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Lesson 1: SCALE UP MANUFACTURING

INTRODUCTION
 Establishing a commercial batch size is a crucial decision in pharmaceutical
operations. Research and development (R&D) is responsible in developing and formulating
drug products in a pharmaceutical company.
 The newly formulated drug is produced in a pilot batch to determine if it is efficiently,
economically, and consistently reproducible on a production scale. A pilot plant is a part of
pharmaceutical industry where a lab scale formula is transformed into a viable product
before large amounts of money are committed to a full-scale production.

 If the pilot batch is successful, then it may scale-up multiple times throughout its life cycle to
meet growing demand. Scale up is the term used to refer to the increase in the batch size of
a product.
 Batch Manufacturing Record (BMR) is a written document from batch that is prepared during
the pharmaceutical manufacturing process. It contains actual data of the batch
manufacturing and step by step manufacturing process. There are several stages of the
pharmaceutical product manufacturing process. All stages are included in the BMR, from the
issuance of the raw material to the final packaging.
 Every batch has a separate BMR having the batch history of batch production. Documents
and the proofs are attached to the BMR during the manufacturing process. A good BMR
should contain the following parts:

A. Bill of Materials (BOM)

 List of raw and packaging materials needed in the production of the batch.
 It contains the name of the materials, lot/reference # of each material, and quantity.
 BOM is issued by the warehouse.

B. Batch Record
 The first page of BMR has all records about the batch as batch number, batch size,
composition, master formula record referred the weight of the batch, shelf-life, storage
conditions, manufacturing license number, manufacturing date, expiry date, date of
starting and date of completion.

C. Manufacturing Process (MP)

 It contains the step by step procedure during compounding, compression, encapsulation,
coating and packaging.
 The process time and specification should be written on the manufacturing process.
 Line clearance should also be performed before starting every process.
 After completion of every stage, tablets must be checked for the compliance of the
specification of that stage.
 Results should be attached with batch manufacturing record.
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D. Yield
 Yield of the batch should be calculated at the end of every stage to calculate the process
loss. Final yield should be calculated at the end of the manufacturing that should not be
less than 99.00%

E. Abbreviation
 List of the abbreviations used in the document should be made to understand the BMR
easily.

F. Equipment Cleaning Record

 Checklist of the cleaning of all equipment is prepared; those are used in the
manufacturing of the batch including the previous product, batch and date of cleaning.
Cleaning of the equipment should be checked by the quality assurance.

Lesson 2: STANDARD OPERATING PROCEDURES

Standard Operating Procedure (SOP) is a written procedure for any process or system that is being
followed during the operation of any system or equipment. SOPs should be written by individuals
who are knowledgeable with the activity and the organization's internal structure. These individuals
are essentially subject matter experts who actually perform the work or use the process.
SOPs should be reviewed (that is, validated) by one or more individuals with appropriate
training and experience with the process. It is especially helpful if draft SOPs are actually tested by
individuals other than the original writer before the SOPs are finalized.
SOPs should be also systematically reviewed on a periodic basis to ensure that the policies
and procedures remain current and appropriate, or to determine whether the SOPs are even needed.

IMPORTANCE OF SOP:

 To provide people with all the safety, health, environmental and operational information
necessary to perform a job properly.
 To ensure that production operations are performed consistently to maintain quality control
of processes and products.
 To ensure that processes continue uninterrupted and are completed on a prescribed
schedule.
 To ensure that no failures occur in manufacturing and other processes that would harm
anyone in the surrounding community.
 To ensure that approved procedures are followed in compliance with company and
government regulations.
 To serve as a training document for teaching users about the process for which the SOP
was written.
 To serve as a checklist for co-workers who observe job performance to reinforce
proper performance.
 To serve as a checklist for auditors.
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 To serve as an historical record of the how, why and when of steps in an existing process
so there is a factual basis for revising those steps when a process or equipment are
changed.
 To serve as an explanation of steps in a process so they can be reviewed in accident
investigations.

DESIGNING OF SOP:

A. HEADER
 Present on all the pages of SOP
It includes the following:

1. Name and logo of the company

2. Document type
3. Title - It should be clear and descriptive.
4. Pages – The number of pages and attachments must be indicated.
5. Document No. – It refers to the recent SOP number.
6. Department – The department where the SOP is created.
7. Supersedes - It refers to the SOP# of the earlier version.
8. Issue date - It is the date from which the SOP shall be distributed to the concerned department,
usually 2-3 weeks from the effectivity date.
9. Review date - It is the date during which the SOP shall be revised.
10. Effectivity date - It is the date from which the SOP shall be put in use.

B. SIGNATURE BLOCK
 It shall be below the header and only on the first page of the SOP.
 Name and designation shall be typed.
It includes the following:

 Prepared by: - Signature with date, name and designation of the person from user
department who has drafted the SOP.
 Verified by: - Signature with date, name and designation of the person from user
department who has verified the draft of the SOP.
 Approved by: - Signature with date, name and designation of the person who approved
the SOP.

C. BODY
 It shall contain the subject matter, which is written in the following manner:

1. Objective - It shall define the purpose of the SOP.

2. Scope - It shall define the area of application.
3. Responsibility - It refers to the persons that performs and monitors the SOP.
4. Procedure - It refers to the step by step process on how the SOP should be performed.
5. Reference - It refers to the SOP# of the earlier version.
6. Attachment - List of forms that may be used in performing the SOP.
7. Revision History - List of previous version of SOP indicating the reason/s for revision.
8. Distribution List - List of concerned departments.
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9. End of Document
Lesson 3: CORRECTIVE ACTION PREVENTIVE ACTION (CAPA)

 Corrective Action Preventive Action (CAPA) is a process which investigates and solves problems,
identifies causes, takes corrective action and prevents recurrence of the root causes. The ultimate
purpose of CAPA is to assure the problem can never be experienced again.

 A corrective action is a reaction to a problem that has already occurred. It assumes that a
nonconformance or problem exists and has been reported by either internal or external sources.
The actions initiated are intended to: a) fix the problem and b) modify the quality system so that
the process that caused it is monitored to prevent a re-occurrence. The documentation for a
corrective action provides evidence that the problem was recognized, corrected, and proper
controls installed to make sure that it does not happen again.

 A preventive action is initiated to stop a potential problem from occurring. It assumes that
adequate monitoring and controls are in place in the quality system to assure that potential
problems are identified and eliminated before it happen. If something in the quality system
indicates that a possible problem is or may develop, a preventive action must be implemented to
avert and then eliminate the potential situation. The documentation for a preventive action
provides evidence that an effective quality system has been implemented that is able to
anticipate, identify and eliminate potential problems.

STEPS OF CAPA FOR PHARMACEUTICAL INDUSTRY

Implementing an effective corrective or preventive action capable of satisfying quality assurance and
regulatory documentation requirements is accomplished in seven basic steps:

1. Identification
 The initial step in the process is to clearly define the problem. It is important to accurately and
completely describe the situation as it exists now.
 This should include:
o The source of the information
o Detailed explanation of the problem
o Documentation of the available evidence that a problem exists.

2. Evaluation
 The situation must be evaluated to determine both the need for action and then, the level of
action required. The potential impact of the problem and the actual risks to the company
and/or customers must be determined.
 An evaluation should include:
o Potential Impact of the problem
o Assessment of Risk
o Remedial Action that may be required
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3. Investigation
 A written procedure for doing an investigation into the problem is created. A written plan helps
assure that the investigation is complete and nothing is missed.
 This procedure should include:
o The objectives for the action
o An investigation strategy
o Assignment of responsibility and required resources

4. Analysis
 The investigation procedure is used to conduct the investigation into the cause of the problem.
The goal of this analysis is primarily to determine the root cause of the problem described, but
any contributing causes are also identified.
o Every possible cause is identified and appropriate data collected.
o The results of the data collection are documented and organized.
o Everything related to the problem must be identified, but the primary goal must be to
find the root cause

5. Action Plan:
 Using the results from the analysis, the best method(s) for correcting the situation (or preventing
a future occurrence) is determined and act ion plan developed. All of the tasks required to correct
the problem and prevent a recurrence are identified and incorporated into an action plan.
 The plan includes changes that must be made and assigns responsibility for the tasks. The action
plan should also identify the person or persons responsible for completing each task.
o Actions to be complete
o Document or Specification Changes
o Process, Procedure, or System changes
o Employee Training

6. Implementation
 The corrective / preventive action plan that has been created is now implemented. All of the
required tasks listed and described in the action plan are initiated, completed, and documented.
o Implementation Summary
o Documentation

7. Follow Up
 One of the most fundamental steps in the CAPA process is completing an evaluation of the
actions that were taken. This evaluation must not only verify the successful completion of the
identified tasks, but also assess the appropriateness and effectiveness of the actions taken.
o Verification results
o Validation results

Lesson 4: LABELLING REQUIREMENTS ON PHARMACEUTICAL PRODUCTS

 Article III, Section 7 of the 1987 Philippine Constitution declares that the State recognizes the
right of the people to gain information on matters of public concern, such as those relating to
health and health products. Labels and labeling materials are the primary sources of information
for consumers. They provide useful information such as those dealing with the safe and effective
use of a drug product, and information dealing with quality.
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 The Food and Drug Administration (FDA), as the regulatory authority of the Philippines
responsible for all matters pertaining to drug products, has issued several guidelines to ensure
that drug establishments provide the most accurate information relating to their products.
Administrative Order 2016-0008 (Revised Rules and Regulations Governing the Generic
Labeling Requirements of Drug Products for Human Use) is issued to rationalize the existing
rules and regulations on generic labeling requirements of drug products, consistent with the
harmonized requirements of the ASEAN Member States; thus providing an updated and
comprehensive guideline.
 This Administrative Order shall apply to all manufacturers and distributors (i.e. exporters,
importers and wholesalers) of drug products for human use, including herbal medicines and
traditionally-used herbal products.

DEFINITION OF TERMS

1. Active Moiety- the molecule or ion, excluding those appended portions of the molecule
that cause the drug to be an ester, salt (including a salt with hydrogen or coordination
bonds), or other noncovalent derivative (such as complex, chelate, or clathrate) of the
molecule, responsible for the physiological or pharmacological action of the drug
substance

2. Active Pharmaceutical Ingredient (API)- a substance or compound that is intended to

be used in the manufacture of a pharmaceutical product as a therapeutically active
compound (ingredient).

3. Adverse Drug Reaction (ADR) - a response to a medicine that is noxious and unintended,
and whichoccurs at doses normally used in man.

4. Batch- a defined quantity of starting material, packaging material or product manufactured

in a single or series of processes so that it can be expected to be homogeneous

5. Batch Number- a distinctive combination of numbers and/or letters which specifically

identifies a batch on the labels, the batch records, and the certificates of analysis, etc.

6. Biological Product - any product of biological origin, prepared with biological processes,
derived from human blood and plasma, or manufactured by biotechnology, consisting of
substances of higher molecular weight whose purity, potency, and composition cannot
readily and reliably be determined by chemical or physicochemical analysis

7. Brand Name - the proprietary name assigned to the product by the Marketing
Authorization Holder (MAH)

8. Contraindication- a statement regarding the conditions wherein the use of the drug
product may cause harm to the patient.

