most promising formulation, selected on the basis of consistent/satisfactory in vitro drug release over a broad hardness range, is then scaled-up from an initial development batch-size of 5000 units to about20,000 units. Samples of the drug product (which may be in the form of uncoated=coated tablets or capsules) are then packaged in all possible configurations intended for future commercialization, and placed on‘‘informal stability’’ (investigative stability assessment) together with the appropriate packaging(s) of innovator product,
‘‘Informal stability’’ is carried out under ‘‘accelerated’’ conditions of elevated temperature=humidity (normally 40 C=75% RH) and light(where applicable) for a period of 2^3 months. It is also useful to place the Reference Listed Drug (RLD or Brand) on accelerated stability.
It is preferable to analyze the samples using validated analytical procedures since those would be the analytical methodologies
Should the generic product prove to be stable over a 2^3 month period of exposure to accelerated conditions, there would be a high degree of probability that the formulation scientist has succeeded in formulating a stable drug product.
It is also vitally important to ensure that all desirable characteristics 7.Assessment of the Final Formulation and Exhibit-Batch Production…. : 7.Assessment of the Final Formulation and Exhibit-Batch Production…. Once the generic drug product has demonstrated a minimum of twomonths satisfactory stability, attention must be focused on the following :
1.Development of specifications for both raw material (API) and the dosage form.
2.Ordering of the API and excipients for exhibit-batch manufacture.
3.Ordering of all relevant tooling, change parts, and capsule shells(if required).
4. Completion of a Development Report. 8. The Development Report : 8. The Development Report A Development Report is a summary of the complete development processand will be the subject of keen regulatory agency scrutiny during aPre-approval Inspection (PAI) (FDA) or any other similar audit.
This report must make detailed reference to the following :
An overview of the actions and uses
A brief description of the innovator product
A detailed summary of the innovator product’s physical characteristics (such as appearance, size, shape, and weight). The inclusion of a photograph, as visual confirmation, is desirable.
A comprehensive account of the APIs used during the formulation development process including sources of supply.
A section dealing with the development of a discriminatory dissolution method including profiles of the generic and RLD product(s) using this method and conditions.
A detailed account of all experimentation undertaken to arrive at the ‘‘final formulation’’.
A detailed account of all experimentation undertaken to prove:
An account of the formulation(s) to be progressed to exhibit- batch level, as well as a brief outline of the desired manufacturing pathway. 9. Master Manufacturing Document : 9. Master Manufacturing Document This document must be drawn up by a team comprising the formulation scientist and his/her counterpart in the exhibit-batch manufacturing section. Once agreement has been reached, a draft of the ‘‘Master’’ document is forwarded to Plant Operations for comment and acceptance.
A copy of the signed Master Manufacturing Document is then provided to the Process Validation Department for generation of the Process and Cleaning Qualification protocols.
The Process Qualification Protocols must monitor and control all key processes in the manufacturing pathway such as:
volume and rate of addition of granulating vehicle,
exact drying conditions,
milling rates, screen-sizes, etc.,
blender rotation speeds and mixing times,
blend uniformity after blending,
blend uniformity after discharge of the granule into ‘‘holding bins’’ (to evaluate if active segregation has resulted on discharge), and
granulometry assessments, bulk and tapped density determinations and loss on drying measurements before and after granule discharge from the blender. 9.Master Manufacturing Document… : 9.Master Manufacturing Document… Prior to compressing the batch of granules into tablets at the optimum hardness and speed, the following parameters need to be established :
‘‘low’’ and ‘‘high’’ hardness levels . (dissolution profiles)
the highest speed at which the particular press can be operated (content uniformity)
humidity and temperature:
Samples from each stage must be tested for assay, content uniformity, and dissolution profile, in addition to full physical characterization (hardness, disintegration, friability, average weight, individual weights, etc.).
A Qualification Report embracing all the results must be completed once the batch(es) have been manufactured and the analyses completed.
Once the specifications have been set, the API and excipients ordered ,received and tested, the necessary tooling received and verified, the Development Report written, the Master Manufacturing Document approved and signed-off, the Process and Cleaning Qualification protocols written and the third month’s satisfactory informal stability results (which indicate drug product stability) generated, the exhibit-batch manufacture can be progressed. 10. Exhibit-batch Production : 10. Exhibit-batch Production Manufacture of the exhibit batch is the responsibility of the formulation scientist/technician(s) associated with the development of the final formulation together with the scale-up or ‘‘technical transfer’’ team.
The formulation and process should be tested by manufacturing a sub-batch using similar equipment as the scale-up equipment and using the same raw materials intended for exhibit-batch manufacture.
This preliminary sub-batch must be progressed to completion and samples submitted to the laboratory to confirm both physical and chemical attributes of the dosage form. Only once the testing has revealed an acceptable comparison to the development batches produced to the same formula and process, should the actual exhibit-batch manufacture be undertaken
Clearly all exhibit-batch manufacture is required to be carried out under cGMP conditions (85). Samples from the exhibit batch must be submitted to the laboratory, and only when the pre-determined acceptance criteria have been met imposed at both ‘‘Batch Release’’ and ‘‘Process Qualification’’ levels), can the generic product be randomized and subsequently packaged.
Randomization is required so that any bias in the manufacturing process is removed. 10. Exhibit-batch Production…. : 10. Exhibit-batch Production…. Prior to packaging of the batch(es), the necessary Packaging Documentation needs to be prepared.
The packaging operation must be carried out under cGMP conditions, using large-plant equipment.
Once the product has been packaged, samples of each pack size are incorporated into formal stability programmes (usually 40 C=75% RH; 30 C=65% RH and 25 C=60% RH) (86,87) according to a Stability Protocol, which outlines the pack sizes and types to be evaluated, the manufacturer(s) of the packaging components and actual composition thereof, the pre-determined times at which samples must be drawn, the necessary testing that needs to be undertaken and the pre-determined
acceptance criteria that are required to be met.
Drug product(s) containing APIs sensitive to light should be tested inappropriate photo stability chambers according to an approved protocol. Samples of innovator product(s) should be included as controls for each accelerated condition specified.
similar considerations apply to the development of a capsule dosage form.