9. Date of Manufacture- refers to the date (month and year) during which processing of the
bulk product, from which the goods are to be filled, is completed.
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10. Dosage - the quantity of a medicine given per administration.

11. Dosage Form- the drug product type (e.g.tablet, capsule, solution, cream) that contains a
drug substance generally, but not necessarily, in association with excipient(s).

12. Drug Product or Drug - (a) any article recognized in the official United States
PharmacopoeiaNational Formulary (USP-NF), official Homeopathic Pharmacopoeia of
the United States (FIPUS), Philippine Pharmacopoeia (PP), Philippine National Drug
Formulary pNDF), British Pharmacopoeia (BP), European Pharmacopoeia (EP),
Japanese Pharmacopoeia (JP), International Pharmacopoeia (Ph. Int), any national
compendium or any supplement to any of them; (b) any article intended for use in the
diagnosis, cure,mitigation, treatment or prevention of disease in humans or animals;
(c) any article other than food intended to affect the structure or any function of the
human body or animals; (d) any article intended for use as a component of any article
specified in clauses (a), (b) and (c) not including devices or their components, parts or
accessories; (e) herbal and/or traditional drugs which are articles of plant or animal
origin used in folk medicine which are: (i)recognized in the Philippine National Drug
Formulary (ii) intended for use in the treatment, cure or mitigation of disease
symptoms, injury or body defects in humans (iii). Other than food, intended to affect
the structure or any function of the human body (iv). In finished or ready-to-use dosage
form; and (v). Intended for use as a component of any of the articles specified in
clauses i, ii, iii and iv.

13. Dosage Strength- may refer to: (a) the concentration of the known API or active
moiety in a given formulation stated in metric units (b) the potency of the known API
or active moiety expressed in terms of, for example, units by reference to a standard
(potency is the specific ability or capacity of the product asindicated by the appropriate
laboratory tests or by adequately controlled clinical data obtained through
theadministration of the product in the manner intended to effect a given result(s). This
shall be stated in accordance with the potency requirements of the monograph of the
product, as officially listed in USP, BP and EP, or any other official compendia
recognized by FDA.

14. Excipient - an ingredient, added intentionally to the drug substance which should not
have pharmacological properties in the quantity used.

15. Expiration Date- the date (i.e. month and year) placed on the label of a drug product
designating the time prior to which a batch of the product is expected to remain within
the approved shelf life specification if stored under defined conditions. After the
expiration date, there is no guarantee that the product will remain within the approved
specifications and, therefore, it may be unsuitable for use and should not be used.

16. Formulation-the name, strength, and reference monograph of all APIs and/or
excipients present in the drug product.
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17. Generic Class Name - the identification of a drug product containing three or more
APIs by its scientifically and internationally recognized name or by its official generic
name as determined by FDA.

18. Generic Name-the identification of a drug product by its scientifically and

internationally recognized API or by its official generic name as determined by FDA.

19. Indication-the FDA approved clinical use of a drug product based on substantial,
scientifically supported evidence of its safety and efficacy in the given dosage form.

20. Investigational Product- a pharmaceutical form of an active ingredient or placebo

being tested or used as a reference in a clinical trial, including a product with a
marketing authorization when used or assembled (formulated or packaged) in a way
different from the approved form, or when used for an unapproved indication, or when
used to gain further information about an approved use.

21. Label-the written, printed or graphic matter on any drug product, its immediate
container, tag, literature or other suitable material affixed thereto for the purpose of
giving information as to the identity, components, ingredients, attributes, directions for
use, specifications and such other information as may be required by law or regulation.

22. Labelling Material -label on the immediate container, and the other printed materials
that are made available with the drug product at the time of purchase and/or when the
product is used, such as the outer wrapper cartons, package insert/leaflet
accompanying the product, which provide the accurate and necessary detailed
information for the identification and proper use of the product.

23. Lot Number -any distinctive combination of letters and/or numbers assigned to a
particular lot, herein defined as a portion of a batch.

24. Manufacturer - an establishment engaged in any and all operations involved in the
production of health products as well as the final release of the finished product, with
the end view of its storage, sale or distribution; provided, that the term shall not apply
to the compounding and filling of prescriptions in drugstores and hospital pharmacies.

25. Marketing Authorization (MA) -an official document issued by the competent drug
regulatory authority (DRA) for the purpose of marketing or free distribution of a product
after evaluation for safety, efficacy, and quality, and containing, inter alia: the name of
the product; the pharmaceutical dosage form; the quantitative formula (including
excipients) per unit Marketing dose; the shelf-life and storage condition(s); and
packaging characteristics, specific information on which authorization is based (e.g.
"The product(s) must conform with all the details provided in
(MA) the application and as modified in subsequent correspondence."), the product
information approved for health professionals and the public, the sales category, the
name and address of the holder of the authorization, and the period of validity of the
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authorization. In the Philippines, the MA is in the form of a Certificate of Product

Registration (CPR).

26. Marketing Authorization Holder - the company or corporate or legal entity in the field
of pharmaceuticals in whose name the MA for a drug product has been granted. This
party is responsible for all aspects of the product, ran including quality and compliance
with the conditions of the MA. The authorized holder must be subjected to legislation
in the country that Holder (MAH) issued the MA, which normally means being
physically located in that country. In the Philippines, the MAH may either be a
manufacturer or distributor (exporter, importer or wholesaler).

27. Mode of Administration -the manner and site where the drug product is to be
introduced into or applied on the body

28. Net Content - the total amount/quantity/number of the dosage form in a certain
container of a drug product expressed in metric system.

29. New Chemical Entity - new chemical or biological API not previously authorized for
marketing for any pharmaceutical use in the country in question.

30. Over-the-Counter (OTC) Drugs - drug products that can be dispensed even without
the written order of a licensed physician or dentist.

31. Pack Size - refers to the quantity of dosage form in the final packaging (excluding the
shipping carton) of a drug product bearing the required labeling information.

32. Package Insert- the document defining information that is supplied with prescription
drug products by the MAH. The PI is intended for use by healthcare professionals.

33. Patient Information leaflet - the document defining information that is supplied with
non-prescription drug products by the MAH. The PIL is intended for use by patients
and is written in layman's language.

34. Pharmacologic Category - refers to the classification of the drug product based on
its therapeutic action as specified in the product registration.

35. Precautions - the instruction and the special care required in the use of the drug
product to avoid undesired effects and to ensure its safe and effective use.

36. Prescription Drug Products - drug products that are to be dispensed only upon the
written order or prescription of a duly licensed ph,vsician or dentist for the management
or treatment of a condition or a diagnosed disease of man.

37. Primary Label - refers to the label on the primary packaging material of a drug product.
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38. Produg- a drug substance that is inactive in the intended pharmacological actions and
must be converted into the pharmacologically active agent by metabolic or physico-
chemical transformation.

39. Product Name - the name (i.e. generic name and brand name, if any) of the drug
product as registered in FDA.

40. Product Description - refers to the complete organoleptic description of the finished
drug product.

41. Registration Number - a combination of letters and/ar numbers assigned to a

particular drug product by FDA as proof of registration.

42. Small Containers - are drug packaging materials that hold less than or equal to 5 mL
volume or 5 g weight, which include: (a) ampoules, vials, and nebules of small volume
parenterals; (b) packaging materials for ophthalmic, otic, and nasal liquid Containers
preparatons; (c) jars and tubes for semi-solid preparations; and (d) any other
packaging material of the same capacity.

43. Storage Condition - the acceptable specified temperature range, humidity, and other
environmental factors within which optimal stability of the drug product is ensured
based on laboratory data.

44. Summary of Product Characteristics (SPC) -the product information as approved

by the DRA. It also serves as the source of information for health personnel as well as
for consumer information on labels and leaflets of drug products, and for control of
advertising. A Company Core Data Sheet (CCDS) approved by the DRA may also be
considered.

45. Warnings - statements regarding the occurrence of potential hazards and undesirable
effects associated with the use of the drug product and the limitation of its use

GENERAL GUIDELINES:
1. The following are the MINIMUM MANDATORY INFORMATION that shall appear in the labeling
materials accompanying a drug product:
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2. All information required to appear on the label shall be

3. Package insert (PI) shall be submitted for all NCEs, biological products, and prescription generic
products and herbal medicine. Patient information leaflet (PIL) shall be submitted for all household
remedies, over-the-counter drug and herbal medicines, and traditionally-used herbal products.
4. In lieu of PI or PIL, the foregoing information shall be printed directly on the reverse side or
inner panel of the outer packaging material or inner carton; provided, that the product is intended
to be sold or dispensed together with such packaging material or inner carton
5. For products intended to be sold without any product information sheet and unit carton, the
minimum mandatory information shall be required to be reflected on the primary label.

SPECIFIC GUIDELINES:
A. Requirements for each Mandatory Information
1. Product Name
 The product name shall indicate the generic name and the brand name (if any) of the drug
product.
 The generic name shall be as the active moiety based on the International Non-proprietary
Name (INN), and consistent with the dosage strength indicated; for prodrugs, the generic
name shall be the INN of the prodrug itself and not its active chemical (metabolite) form.
 The generic name shall appear prominently with an outline box, with the generic name's
prominence over the other information being clearly and distinctly readable by normal vision
as may be determined by common visual sense.
 For herbal medicines and traditionally-used herbal products, the generic name shall be the
botanical origin or as recognized by FDA.
 If a product is identified by a brand name together with its generic name, the generic name
enclosed in an outline box shall in all cases appear immediately above the brand name; for
narrative texts (whether in the unit carton, primary label or insert), the brand name shall in all
cases be preceded by the generic name and enclosed in parentheses or brackets.
 For products with multiple APIs, the product name shall indicate all of the APIs, enumerated
in the order of decreasing pharmacologic activity and placed inside the box in either of the
given format.

 If the APIs have more or less similar pharmacologic activity, they shall be enumerated in the
order of decreasing potency and strength; provided, that if there exists a single approved
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name for fixed-dose combination (ex: Cotrimoxazole for the standard formulation
Sulfamethoxazole / Trimethoprim), the single approved name shall be used; provided further,
that if there is no single approved name but there exist a generic class name (e.g.
Multivitamins for multi-vitamin containing preparations, as approved by FDA), the generic
class name shall be used. The individual components of the single approved name and
generic class name shall be enumerated under Formulation.

2. Dosage Form and Strength

 The label shall:
 specify the dosage form of the product such as tablet, capsule, suspension, ointment, etc.,
 specific delivery system, if any, such as modified release, and
 specific mode of administration, if any, such as vaginal, rectal suppository, etc., as approved
by FDA.
 If there is no qualifier for tablets, it is understood as an oral, uncoated, immediate release
tablet.
 The label shall specify the dosage strength of the product which shall be expressed in metric
units reduced to lowest terms and in the number of the largest unit specified (e.g. 500 mcg,
not 0.5 mg).
 FDA, as deemed necessary and appropriate, shall allow the strength of certain dosage forms
(e.g. semisolid, ophthalmic, otic, nasal, and topical preparations) to be expressed as
percentage.
 For products with multiple APIs, the dosage strength shall be stated in accordance with the
generic name indicated: for multiple APIs, the individual strengths shall be indicated,
separated by a slash sign (/); it a single approved name is used, the dosage strength shall be
indicated as the sum.

3. Pharmacologic Category
 The pharmacologic category shall be as determined by FDA, taking into consideration current
acceptable standards for therapeutic categories.

4. Formulation/Composition
 The label shall state the name and strength of all APIs present per unit dose of the product,
which shall be arranged in decreasing pharmacologic activity, or if having more or less similar
pharmacologic activity, in decreasing potency and strength.
 The generic name of the API shall be stated in fulI (including salts and esters, if any) and
correlated to the active moiety, when applicable. The name of the API shall be in accordance
with its INN; for herbal medicines and traditionally-used herbal products, the official Philippine
Pharmacopoeia name shall be used, or as determined by FDA.
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 The reference monograph recognized by FDA (e.g. USP, BP, EP, JP, PP, Ph. Int) used fior
the analysis of the finished drug product shall be indicated immediately after the API, unless
a non-official method is used; for multiple APIs, it shall be indicated after the first APL

 Alcohol, when present in the product shall also be indicated, expressed as a percentage (%).
The name "alcohol" without qualification shall mean ethyl alcohol.
 The coloring, antimicrobial, and antioxidant agents, and preservatives used in the
manufacture of the product that may cause hypersensitivity and/or other adverse drug
reactions shall also be indicated, with the amount expressed in the same manner as the API.

5. Indication(s)
 The indication(s) stated in the labeling materials shall include only the FDA-approved clinical
use(s) of the drug product.

6. Dosage and Mode of Administration

 The label shall contain full information on the product's recommended dosage, including the
(i) initial or loading dose, (ii) optimal use or usual dose, (iii) frequency interval, (iv) duration of
treatment, (v) dosage adjustment, and other pertinent aspects of drug therapy, if applicable.
 Relevant information regarding dilution (e.g. the specific volume of diluent to be added),
reconstitution, preparation, and administration shall also be included (such as "Shake well
before use" for suspensions, "Do not crush" for tablets with special delivery system, etc.) in
all labeling materials. The label shall include a description ofthe reconstituted preparation.
 Separate directions for use by special populations, adults, and children shall be stated. If the
product is not recommended for children, the dosage shall be clearly identified as "Adult
dose", or any statement to that effect.

7. Contraindication(s), Precaution(s), Warning(s)

 The label shall contain full information regarding the contraindication(s) of the drug product,
as well as the precaution(s) to be observed in its administration and use.
 The label shall include warning statements, as required and/or specified by FDA (e.g.
"Flammable," "For external use only," "Keep out of reach of children"). Other specific
additional instructions shall be issued by FDA in appropriate regulations.
 Where the contents of a container are to be used on one occasion only, the label shall include
the statement, "Single use only", "Single dose", "Use only once", "Discard any remaining
portion", or any statement to that effect.

8. Interactions
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 The label shall include drug-drug, drug-food, drug-laboratory testing interactions, as well as
other relevant interactions, if applicable.

9. Adverse Drug Reaction(s)

 The label shall include detailed information on adverse drug reaction(s) for a drug product
arranged by system organ class.

10. Overdose and Treatment

 The label shall include signs and symptoms of overdose, as well as possible treatment.

11. Storage Condition(s)

 The label shall indicate appropriate storage condition(s) and special instructions for handling
of the drug product.
 Special labeling instructions shall be added for drug products with the following properties:

12. Pack Size or Net Content

 The unit carton shall indicate the pack size of the drug product expressed in terms of the
number of units in the pack or the volume of each unit, e.g. 60 mL (for liquids), 10 blister packs
x 10 tablets (for tablets), 100 tablets, 12 sachets x 5 g, etc.; Provided, that in case of drug
products for reconstitution for oral administration, the pack size shall reflect the volume of the
product as reconstituted.
 For the primary label excluding blisters and foil strips, the net content of the product, stating
the total amount/quantity/number of the dosage form in a given container shall be expressed
in metric units, e.g. 60 mL (for liquids), 5 g (for sachets)

13. Name and Address of Marketing Authorization Holder

 The label shall state the name and full address of the MAH of the drug product.

14. Name and Address of Manufacturer

 The label shall state the name of the manufacturer and full address of the specific
manufacturing site of the drug product as determined by FDA.

15. Rx Symbol and Caution Statement

 The labeling materials of prescription drug products shall always include the Rx symbol, which
shall be prominently displayed. The Rx symbol may be allowed to be over-printed or
superimposed, provided, that such will not result in the obliteration by or being rendered less
legible than other required labeling information.
 | |

 The caution statement, "Foods, Drugs, Devices, and Cosmetics Act prohibits dispensing
without prescription." shall always be included in the package insert or unit carton, primary
label except blister pack! foil strip, and small containers of prescription drug products. In
addition, for products classified as Dangerous Drug as per Republic Act No. 9165, the caution
statement shall be followed by an additional statement as specified by the Philippine Drug
Enforcement Agency (PDEA).

16. ADR Reporting Statement

 For the product information sheet and the unit carton or primary label except blister pack, foil
strip, and small containers of products intended to be sold without a unit carton, the statement
'For suspected adverse drug reaction, report to the FDA: www.fda.gov.ph" shall appear. In
addition, a statement instructing the patient to seek medical attention immediately at the first
sign of any adverse drug reaction shall appear. The MAH may also include a reporting
statement for their own pharmacovigilance system.

17. Registration Number

 The label shall indicate the registration number assigned by FDA to the product, which is
denoted by a combination of letters and/or numbers.

18. Batch Number and Lot Number

 The label shall indicate the product's batch number; provided, that if the entire batch is
marketed by one drug establishment, only the batch number shall be indicated. However, if a
batch is divided into lots marketed by different drug establishments, the lot number and
corresponding batch number shall be indicated.

19. Expiration Date and Date of Manufacture

 The label shall bear the month and year of the product's manufacturing and expiration date
either in letters or words and numbers, or in numbers alone; if expressed in numbers alone,
the year shall be stated completely in order to distinguish it from the month; and if the day is
specified, the month shall be spelled out, as shown below:
 June 2007 or Jun2007
 06/2007
 03 June 2007 or 03 Jun 2007
 Unless a certain day of the month is specified, the last day of the stated month shall be
deemed as the date of the product's expiration/manufacturing date.
 For products reconstituted prior to use and those which can be administered multiple times
(e.g. suspensions), the label shall include the period of guaranteed safety, efficacy, and quality
of the reconstituted preparation/after first opening at a given storage condition(s).

B. Special Labeling Instruction

In addition to the minimum mandatory requirements mentioned, the following shall be required to
appear on the label of specific product types:

I. Parenterals
 A statement of the recommended mode of administration such as "IV", "IM'or "SC", etc., as
the case may be.
 | |

 Where the product consists of a concentrated solution for injection, a direction not to
administer the solution undiluted and a direction to dilute the solution with the specified diluent
to the appropriate volume before use shall be stated.

II. Fluid Replacement Products

 For fluid replacement products which follow the standard formulations contained in the current
edition of the official compendium, the nomenclature to be adopted as the generic class name
shall be determined by FDA.
 For fluid replacement products not included in any official compendium, FDA shall determine
the generic class name.
 Directly below the generic class name but still inside the generic outline box are the individual
components (including excipients) with the corresponding mEq or mmol enumerated in the
order of decreasing pharmacologic activity.
 Where one or more substances are amino acids and/or proteins, the total amount of nitrogen
in the volume of fluid in the container shall be reflected.
 The osmolality, such as "hypotonic" or "hypertonic"; and the pH value or range (where
applicable) of the solution shall be indicated.

III. Products for External Use

 For products that are intended for external use, the statement "For external use only'' shall
appear on all labeling materials, rendered in capital letters against a red background or printed
in red font.

IV. Biological Products

 The name of the species of animal or organism from which the product has been prepared.
 The name of any adjuvant in the product or any substance which, when administered with an
antigen, modifies the immune response to that antigen.

V. Multivitamin/ Mineral/ Herbal Products with Non-vitamin/ Mineral/ Herbal Components

 Multivitamins, consisting of at least three vitamins, and minerals, consisting of at least three
mineral ingredients, shall have the following additional requirements:
 The generic name adopted for multivitamin-containing products shall be "Multivitamins"; for
multi-mineral-containing products the official name shall be "Minerals".
 For multivitamin and/or multi-mineral preparations containing at least three herbal ingredients,
the generic class name of the herbal ingredients shall be "Herbs".
 For multivitamin products with non-vitamin components (i.e. mineral or herbal ingredient), or
multi-mineral products with non-mineral components (i.e. vitamin or herbal ingredient), or multi
herbal products with non-herbal components (i.e. vitamin or mineral ingredient) the term
"Multivitamins" or "Minerals" or "Herbs", respectively, shall first be stated, followed by the
generic name of the specific additional individual components, as shown below:
 | |

 The unit content of each vitamin, mineral, and/or herbal ingredient present shall no longer be
required to be indicated in the generic box, but rather shall be reflected under Formulation.

VI. Physician's Samples

 In addition to the minimum requirements, each individual dosage unit of the physician's
sample shall include batch and/or lot numbers, date of manufacture and expiration date.
 On each of the labeling material(s), the following statement, shall appear in red background
or red font:

VII. Drugs under Maximum Drug Retail Price (NDRP) Control

 On the label of the minimum pack and the outer presentation of drugs listed under Section I
of Executive Order No. 821 and other drugs as determined by the Secretary of Health, the
following statement shall be required to appear in red background or red font:

VIII. Reproductive Health Products

 The product information for reproductive health (RH) products that are drugs shall include
both PI and PIL. The PIL shall be written in English and Filipino, and/or local dialect.

C. Exemptions
 The requisites provided in this Administrative Order shall not apply to the following cases:
 Drug products manufactured for export;
 Veterinary drug products;
 If the container or primary pack containing the product is enclosed in a transparent covering
and the particulars which are required to be set on the label on the container or primary pack
are clearly visible through transparent covering, the transparent covering is exempted,
 Products that are compounded by a pharmacist in accordance with the individual prescription
of a medical practitioner or dentist for immediate use;
 Investigational products,
 Foreign donations of drug products;
 Products that require special handling or with special packaging (e.g. products that require cold-chain
management, pre-filled syringes); and
 Low volume of importation (<12,000 units per years, wherein units is defines as the number of
individual finished dosage form [such as tablets, capsules] or finished packed products [such as vials,
sachets, and bottles of liquid preparations], where appropriate).

D. Sanctions
 Any violation of this Administrative Order consistent with Republic Act No. 3720 and Republic Act No.
9711 and its implementing rules and regulations shall be a ground for filing of appropriate
 | |
administrative charges and/or imposition of administrative sanctions such as, but not limited to,
imposition of fines, suspension, cancellation or revocation of any license, permit or registration issued
by FDA.
 | |

Module 2: Liquid Pharmaceuticals

Introduction
The oral use of liquid pharmaceuticals has generally been justified on the basis of ease of
administration to those individuals who have difficulty swallowing solid dosage forms. A drug
administered in solution is immediately available for absorption and is more rapidly and efficiently
absorbed than the same amount of drug administered in a tablet or capsule (in most cases).
According to its physical characteristics, liquid dosage forms may be dispersed
systems or solutions.
Steps of Liquid Manufacturing Process

I. Planning of Material Requirements

 Research and development protocols
 Acquisition and analysis of raw materials
 Physical plant design, building and installation
 Equipment selection and acquisition
 Personnel selection and initial training
 Monitoring information systems
Protocols
 Patterns developed by repeating procedures and fixing the identified problems each time the
procedure is followed
 They are dynamic entities that originally can be developed in the laboratory level but must
be adjusted in every new step of the scale-up process

II. Liquid preparation

 Research and development protocols concerning liquid compounding
 Scale-up of bulk product compounding
 Physical plant control and maintenance
 Equipment maintenance and renovation
 Continuous training of personnel and personnel compensation plans
 Supervision of system reports

III. Filling and packing

 Research and development protocols concerning filling and packing
 Scale-up of the finished drug filling and packing
 Physical plant control and maintenance
 | |

IV. Sales of drug product

 Research and development protocols concerning product storage
 Distribution process
 Continuous training of personnel and personnel compensation plans
 Supervision of system reports

V. Vendor handling
 Research and development protocols concerning precautions to maintain product stability
 Control of vendor stocks
 Sales system reports

VI. Customer service

 Research and development protocols concerning home storage and handling to maintain
product stability
 Relationship with health insurance companies and health professionals
 Educational materials for patient counseling
 Customer service system reports

Lesson 1: Solutions

 The formulation of solutions presents many technical problems to the industrial pharmacist.
Some drugs are inherently unstable. Special techniques are required for poorly soluble
drugs. The final preparation must satisfy the requirements of pharmaceutical
elegance (the harmony of taste, color, odor and viscosity).

o Poor Pharmaceutical Elegance in Liquids imply patient non-compliance and

decreased product acceptance
o Quality Pharmaceutical Elegance increases patient compliance and product
acceptance

SPECIAL TECHNIQUES to aid solubility of poorly-soluble drugs.

CO-SOLVENCY
 Solubility is increased by using a water-miscible solvent, in which the drug has good
solubility.
 Co-solvents used may be ethanol, propylene glycol, sorbitol and glycerine.

pH CONTROL
 A large number of modern pharmaceutical agents are either weak acid or weak bases
 Its solubility can be markedly influenced by modifying/adjusting its pH
 A number of buffer systems can be used to achieve this technique
 Functions of buffer
o Contributing toward overall isotonicity
o Preferential hydration of proteins and peptides
o Serving as bulking agents in lyophilized formulation
 | |

SOLUBILIZATION
 It involves the addition/use of solubilizing agents (usually in solid form, the salt form of the
active/s), to increase the water-solubility of the drug in water
 It is also achieved through the addition of surface active agents (ex. Polyoxyethylen (20)
sorbitan monolaurate) to form colloidal aggregates known as micelles
 The solutes are adsorbed onto or dissolves into the micelles

COMPLEXATION
 Organic compounds in solution generally tend to associate with each other (to some extent)
 An amount of specific complexing agent is added to form a soluble complex compound
 Complexing agents
o EDTA and citric acid
o Calcium++ EDTA - a chelating agent that may exhibit microbial growth, as calcium is
required for bacterial growth

HYDROTROPY
 Increase in the solubility of a substance, through the addition of additives, consisting of fairly
high concentrations of alkali metal salts of various organic acid
 Uses non-micelle forming substances, capable of dissolving insoluble compounds
 Use of hydrotropes like sodium benzoate, sodium citrate, urea, niacinamide, etc. and have
many advantages like, it does not require chemical modification of hydrophobic drugs, use
of organic solvents, or preparation of emulsion system, etc.

CHEMICAL MODIFICATION OF THE DRUG

 Conversion of poorly water-soluble drugs to its water-soluble derivatives
 The most commonly employed technique for the pure form of drugs converted to their
corresponding water-soluble salt or ester forms
 This approach is successful in some drugs, but in some biological activities, toxicity should
be considered

Requirement of PHARMACEUTICAL ELEGANCE (the harmony of taste, color,

odor and viscosity)
 Modern pharmaceutical preparations present the API’s (which are unpalatable and
unattractive to the patient), as colorful and flavorful formulations attractive and appealing to
the senses of sight, smell and taste. Pharmaceutical elegance implies product acceptance
to the patient.

Choice of Coloring Agent

Certified Colors Dyes (Aluminum) Lake Pigments

 Synthetically produced  Dissolve in water, but are not  Are made by combining dyes
 They impart an intense soluble in oil. with salts to make insoluble
uniform color  Manufacture as powders, compounds.
 Less uniform granules and liquids.  Tint by dispersion
 | |

 Blend more easily to create  Have side effects which lakes  Not oil soluble but are oil
variety of hues do not (large amounts of dispersible
 Generally, do not add dyes ingested can color  More stable than dyes
undesirable flavors to foods. stools.  Uses include coated tablets,
lipsticks, soaps, shampoos,
talcs, etc.

Choice of Flavoring Agents

 The choice of flavoring should be based on the natural “taste sensation” of the drug
 Natural taste sensation of drug and the recommended flavoring agent
Sweet Metallic Sour Salty Bitter
 Vanilla  Grape  Citrus fruits  Apricot  Chocolate
 Honey  Lemon (lemon, lime,  Butterscotch  Coffee
 Fruits  Lime orange)  Vanilla  Anise
(grape,  Raspberry  Peppermint  Grapefruit
strawberry,  Root beer  Licorice  Cherry
mango)  Peach  Walnut
 Mixed  Maple sugar  Mint
berries  Mixed citrus  Passion fruit
 Wintergreen

Choice of Preservatives
PRESERVATIVES
 Substances which prevent bacterial and fungal growth in liquid formulations
 Bacteria and fungi affect product stability and poses as a health hazard to the patient
 Characteristics of an ideal preservative
o Effective against a broad-spectrum range of microbes
o Physically, chemically and microbiologically stable until the expiry date of the product is
reached
o Non-toxic
o Non-sensitizing
o Adequately soluble
o Compatible/acceptable to the taste and odor/color of the product
 The USP presents standard protocols for assessing the relative efficacy of a preservative in
a formulation using the ANTIMICROBIAL EFFECTIVENESS TEST (AET).
 Briefly, by comparing the relative kill efficiency of the formulation containing
varying concentrations of the preservative, the formulator can determine the
minimal concentration required for preservative efficacy and design the
formulation accordingly.
 | |

Acidic Neutral/Alcohol Mercurials Quaternary Esters of p-

ammonium hydroxybenzoic
compounds acid
 Benzoic  Chlorobutanol  Thimerosal  Benzalkonium  Methyl
acid and its  Ethyl alcohol  Nitromersol chloride (for paraben
salts  Benzyl alcohol  Phenyl SVPs)  Propyl
 Boric acid  Phenyl alcohol mercuric  Cetylpyridium paraben
 Sorbic acid acetate/nitra chloride
 Potassium te
sorbate
 Phenols

Choice of Sweetening Agents

Sweetening agents
o Sucrose (refined white sugar)
o Liquid glucose
o Synthetic/artificial sweeteners
 Examples:
 Saccharin sodium
 Acesulfame potassium
 Stevia powder
 Xylitol
 Malitol
 Sucralose
 Monoammonium glyzirrhizinate
 Aspartame
 Sucralose

Choice of Viscosity-building Agents

 Sometimes desired to serve as:
 Adjunct to palatability
 To improve drainage (pourability)
 Examples of viscosity-controlling agents
(Use with CAUTION. Highly viscous systems resist dissolution by the GIT fluid that may
impede drug release and absorption)
o PVP
o Methyl cellulose
o Carboxymethyl cellulose (CMC)

 The basic principles involved in the preparation of homogenous liquids are the same,
regardless of the quantities of materials involved. The solubility of the solute/s and the
intra/intermolecular interaction in the final solution (at equilibrium) are independent of the
manner in which the liquid dosage form is made. For example, the order of addition and
techniques of adding solutes to a liquid tank can be very important. Flavors are generally
 | |

added after first mixing them in a smaller volume of the solvent or liquid base and rinsing them
with a portion of liquid as well. This also holds for all other additions, particularly those of
smaller quantities of ingredients. Proper mixing is validated; however, unlike solid mixing,
where overmixing may result in segregation, the problems in liquid mixing pertain to air
entrapment. Appropriate temperature of the liquid phase is often important to ensure that there
is no precipitation of the solute added.

EQUIPMENT
 Fully sanitizable stainless steel 314 or better quality is recommended. Equipment must be
cleaned or sterilized; appropriate disinfectants include dilute solutions of hydrogen peroxide,
phenol derivatives, and peracetic acid. Equipment lines can be sterilized by using alcohol,
boiling water, autoclaving, steam, or dry heat. Where lids are used, be cautious of the
condensate, which may be a source of microbial contamination. Operators must conform to
all sanitary presentation requirements, including head covering, gloves, and face masks.
Use of portable laminar flow hoods to expose ingredients before addition is often desirable.
 Mixing tanks with agitators
o Must be constructed of stainless steel
o Jacketed mechanism to allow for the heating and cooling of the contents
o Completely covered, equipped with “see-through” charging ports and illumination for
easy observation of the contents
 Miscible liquids are most commonly mixed by impellers rotating in tanks. These impellers
are classified as:
o Paddles
o Propellers
o Turbines

After compounding the liquid is clarified by filtration into another adjacent tank called, “storage
tanks,” until release by the QC
After QC release, the liquid is automatically transported into portable transport tanks or by pumping
through a suitable liquid delivery container
The distance that the product travels between the holding tank and the filling line should be held to
a minimum to reduce the chance of microbial contamination
 | |

 Measuring and weighing devices

o Used for small and large amounts of liquid and solid ingredients such as:
 Top loading balances
 Pipettes
 Graduated cylinders
Classes of Filter Media
 Filtration system (for final polishing of the liquid product)
o It is a unit operation in which mixtures of liquids and solids, slurry or feed is forced
through a porous medium, in which solids form a cake on the surface and the clear liquid
is obtained
o The usual objective of filtration or clarification is to produce a sparkling liquid free from
turbidity, precipitates, colloidal hazes or insoluble liquid droplets

Considerations in Filling of Liquids

 Characteristics of the liquid (viscosity, surface tension, foam-producing properties
compatibility with the filling machine).
 Type of package used
 Required production output

Basic Filling Methods
Gravimetric method
 Limited to very large containers and/or highly viscous liquid products
 When large quantities of liquid materials are handled, it is more convenient and accurate to
adapt the gravimetric method of filling
 For this reason, all liquid components of the cited formula are expressed in units of both
volume and weight

Volumetric method
 Accomplished by pumping the liquid, at constant pressure, through the orifice of constant
diameter and size, for a predetermined period of time

Oral Liquid Syrup Filling line ; Oral Liquid Production Line

 Constant Level Method
o Makes use of container height as the means of controlling the fill amount of each bottle
 | |

o The fill amount varies by adjusting the height to which the container is filled
o Any dimensional variations in the container which results to comparable variations in the
net fill per unit
Evaluation of Physical Stability of Finished Liquid Products
 It is shown by the maintenance of the physical properties (color, clarity, taste, viscosity, and
odor) throughout its shelf life until the expiry date is reached
Includes:
 Package and the label
 Effect of the package into the contents and/or contents into the package
 Bottle caps and closures undergo:
o Stress cracking tests
o Corrosion tests
 Cap liners
o Undergo compatibility tests
 Adequate seal
o Evaluated by torque testing
o Torque tester
 An instrument designed to check the circular force required to open and close the
closures
 It checks the tightness of caps and closures
 Sample size for testing – 10 bottles
 Unit of force: Inch per pound

Lesson 2: Dispersed System

Dispersed systems consist of at least two phases: the substance that is dispersed known as the
dispersed (or) internal phase, and a continuous (or) external phase. It will be based on the
classification as coarse or colloidal dispersion, depending on the size of particles.

SUSPENSIONS
PHARMACEUTICAL SUSPENSIONS
 These dosage forms are heterogeneous / disperse systems consisting of 2 phases:
o CONTINUOUS PHASE – also called external phase or dispersion system.
o DISCONTINUOUS PHASE – also called internal phase or dispersed system.
*ALMOST ALL SUSPENSIONS SEPARATE UPON STANDING.

The main concerns of the formulator are:

o Decrease the rate of sedimentation / settling.
o Permit easy re-suspendability of any settled particulate matter (suspensoids)

IDEAL SUSPENSION
 A satisfactory suspension must remain sufficiently homogenous, for at least the time needed
to remove and administer the required dose, after shaking the container.
 | |

TYPES OF SUSPENSION SYSTEMS

1. Flocculated system
2. Deflocculated system

FLOCCULATED SYSTEM
 Also called Coagulated System and Colloidally Unstable System.
 Particles appear like tufts of wool, with loose fibrous structure.

*Coarse textured due to the floccules formed.

DEFLOCCULATED SYSTEM
 Also called Peptized System or Colloidally Stable System.
 Frequently results to a pharmaceutically poor suspension.
 Particles settle as a dense sediment, which becomes more compact after a given time
interval.

PREPARATION TECHNIQUES

 The actual preparation of suspensions involves the following:

o Choice of ingredients
o Type of Equipment used
 If a suspension is to be made by Dispersion Method, it is best to achieve particle size
reduction by:

A. MICRONIZATION METHOD
o Using Jet Mill
o The particles are subjected in a turbulent air chamber.
o Where powders collide with each other and fracture, obtaining particles with sizes 5 microns and below.

B. SPRAY-DRYING METHOD
o Using Spray Dryer
o Produces finely divided particles by spraying a mist of liquid thru a heated chamber,
drying immediately and collecting the dried powders in a clean receptacle.
 | |

C. CRYSTALLIZATION / PRECIPITATION METHOD

o A supersaturated solution is formed and quickly cooled with rapid stirring.
o This causes the formation of nuclei, so that the crystals will not grow too large.

D. HOMOGENIZATION METHOD
o It is accomplished by using a HOMOGENIZER or COLLOID MILL to produce particle
size of less than 1 micron.

EMULSION
 A heterogenous system of 2 immiscible liquids.
 Generally, one of the liquids is a type of oil or lipid (HIGH GRADE MINERAL OIL) or a
variety of animal or vegetable oil and the other liquid is water
 It may be an O/W type or W/O type.

THE MAJOR FACTORS IN THE PREPARATION OF EMULSION ARE:

a. DEGREE OF SHEAR
 Splitting of emulsion into tiny droplets.
b. TURBULENCE
 Agitation required to the given dispersion of droplets.

EQUIPMENT USED IN THE PREPARATION OF EMULSIONS

MECHANICAL STIRRERS
 Emulsions are stirred by means of various impellers mounted on shafts, which are placed
directly into the system to be emulsified.
 The degree of agitation is controlled by the speed of the impeller system.
 This equipment is ideal for slow mixing of finished emulsions, which have been prepared by
melting the waxes.
 | |

HOMOGENIZERS
 It is used to produce fine droplets, by:
 First compressing the liquid, with high pressure
 Escape of liquid radically past a flat disc, held by a strong spring (rotor-stator) mechanism.
 The high shearing stress produced at pressures ranging from 500 to 1000 PSI can produce
extremely fine droplets, depending on the viscosity and interfacial tension of the system.

ULTRASONIFIER/ULTRASONICATOR
 The use of this equipment will produce extremely fine particles for moderately viscous
emulsions.
 This equipment is not available for commercial scale.

EVALUATION OF EMULSION STABILITY AND PROPERTIES

 Emulsion stability implies consumer acceptance and the acceptance varies with the use of
the product
 Emulsion type of aerosols, though completely separated inside, will become acceptable for
use, upon shaking the container before using
 IMPORTANCE OF THE “SHAKE WELL” LABEL:
o Creaming and Sedimentation in fluid emulsions will be eliminated with a “Shake Well”
Label.
o This will make the product acceptable for use.

EMULSION STABILITY METHODS OF EVALUATION

PHASE SEPARATION / SUBSIDENCE

 The rate and extent of phase separation is observed by allowing an emulsion to stand in the
container (for a given period of time).
 The volume of the separated phases are measured.
 Such changes may be due to either Creaming, Sedimentation or Coalescence.

PARTICLE / DROPLET SIZE ANALYSIS

 By microscopic examination, the diameter of the droplets / particles could be measured.
 Over a period of time particles are seen to increase in size.
 To remedy this, a higher concentration of emulsifier is added, to produce smaller droplet /
particle size and to stabilize the product.

INFLUENCE OF TEMPERATURE
 Method A (Accelerated Studies)
o To place the emulsion in a 600C oven for a number of hours, remove then transfer to a
refrigerator temperature.
o Continued emulsion stability studies for a few more weeks at 600C, will be the basis that
the emulsion will be stable for the next two (2) years.
 Method B (Real Time Studies)
o Perform Long Term /Real Time Stability Studies at different climatic zones, for
o Prediction of the appropriate storage conditions
o Projected shelf life of the product.
 | |

Module 3: Solid Pharmaceutical Products

INTRODUCTION

Drug substances are most frequently administered as solid dosage formulations, mainly by the oral
route. The drug substance’s physicochemical characteristics, as well the excipients added to the
formulations, all contribute to ensuring the desired therapeutic activity. Tablets and capsules are the
most frequently used solid dosage forms, have been in existence since the nineteenth century, and
are unit dosage forms, comprising a mixture of ingredients presented in a single rigid entity, usually
containing an accurate dose of a drug. There are other types of solid dosage forms designed to fulfill
specific delivery requirements, but they are generally intended for oral administration and for
systemic delivery. The major solid oral dosage form is the tablet, and these can range from relatively
simple, single, immediate – release dosage forms to complex modified - release systems. Most
tablets are intended to be swallowed whole and to rapidly disintegrate and release drug in the
gastrointestinal tract. Tablets are classified by their route of administration or their function, form, or
manufacturing process. For example, some tablets are designed to be placed in the oral cavity and
to dissolve there or to be chewed before swallowing, and there are many kinds of formulation
designed for sustained or controlled release.

Solid dose formulations, including tablets and capsules, must have the desired release properties
coupled with manufacturability and aesthetics and must involve rational formulation design. The dose
of the drug and its solubility are important considerations in the design of the formulation as are the
type of dosage form and its method of preparation.

Lesson 1: Tablets

Quality Attributes of a Tablet

1. The tablet should include the correct dose of the drug.
2. The appearance of the tablet should be elegant and its weight, size and appearance should
be consistent.
3. The drug should be released from the tablet in a controlled and reproducible way.
4. The tablet should be biocompatible, i.e. not include excipients, contaminants and microbes
that could cause harm to patients.
5. The tablet should be of sufficient mechanical strength to withstand fracture and erosion during
handling.
6. The tablet should be chemically, physically and microbiologically stable during the lifetime of
the product.
7. The tablet should be formulated into a product acceptable by the patient.
8. The tablet should be packed in a safe manner.

UNIT OPERATIONS & OPERATING PRINCIPLES

 Particle size reduction / Milling / Screening

o Mechanical process of breaking particles into smaller pieces via one or more particle size
reduction mechanisms; generally is referred to as milling
 | |

 Blending & Mixing

o Reorientation of particles relative to one another in order to achieve uniformity

 Granulation
o Process of creating granules
o Powder morphology is modified through the use of either a liquid that causes particles to
bind through capillary forces or dry compaction forces

 Drying
o Removal of a liquid from a solid by evaporation

 Compression
o Used to make tablets by compressing a formulation containing a drug or drugs with
excipients

 Coating
o Uniform deposition of a layer of material on or around a solid dosage form includes:
Sugar coating, Film coating, Microencapsulation, Compression coating, Printing, and
Drilling

 Printing
o Marking of a capsule or tablet surface for the purpose of product identification Packaging
o To protect the tablet from extreme conditions (moist & dry),
o To facilitate the shipping and distribution of the medicine until it reaches the patients

TABLET COMPRESSION OPERATION

Tablet compression machines (Tablet Presses)
 Used to make tablets by compressing a formulation containing a drug or drugs with excipients
 Include: 1) single-punch or 2) multi-station rotary presses
Tablet Compression Single Punch (Eccentric Rotary Press (Multi-station
Machines Press) press)
DESCRIPTION  Compression is applied by  Termed rotary because
the upper punch, making the head of the tablet
the single punch machine machine that holds the
a "stamping press” upper punches, dies, and
lower punches in place
rotates
 As the head rotates, the
punches are guided up &
down by fixed cam tracks
OUTPUT  200 tablets per minute  10,000 tablets per minute
PRIMARY USE  Production of small  During scale-up in the
batches of tablets during latter part of the
formulation development formulation work
 | |

 During small-scale  During large-scale

production such as production
production for clinical trials

Basic Components of a Tablet Press

1. Hopper
 For holding & feeding granulation to be compressed

2. Dies
 Define the size and shape of the tablets

3. Punches
 For compressing the granulation within the dies
 May be engraved with company names or symbols, trade names, dosage strength,
National Drug Code numbers
 May be scored

4. Cam tracks
 For guiding the movement of the punches; control the sequence of filling, compression, &
ejection

5. Feed shoe
 Feeding mechanism for moving granulation from the hopper into the dies

6. Upper & lower turrets

 Portions of the head that hold the upper & lower punches

7. Die table
 Portion holding the dies
 | |

Stages in Tablet Formation (Compaction Cycle)

1. Die filling
 Accomplished by gravitational flow of the powder from a hopper via the die table into the
die

2. Tablet formation
 Upper punch descends and enters the die and the powder is compressed until a tablet is
formed
 During the compression phase, the lower punch can be stationary or can move upwards
in the die
 After maximum applied force is reached, the upper punch leaves the powder

3. Tablet ejection
 The lower punch rises until its tip reaches the level of the top of the die.
 Tablet is removed from the die and die table by a pushing device.
SELECTED PROCESSING PROBLEMS ENCOUNTERED IN THE MANUFACTURE OF TABLETS

CAPPING AND LAMINATION

 Capping - Partial or complete separation of the top or bottom crowns of a tablet from the main
body of the tablet
 Lamination - Separation of a tablet into 2 or more distinct layers

PICKING
 used to describe the surface material from a tablet that is sticking to and being removed from
the tablet's surface by a punch; Of concern when punch tips have engraving or embossing
such as small enclosed areas found in the letters B, A, & O

STICKING
 Refers to tablet material adhering to the die wall
 Caused by excessive moisture of granulation

MOTTLING
 Unequal distribution of color on a tablet
 Dye migrating to the surface of a granulation during drying

DOUBLE IMPRESSION
 Involves only the punches that have a monogram or other engraving on them; the punch may
make a new, although lighter impression, on the bottom of the tablet because of the
uncontrolled rotation of the lower punch.
 | |

Lesson 2: Capsules

CAPSULES
 Solid dosage forms in which one or more medicinal and inert ingredients are enclosed in a
small shell or container usually made of gelatin.
 There are two types of capsules, “hard” and “soft”
 The hard capsule is also called “two-piece” as it consists of two pieces in the form of small
cylinders closed at one end, the shorter piece is called the “cap” which fits over the open end
of the longer piece, called the “body”.
 Capsules are available in many sizes to provide dosing flexibility.

STARTING MATERIALS FOR CAPSULE SHELL

 The starting materials used in the manufacture of both hard and soft gelatin capsules are
similar. Both contain gelatin, water, colorants and optional materials such as process aids and
preservatives.

Gelatin
 Gelatin has been the starting material of choice because of the ability of a solution to gel to
form a solid at a temperature just above ambient temperate conditions, which enables a
homogeneous film to be formed rapidly on a mold pin.
 Gelatin is a translucent brittle solid substance, colorless or slightly yellow, nearly tasteless and
odorless, which is created by prolonged boiling of animal skin connective tissue or bones.
 Type A gelatin is derived from an acid-treated precursor whereas Type B gelatin is from an
alkali-treated precursor
 Capsules may be made from either type of gelatin, but mostly a mixture of both types is used
considering availability and cost.
 Difference in the physical properties of finished capsules as a function of the type of gelatin
used is slight.
 Blends of bone and pork skin gelatins of relatively high strength are normally used for hard
capsule production.
o The bone gelatin produces a tough, firm film, but tends to be hazy and brittle.
o The pork skin gelatin contributes plasticity and clarity to the blend, thereby reducing
haze or cloudiness in the finished capsule.

 Production of gelatin:
o On a commercial scale, gelatin is made from by-products of the meat and leather industry,
mainly pork skins, pork and cattle bones, or split cattle hides.
o The starting materials are prepared by different curing, acid, and alkali processes which
are employed to extract the dried collagen hydrolysate.
o The entire process takes several weeks.

 Process aids
o Preservatives and surfactants are added to the gelatin solution during capsule
manufacture to aid in processing.
 | |

o Gelatin solutions are an ideal medium for bacterial growth at temperatures below 55°
o Preservatives are added to the gelatin and colorant solutions to reduce the growth of
microorganisms until the moisture content of the gelatin film is below 16% w/v.
o At moisture content below that value, the bacterial population will decline in numbers
with time.
o The materials used as preservatives include:
 Sulfur dioxide which is added as the sodium salts bisulfite or metabisulfite;
 Sorbic acid or the methyl propyl esters of para hydroxybenzoic acid; and
 Organic acids, benzoic and propanoic acids.
 Some hard gelatin capsules may contain 0.15 % w/w of sodium lauryl
sulfate which functions as wetting agent, to ensure that the lubricated metal molds
are uniformly covered when dipped into the gelatin solution.

 Hypromellose
o Hydroxypropyl methylcellulose (HPMC)
o An alternative to gelatin

HARD GELATIN CAPSULES

 Hard capsules are usually made up of a base containing plasticizer and water.
 The base may also contain preservatives, colors, flavors and sugars.
 Steps involved in making empty gelatin capsules shells

PREPARATION OF THE GELATIN

 Once starting materials have been received and released by Quality Control, the gelatin and
hot demineralized water are mixed under vacuum in Stainless Steel Gelatin Melting System.
 After aging in stainless steel receiving tanks, the gelatin solution is transferred to stainless
steel feed tanks.
 Dyes, opaquants, and any needed water are added to the gelatin in the feed tanks to complete
the gelatin preparation procedure. The feed tanks are then used to gravity-feed gelatin into
the Capsule Machine.

DIPPING
 From the feed tank, the gelatin is gravity fed to specially engineered Dipper section.
 Here, the capsules are molded onto stainless steel Pin Bars which are dipped into the
gelatin solution.
 The dipping solution is maintained at a temperature of about 50°C in a heated, jacketed
dipping pan.

SPINNING
 Once dipped, the Pin Bars rise to the upper deck allowing the cap and body to set on the
Pins.
 | |

 (Spinning) The pins are rotated to distribute the gelatin over the pins uniformly and to avoid
the formation of a bead at the capsule ends.

DRYING
 The Pin Bars pass through the upper and lower kilns of Capsule Machine Drying System.
Here gently moving air which is precisely controlled for volume, temperature, and humidity,
removes the exact amount of moisture from the capsule halves.

STRIPPING
 Once drying is complete, the Pin Bars enter the Table section which positions the capsule
halves for stripping from the Pins in the Automatic section

TRIMMING AND JOINING

 The stripped cap and body portions are trimmed to the required length by stationary knives.
After trimming to the right length, the cap and body portion are joined and ejected from the
machine.

POLISHING
 Finished capsules are pushed onto a conveyer belt which carries them out to a container
 Perfect capsules are imprinted with the client logo on highspeed capsule printing machines.
Capsules are now ready to be sterilized and packaged.

PROPERTIES OF EMPTY HARD GELATIN CAPSULE SHELLS

 Empty capsules contain a significant amount of water that acts as a plasticizer for the gelatin
film and is essential for their function.
 The standard moisture content specification for hard gelatin capsules is between 13 % w/w
and 16 % w/w.
 This value can vary depending upon the conditions to which they are exposed that is at low
humidity’s they will lose moisture and become brittle, and at high humidity’s they will gain
moisture and soften.
 The moisture content can be maintained within the correct specification by storing them in
sealed containers at an even temperature.
 Capsules are readily soluble in water at 37°
 When the temperature falls below this, their rate of solubility decreases.
 At below about 30°C they are insoluble and simply absorb water, swell and distort.
 This is an important factor to take into account during disintegration and dissolution testing.
 Because of this, most Pharmacopoeia have set a limit of 37°C ± 1°C for the media for carrying
out these tests.

Capsule shell filling – Industrial Scale Filling

 Machines for industrial-scale filling of hard gelatin capsules come in great variety of shapes
and sizes, varying from semi- to fully automatic and ranging in output from 5000 to 15000
per hour.

The dosing systems can be divided into two groups:

1. Dependent – dosing systems that use the capsule body directly to measure the powder.
Uniformity of fill weight can only be achieved if the capsule is filled completely eg. Auger filling.
 | |

2. Independent – dosing systems where the powder is measured independently of the body in
a special measuring device. Weight uniformity is not dependent on filling the body completely.
With this system the capsules can be part filled eg. Dosator.

Difficulties in filling capsules

1. Deliquescent or Hygroscopic powders

 A gelatin capsule contain water which is extracted or taken up by a hygroscopic drug and
renders the capsule very brittle which leads to cracking of the capsule.
 The addition of an adsorbent like magnesium carbonate, heavy magnesium oxide or light
magnesium oxide overcomes this difficulty provided the capsules are packed in tightly closed
glass capsule vials.

2. Eutectic mixtures
 Certain substances when mixed together tend to liquefy and form a pasty mass due to the
formation of a mixture which has a lower melting point than room temperature.
 For filling these types of substances each troublesome ingredient is mixed with an absorbent
separately then mixed together and filled in capsules.
 The absorbents used are magnesium oxide and kaolin.
 Another method in dealing with such type of difficulty is that the substances are mixed together
so as to form a eutectic mixture, then an absorbent like magnesium carbonate or kaolin is
added.

3. Very small drug quantity

 When the quantity of the drug to be filled in capsules is very small and it is not possible to fill
this much small amount in capsules then inert substance or a diluent is added so as to
increase the bulk of the powder, which can be filled easily in capsules.

4. Incompatible ingredients
 Some of the manufacturers separate the incompatible ingredients of the formulation by
placing one of the ingredients in smaller capsule, and then placing this smaller capsule in a
larger capsule containing the other ingredients of the formulation.

5. Filling of granular powder (usually encountered in Punch-method)

 Some powders which lack adhesiveness and most granular powders are difficult to fill in the
capsules by punch method because they are not compressible and flow out of the capsule as
soon as they are lifted from the pile of powder into which they are punched.
 To overcome this difficulty the non-adhesive powders should be moistened with alcohol and
the granular powders should be reduced to powder before filling into capsules.

SOFT GELATIN CAPSULES

 Made of gelatin to which glycerin or a polyhydric alcohol such as sorbitol has been added.
 Soft gelatin capsules, which contain more moisture than hard capsules, may have a
preservative, such as methylparaben and/or propylparaben, to retard microbial growth.
 Soft gelatin capsules may be oblong, oval, or round.
 | |

 They may be single colored or two-toned and may be imprinted with identifying markings.
 As with hard gelatin capsules, they may be prepared with opaquants to reduce transparency
and render characteristic features to the capsule shell.
 Soft gelatin capsules are used to encapsulate and hermetically seal liquids, suspensions,
pasty materials, dry powders, and even preformed tablets.
o They are most suitable for liquids and semisolids and are widely used, in spherical and
ovoid forms for vitamin preparations such as cod liver oil, vitamins A and D and multiple
vitamins.
 Soft gelatin capsules are pharmaceutically elegant and are easily swallowed.

Formulation of Soft Gelatin Capsule

1. Gelatin shell formulation

 Typical soft gels are made up of gelatin, plasticizer, and materials that impart the desired
appearance (colorants and/or opacifiers), and sometimes flavors.

2. Plasticizers
 These are used to make the soft gel shell elastic and pliable.
 The most common plasticizers used in soft gels is glycerol,
although sorbitol and propylene glycol are used frequently often in combination with
glycerol.

3. Water
 The other essential component of the soft gel shell is water.
 Water usually accounts for 30-40 % of the wet gel formulation and its presence is important
to ensure proper processing during gel preparation and soft gel encapsulation.
 Following encapsulation, excess water is removed from the soft gel through controlled drying.
 In dry gels the equilibrium water content is typically in the range 5-8% w/w, which represents
the proportion of water that is bound to the gelatin in the soft gel shell.
 This level of water is important for good physical stability, because in harsh storage conditions
soft gels will become either too soft and fuse together, or too hard and brittle.

4. Colorants/opaquants:
 Colorants (soluble dyes, or insoluble pigments or lakes) and opaquant are typically used in
the wet gel formulation.
 Colorants can be either synthetic or natural and are used to impart the desired shell color for
product identification.
 An opaquants, usually titanium dioxide may be added to produce an opaque shell when the
fill formulation is a suspension, or to prevent photo degradation of light-sensitive fill
ingredients.
 Titanium dioxide can either be used alone to produce a white opaque shell or in combination
with pigments to produce a colored opaque shell.
 | |

PLATE DROPLET ROTARY DIE RECIPROCATING

PROCESS PROCESS PROCESS DIE PROCESS
 By the plate  Seamless Soft  Most soft gelatin  The reciprocating
process, a warm Gel Capsule capsules are die process is
sheet of plain or Manufacturing prepared by the similar to the
colored gelatin is  The essential part rotary die rotary process in
placed on the of the apparatus process, a that ribbons of
bottom plate of consists of two method gelatin are
the mold and the concentric tubes. developed in formed and used
medication-  Through the inner 1933 by Robert to encapsulate
containing liquid tube flows the P. Scherer. the fill, but it
is evenly poured medicament and,  By this method, differs in the
on it. through the liquid gelatin actual
 Then a second surrounding outer flowing from an encapsulating
sheet of gelatin is tube, the gelatin overhead tank is process.
carefully placed solution. formed into two  The gelatin
on top of the  The medicament, continuous ribbons are fed
medication and therefore, issues ribbons by the between a set of
the top plate of from the tube rotary die vertical dies that
the mold is put surrounded by machine and continually open
into place. gelatin and brought together and close to form
 Pressure is then forming a between twin rows of pockets
applied to the spherical drop. rotating dies. in the gelatin
mold to form, fill,  This is ensured  At the same time, ribbons.
and seal the by allowing the metered fill  These pockets
capsules drop to form in material is are filled with the
simultaneously. liquid paraffin in injected between medication and
 The capsules are which the gelatin the ribbons are sealed,
removed and is insoluble. precisely at the shaped, and cut
washed with a  Regular induced moment that the out of the film as
solvent harmless pulsations cause dies form they progress
to the capsules. drops of the pockets of the through the
correct size to be gelatin ribbons. machinery.
formed, and a  These pockets of  As the capsules
temperature of fill-containing are cut from the
4°C ensures that gelatin are ribbons, they fall
the gelatin shell is sealed by into refrigerated
rapidly pressure and tanks that prevent
congealed. heat and then the capsules from
 The capsules are severed from the adhering to one
subsequently ribbon. another.
degreased and  Use of ribbons of
dried. two different
colors results in
bicolored
capsules.
 | |

QUALITY CONTROL TESTING FOR TABLETS

Selected Quality Control Test (During and After the Compression Cycle – IPQC and FPQC )
DISINTEGRATION
Objective Instrument/s Specifications Implications
 To assure  Disintegration  Majority of the  As the tablet breaks
that the tester uncoated tablets down into small particles,
dosage form  have a maximum it offers a greater surface
breaks down disintegration time area to the dissolving
into smaller of 30 mins media and therefore must
particles or be related to the
granules  Enteric coated availability of the drug to
tablets need to the body.
 Simulates show no evidence
how a of disintegration  This test offers no
dosage form after 1 hour in assurance that the
such as a simulated gastric resultant particles will
tablet or a fluid (SGF). release the drug in
capsule solution at an appropriate
would break  The same tablets rate
apart in an are then tested in
aqueous simulated intestinal  A slow disintegrating
environment. fluid (SIF) and are solid oral dosage form
to disintegrate in 2 may not release the drug
hours. in time for it to be
dissolved and absorbed
 All particles must in its site of absorption.
pass through the
10- mesh screen in  A dosage form
the time specified. disintegrating too fast
may render a drug
 If any residue inactive or even be
remains, it must destroyed if released in a
have a soft mass hostile environment to the
with no palpably drug such as the stomach
firm core

DISSOLUTION
Objective Instrument/s Specifications Implications
 To evaluate as to  Dissolution  That the release of  The rate of
whether or not a tablet tester the drug from the dissolution
releases its drug tablet is as close as may thus be
contents when placed possible to 100% directly related
in the environment of to the efficacy
the GI tract of the tablet
 | |

 That the rate of drug product, as

 This test simulates the release is uniform well as to BA
physiological batch to batch and is differences
conditions of the body the same as the between
and can therefore release rate from formulations
predict bioavailability those batches proven
as this is a to be bioavailable
prerequisite for and clinically
absorption effective.

THICKNESS
Objective Instrument/s Specifications Implications
 Provides  Vernier  A function of the  Packaging problem with
information on caliper die fill and tablets of variable
the variation compression force thickness
within or  Thickness
between lots decreases as  Tablets with greater
additional thickness have reduced
 Facilitate compression force internal stresses thus,
packaging is applied less tendency to cap

 Determines the  Increase in  Tablets that are of

maximum pressure causes inconsistent thickness
packaging the tablet to block the channels of
quantity of a laminate or cap counting machinery
dosage form

CONTENT UNIFORMITY
Objective Instrument/s Specifications Implications
 To assure  Analytical  In evaluating a  Factors that directly
uniform balance particular lot of contribute to content
potency tablets, several uniformity problems:
for tablets samples of tablets o Non-uniform
of low- should be taken distribution of the drug
dose from various parts substance throughout
drugs of the production the powder mixture or
run to satisfy granulation
statistical o Segregation of the
procedures powder mixture or
granulation
o Tablet weight variation
o Improper filling of the
dies with granulation
o Poorly flowing
granulation

WEIGHT VARIATION
 | |

Objective Instrument/s Specifications Implications

 This test  Analytical  USP  Not sufficient to assure
provides an balance uniform potency of
idea whether tablets of moderate or
the dose in a low-dose drugs, in
batch of units is which excipients make
uniform and if up the bulk of the
the dosage tablet weight
form can deliver
the right  If uniform, this would
amount of dose make each dosage
in each patient unit a representative
formulation to produce
its desired effect

FRIABILITY
Objective Instrument/s Specifications Implications
 Another  Roche type  Chewable tablets  Tablets that tend
measure of friabilator and effervescent to powder, chip,
tablet’s tablets undergo high and fragment
strength  Induces self- friability weight when handled
abrasion of the losses, which lack elegance
 Shows how tablets as the accounts for the and consumer
well a tablet cylinder section special stack acceptance
resists rotates packaging that may
chipping be required for these  Friable tablets
and  Tablets undergo types of tablets can create
crumbling shock as they fall excessively dirty
when six inches on  Very dry granulations processes in
external each turn that contain only such areas of
stresses are fractional manufacturing as
applied  Loss due to percentages of coating &
abrasion or moisture often packaging
fracture is the produce more friable
measure of tablet tablets than do
friability granulations
containing 2 to 4%
 When capping moisture
occurs, friability
values are no
longer calculated


HARDNESS
The force required to break a tablet in a diametric compression test; aka tablet
crushing strength
 | |

Objective Instrument/s Specifications Implications

 To test if  Monsanto  A tablet is  Adequate tablet
tablet has tester placed between hardness &
adequate  Strong- 2 anvils, force is resistance to
strength to Cobb tester applied to the powdering &
withstand  Pfizer anvils, and the friability are
the rigors of tester crushing necessary
mechanical  Erweka strength that requisites for
shocks tester just causes the consumer
encountered  Schleuniger tablet to break acceptance
in the tester is recorded
production,  Correlated to tablet
packaging,  Rough  Function of the disintegration &
shipping, & handling die fill and dissolution
dispensing tests can compression
be force  Tablets are harder
 Especially performed several hours after
important to give an  How the tablets compression than
for drug indication withstand the they are
products of how well mechanical immediately after
that a tablet will shocks of a compression
possess hold up in production
real or its specified environment is  Lubricants can
potential BA package & related to the affect tablet
problems shipping large number of hardness when they
container tablets involved, are used in too high
during the production a concentration or
shipment equipment mixed for too long a
 used, and the period
skill of the
production
personnel

QUALITY CONTROL: COMPENDIAL REQUIREMENTS FOR CAPSULES

Added Substances
 Substances added to official preparations, including capsules, to enhance their stability,
usefulness, or elegance or to facilitate their manufacture may be used only if they;
1. Are harmless in the quantities used
2. Do not exceed the minimum amounts required to provide their intended effect
3. Do not impair the product’s bioavailability, therapeutic efficacy, or safety
4. Do not interfere with requisite compendial assays and tests

Disintegration Test for Capsules

 | |

 The capsules are placed in the basket rack assembly, which is immersed 30 times per minute
into a thermostatically controlled fluid at 37°C and observed over the time described in the
individual monograph.
 To satisfy the test, the capsules disintegrate completely into a soft mass having no palpably
firm core and only some fragments of the gelatin shell.

Dissolution Test for Capsules

 The dissolution test for capsules uses the same apparatus, dissolution medium, and test as
that for uncoated and plain-coated tablets.
 However, if the capsule shells interfere with the analysis, the contents of a specified number
of capsules can be removed and the empty capsule shells dissolved in the dissolution medium
before proceeding with the sampling and chemical analysis.

Weight Variation
 The uniformity of dosage units may be demonstrated by determining weight variation and/or
content uniformity.
 The weight variation method is as follows;

Hard Capsule
 Ten capsules are individually weighed and their contents removed.
 The emptied shells are individually weighed and the net weight of the contents is calculated
by subtraction.
 From the results of an assay performed as directed in the individual monograph, the content
of the active ingredient in each of the capsules is determined.

Soft Capsule
 The gross weight of 10 intact capsules is determined individually.
 Then each capsule is cut open and the contents are removed by washing with a suitable
solvent.
 The solvent is allowed to evaporate at room temperature over about 30 minutes, with
precautions to avoid uptake or loss of moisture.
 The individual shells are weighed and the net contents calculated.
 From the results of the assay directed in the individual monograph, the content of the active
ingredient in each of the capsules is determined.

Content Uniformity
 Unless otherwise stated in the USP monograph for an individual capsule, the amount of active
ingredient, determined by assay, is within the range of 85% to 115% of the label claim for 9
of 10 dosage units assayed, with no unit outside the range of 70% to 125% of the label claim.
 Additional tests are prescribed when two or three dosage units are outside of the desired
range but within the stated extremes.

Content Labeling Requirement

 | |

 All official capsules must be labeled to express the quantity of each active ingredient in each
dosage unit.

Moisture Permeation Test

 The USP requires determination of the moisture permeation characteristics of single-unit and
unit-dose containers to ensure their suitability for packaging capsules.
 The degree and rate of moisture penetration are determined by packaging the dosage unit
together with a color-revealing desiccant pellet, exposing the packaged unit to known relative
humidity over a specified time, observing the desiccant pellet for color change (indicating the
absorption of moisture), and comparing the pretest and posttest weight of the packaged unit.
 | |

Module 4: Semi-solid Dosage Forms

 Semi-solid dosage forms are preparations that are commonly known as medicated
applications. These are preparations that have a viscous consistency intended to be applied
externally. Usual examples include ointments, creams and paste.
 These semi solid dosage forms are commonly used as vehicles, emollients, and
protective/occlusive dressings.

Lesson 1: Semi-solids

 Ointments, creams, paste and gels are semisolid dosage forms intended for topical
application. Most of these preparations are medicated while others are non-medicated used as
protectants or lubricants. Topical preparations are used for both local and systemic effects,
whose main route is the biggest organ of the boy which is the skin

 Drug Transport and Permeation Through the Skin

o The main drug transportation route of the semi-solid dosage form, is our skin. When a drug
is applied topically, the drug diffuses out of its vehicle onto the surface of the skin.
o The drug molecules have three routes to traverse the intact stratum corneum depending on
their physicochemical properties, these being:
 Intracellular (across corneocytes)
 Intercellular (across lipids) considered the major route of penetration
 Appendageal (via skin appendages)

Factors Influencing Drug Absorption through the Skin

1. Partition Coefficient of Drugs through the Skin

 Drugs with both water and lipid solubility are favorably absorbed through the skin.

2. Moisture and Temperature in the Environment of the Skin

 Moisture Balance in the Skin
o It is found in the stratum corneum layer of the epidermis.
o It prevents the NMF (Natural Moisturizing Factor) from being stripped from the skin.
o NMF prevents skin from drying out, even during excessive contact of the skin with water.
 Insensible Perspiration
o The skin constantly releases water in the skin surface, which evaporates quickly without
being noticed.
o When the surrounding environment has a high moisture content, the rate of evaporation
of sweat is slowed down, and the person becomes aware of the clammy moist sensation
on his skin.

3. Pathological Injury to the Skin

 Skin penetration has been enhanced by abrasions or when the skin is stripped of its
barrier layer.

4. Type of Vehicle Used Skin

 Penetration of drug substances may be enhanced by the use of a suitable semi solid
base.
 | |

 The vehicle may help increase the rate of penetration of drug substances into the skin.
 It serves as a carrier for the API.

Starting Material and Vehicle

 FDA approves chemical substances and states the maximum concentration considered
safe for food and cosmetics (GRAS grade/ generally regarded or recognized as safe
ingredients).
 The supplier of these drug substances supplies brochures / information which indicates
that FDA APPROVAL SAFETY TESTS are conducted.

THE FREQUENT STARTING MATERIALS FOR MEDICATED SEMI-SOLIDS

HYDROCARBONS
 Petrolatum and Mineral oil are the MOST WIDELY USED substances in semisolids, next to
water.
 PETROLATUM— a complex mixture of semisolids containing hydrocarbon aliphatic, cyclic,
saturated, unsaturated, branched and unbranched substances in varying proportions.
 MINERAL OIL— derived from petroleum acid. It is less tacky and with lower viscosity.

HYDROCARBON WAXES
 Help increase the viscosity of hydrocarbons such as petrolatum and mineral oil
 Prevent separation of hydrocarbons from the ointment.
 Examples: paraffin, beeswax, ceresin wax (mixture of paraffin and ozokerite)

OLEAGINOUS SUBSTANCES
 Vegetable fixed oils which contain glycerides of mixtures of saturated and unsaturated fatty
acids (MCT’s and FA’s),
 These are employed for its EMOLLIENT and SKIN-LUBRICATING effects.
 Examples: Fixed oils of peanut, olive, sesame, cottonseed, coconut, corn

FATTY ACIDS and ALCOHOLS

 Functions as Auxiliary emulsifiers and as Viscosity-builders
 Stearic acid — emulsifiers in water-removable creams
 Stearyl /Cetyl Alcohols—emollients, provides the firmness/softness in consistency of
creams.

EMULSIFIERS
 Substances that Prevent coalescence and Act as product stabilizers
 Examples: Triethanolamine stearate (TEA), SPANS, TWEENS, CARBOWAX‘"

POLYOLS
 Used as Humectants, prevents dehydration and ”Crusting" on top of creams and ointments
in jars.
 Examples: Glycerin, PG, Sorbitol 70%, PEG (lower MW)
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INSOLUBLE POWDERS
 These must be uniformly dispersed throughout the semisolid vehicle to assure product
homogeneity.
 These solids must be impalpable to the touch
 Particles less than 74 microns (equivalent to 200 mesh) is said to be (equivalent to 200
mesh)

Factors which influence the choice of semisolid vehicles/base

 Nature of the skin lesion
 Skin type
 Solubility of the formulation components
 Stability of the API’s

TYPES OF SEMISOLID VEHICLES (NON-MEDICATED BASES)

1. WATER-SOLUBLE / GREASELESS BASES

 Prepared from mixtures of high and low MW PEG
 No water is required in its preparation
 Water soluble, due to many polar groups and ether linkages
 Suitable combinations of high and low MW PEG yield products having an ointment-like
consistency, which soften or melt when applied topically
o Low MW PEG - liquids
o Moderately high MW PEG— unctuous
o Very High MW PEG - solids

2. WATER-REMOVABLE/WASHABLE BASE (O/W)

 These are O/W emulsions referred to as Creams
 Upon application, there is little or no evidence of its presence onto the skin
 Best for moist skin lesions, since its O/W character tend to adsorb serous discharges
 Examples
o Vanishing creams, foundation creams, shaving creams
o Vanishing creams type of vehicles are of O/W type
Commercially available creams:
o Fluocinolone acetonide cream (SYNALAR)
 Relief of inflammatory dermatoses
o Capsaicin cream (ZOSTRIX)
 For osteoarthritic joint pain

3. ABSORPTION/EMULSIFIABLE BASE (W/O)

 These are hydrophilic mixtures formed by the addition of substances that possess polar
groupings (sulfates, carboxyl, hydroxyl or ether linkages) to a hydrocarbon base.
 Lanolin, cholesterol, sorbitan monostearate/monooleate are added to hydrocarbon bases to
make it hydrophilic.
 Absorption bases are of w/o type.
 Commercial availability: AQUAPHOR and EUCERIN (a 50% W/O emulsion)
 | |

4. HYDROCARBON BASES
 Typically lipophilic
 Spreads easily onto the skin
 Difficult to remove
 Act as occlusive dressings, since the normal evaporation of insensible perspiration is
inhibited.
 Examples: White petrolatum, Mineral oil, White / Yellow Ointment, USP

Starting Materials -Miscellaneous Excipients

OPHTHALMIC OINTMENTS
 Semisolid ophthalmic vehicles frequently contain any of the ff. bases that have been
sterilized;
1. Petroleum jelly
2. Absorption base (Lanolin or Lanolin Alcohol)
3. Water-soluble base
4. Other ophthalmic ointment bases
 Lanolin sterilized by gamma radiation or sterilization by filtration
 Lanolin alcohol possesses emollient properties suitable for eye ointment formulation.
 Insoluble API powders should meet the requirements for IMPALPABILITY
 Ophthalmic ointments should be rendered STERILE and ISOTONIC

PRESERVATION FROM MICROBIAL SPOILAGE

 The chemical preservative for semisolids should be evaluated as to:
o Stability with regard to formulation components
o Container to be used

CHARACTERISTICS OF PRESERVATIVES FOR SEMISOLID PRODUCTS

 Some preservatives become inactive in the presence of other ingredients.
 Boric acid may be used in ophthalmic ointments against bacterial/ fungal contamination.
 Bacterial counts should be made on the (1) water supply, (2) starting materials, (3)
pipelines, (4) filling equipment and (5) containers.

USE OF ANTI-OXIDANTS
 Anti-oxidants are added to semisolids, whenever oxidative deterioration is anticipated.
 BHA, BHT, Propyl gallate
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 The choice of anti-oxidant is made upon consideration of the following factors:

1. Toxicity / irritating potency
2. Compatibility
3. Odor
4. Discoloration
5. Solubility
6. Stability

EVALUATION OF MEDICATED APPLICATIONS

FUSION METHOD
 ANHYDROUS OINTMENTS are manufactured by this process, which is made by dissolving
the API’s in the previously melted fats and waxes.
 The melted mass must be mixed while cooling to ensure the homogenous distribution of the
ingredients.
 If a perfume or volatile oil is added it is best done at temperature 40-43°C
 Factors to be controlled during the Fusion Method:
o Time of mixing
o Temperature of mixing
o Rate of agitation (and other mechanical works)

STEPS IN FUSION METHOD

1. PREPARATION OF THE OIL PHASE

 Flake / pulverize the dry ingredients.
 Heating is required to melt some ingredients (waxes), usually at 70°C to 75°C.
 Blend in advance and disperse in mineral oil or silicone oil.

2. HYDRATION OF THE INGREDIENTS IN THE AQUEOUS PHASE

 Emulsifiers, stabilizers, thickening agents are dispersed into water in a separate vessel.
 Usually followed by a filtration procedure, if needed.
 Heating may be required to accelerate hydration.

3. FOAMING THE EMULSION

 The aqueous and oil phases are blended under vigorous agitation, to form the emulsion.
 Temperature is controlled between 30°C to 40°C.
 Defoaming procedures are done to minimize foam formation after the product has
emulsified.

4. DISPERSION OF THE ACTIVE/S

 The API’s make up only a small proportion of the formulation.
 It must be EFFICIENTLY DISPERSED to maximize yield and product effectiveness.
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METHODS OF FILLING OPTHALMIC OINTMENTS

 BLOW FILL SEAL METHOD (BFS) SEQUENCE in ONE EASY OPERATION:
1. Fabrication of containers
2. Filling the product
3. Sealing
 FORM FILL SEAL METHOD (FFS)
o The conventional method of filling ophthalmic ointments.
EVALUATION OF MEDICATED APPLICATIONS AS PER USP REQUIREMENTS
 STORAGE and LABELING
 MICROBIAL SCREENING (Microbial Limit Tests)
o Staphylococcus aureus
o Pseudomonas aeruginosa

 MINIMUM FILL
o Assessment of the Content Uniformity of semi-solids.
 For product weighing 60 g or mL: NLT 90% of the labeled amount.
 For product weighing 60 g or mL to 150 g or mL: NLT 95% of the labeled amount.

 STANDARD ASSAYS of the API’s (Quantitative assay of % Purity or % Content)

 STERILITY TESTS
1. Membrane Filtration Technique
2. Test Tube Inoculation Method

 In vivo BA/BE – Dermatopharmacokinetic Studies (DPS)

o Applicable to semisolids that contain:
1. Antifungals
2. Antivirals
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3. Corticosteroids
4. Antibiotics
5. Topicals for vaginal use

o Not applicable to semisolids for;

 Otic use
 Opthalmic use
 That damage the stratum corneum of the skin.
o It involves measurement of the ff.;
 Drug concentration in the stratum corneum
 Drug uptake
 Apparent steady state
 Elimination after drug application onto the skin

EVALUATION OF MEDICATED APPLICATIONS AS PER NON-USP REQUIREMENTS

 pH
 Water Content (Karl Fischer Method) Water affects the;
o physical stability
o chemical stability
o microbial stability
 Usual water limit: 0.5% to 1%
o NMT 0.5% water content for Ointments containing:
 Bacitracin
 Chlortetracycline HCl
 Nystatin
o NMT 1% water content for ointments, creams or gels containing;
 Erythromycin
 Gentamycin sulfate
 Neomycin sulfate
 Tetracycline HCl

 Foreign Substances
o Introduced by contamination or adulteration and not a consequence of the synthesis or
preparation of compendial articles
 Homogeneity (also refers to Content Uniformity by Minimum Fill testing)
 Metal Particle Detection Test
o Mandatory for ophthalmic ointments only.
o Procedure
 Count the number of metal particles that are 50 μm or larger in any dimension: the
requirements are met if the total number of such particles in all 10 tubes does not
exceed 50, and if not more than 1 tube is found to contain more than 8 such
particles.
 If these results are not obtained, repeat the test on 20 additional tubes: the
requirements are met if the total number of metal particles that are 50 μm or larger in
 | |

any dimension does not exceed 150 in all 30 tubes tested, and if not more than 3 of
the tubes are found to contain more than 8 such particles each

 Leaker Test
o Mandatory for ophthalmic ointments filled in collapsible tubes.
o By Classical Blotting Paper Method
o Procedure
 Select 10 tubes of the ointment, with seals applied
 Place the tube in a horizontal position on a sheet of absorbent blotting paper in an
oven maintained at temperature of 60 ± 3 degrees Celsius for 8 hours.
o Specs / Limits:
 Requirements are met if:
 Out of the first 10 tubes tested, NO LEAK is observed.
o If 1 tube leaks, repeat the test on 20 additional tubes.
 Requirements are met if:
 NMT 1 tube out of the 30 tubes should leak