Federal Democratic Republic of Ethiopia

Ministry of Education
Amhara National Regional State
TVET bureau

VICTORY HEALTH SCIENCE COLLEGE

DEPARTMENT OF PHARMACY

MODULE TITLE:
Supervising small scale compounding of aseptic pharmaceutical
products

A course for level-IV (third year) pharmacy technician students

By: Tadesse Negash (B.Pharm, in clinical pharmacy)
Total contact hours = 186 hrs Academic Year: 2013
Course objectives: At the end of the module the learner will be able to:
 Design master batch/work sheet and labels
 Identify Source information on formula
 Seek approval and release of batch/work sheets for use
 Prepare for aseptic production process and obtain equipment, etc required for…..
 Prepare for cytotoxic production, aseptically
 Prepare for sterile manufacturing
 Manufacture/ compound products using aseptic techniques
 Complete production process
 Participate in quality control
 Transport and store release product

Unit one: Introduction to Aseptic pharmaceutical compounding

Introduction to sterile pharmaceutical products
Sterile: state of being free from any viable organisms and entities.
Sterilization: Process of killing or removing microorganisms from a product to ensure that it is
sterile.
Question
1.Parenteral drug delivery systems and many medicinal products, such as dressings
and sutures, must be sterile. why?
 Injections, ophthalmic preparations, fluids, dialysis solutions, sutures , implants, certain
surgical dressings, as well as instruments necessary for their use or administration, must
be presented in a sterile condition.
 Sterile product should not contain viable bacteria, yeasts or fungi, nor other
microorganisms such as rickettsiae, mycoplasmas or protozoa and viruses.
 Sterilization processes concentrate on the destruction or removal of microorganisms.
Each process is designed to remove the most problematic microorganism (i.e. the
smallest bacteria in filtration or the most heat resistant bacterial spores in heat
sterilization processes) on the basis that, once a sterilization process has been chosen,
elimination of the most problematic species will have led to the elimination of all less
resistant microorganisms.
The most obviously recognized sterile pharmaceutical preparations are injections. Other sterile
products include ophthalmic preparations, creams and dusting powders
 Principles of aseptic production
According to the U.S. Pharmacopoeia (USP), compounded sterile preparations (CSPs) are
parenteral products and include diagnostic agents, radiopharmaceuticals, inhalation solutions,
baths and soaks for live organs, irrigations for wounds and body cavities, ophthalmic drops and
ointments, and tissue implants.
 Parenteral products must have the following unique qualities:
 They must be sterile/free from microbial/.
 They must be free from contamination by endotoxins.
 They must be free from visible particles which includes reconstituted sterile powders.
 They should be isotonic; depends on the route of administration.
 They must be chemically, physically, and microbiologically stable.
 They must be compatible with IV delivery systems, diluents, and other drug products to
be co-administered.
 The manufacture of parenteral products is focused at all times on the requirement for
sterility of the finished product.
Common terms used
 Definition of terms (related to documentations)
Batch records: All documents associated with the manufacture of a batch of bulk product or
finished product. They provide a history of each batch of product and of all circumstances
pertinent to the quality of the final product.
Master formula: A document or set of documents specifying the starting materials with their
quantities and the packaging materials, together with a description of the procedures and
precautions required to produce a specified quantity of a finished product as well as the
processing instructions, including the in-process controls.
Master record: A document or set of documents that serve as a basis for the batch documentation
(blank batch record).
Standard operating procedure (SOP): An authorized written procedure giving instructions for
performing operations not necessarily specific to a given product or material (e.g.: equipment
operation, maintenance and cleaning; validation; cleaning of premises and environmental
control; sampling and inspection).
Active ingredient – means any component that is intended to furnish pharmacological activity or
other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease
Batch number or control number – means any distinctive combination of letters, numbers, or
symbols, or any combination of them from which the complete history of the preparation,
processing, packing, holding and distribution of a batch or lot of drug product or other material
can be determined.
Batch – means a specific quantity of a drug or other material that is intended to have a uniform
character and quality, within specified limits, and is produced according to a single
manufacturing order during the same cycle of manufacture.
Label – means a display of written, printed, or graphic matter upon the immediate container of
any drug product or material.
Package – means the immediate container or wrapping in which any preparation is contained
Bulk preparations – are preparations prepared in large volumes or in masses, intended to be used
for a short period of time. Not to be stocked for long period.
  Definition of terms (related to Aseptic pharmaceutical production/compounding)
Admixture: parenteral dosage forms are combined for administration as a single entity.
Ante area: an ISO Class 8 or better area where personnel perform hand hygiene and garbing
procedures, staging of components, order entry, CSP labeling, and other high-particulate
generating activities.
Aseptic processing: product components, containers, and closures, and the product itself, are
sterilized separately and then brought together and assembled in an aseptic environment; the
primary objective of aseptic processing is to create a sterile product.
Aseptic technique: a means of manipulating sterile products without contaminating them.
Buffer area: usually an ISO Class 7 area where the laminar flow hood is located. It has positive
pressure to the rest of the pharmacy and is supplied with HEPA-filtered air.
Critical area: an ISO Class 5 area, clean work bench supplied with laminar air flow.
Critical site: any opening or surface that can provide a pathway between the sterile product and
the environment (e.g., the hub of the needle, the tip of the syringe, the open neck of the ampoule,
the top of the vial closure, the ribs of the plunger on a syringe).
Direct compounding area (DCA): a critical area within the ISO Class 5 primary engineering
control (PEC) where critical sites are exposed to unidirectional HEPA-filtered air, also known as
“first air.”
Hypertonic: a solution containing a higher concentration of dissolved substances (hyper
osmotic) than the red blood cell, which causes the red blood cell to shrink.
Hypotonic: a solution containing a lower concentration of dissolved substances (hypo osmotic)
than the red blood cell, causing the red blood cell to swell and possibly burst.
Isotonic: a solution with an osmotic pressure close to that of body fluids. This minimizes patient
discomfort and damage to red blood cells. Dextrose 5 percent in water and sodium chloride 0.9
percent solutions is approximately isotonic.
ISO Class 5 area: the air in the area has no more than 3,520 particles per cubic meter of air 0.5
microns and larger. This is equivalent to the air in a Class 100 area, which is the number of
particles per cubic foot of air 0.5 microns and larger.
ISO Class 7 area: the air in the area has no more than 352,000 particles per cubic meter of air
0.5 microns and larger. This is equivalent to a Class 10,000 area.
ISO Class 8 area: the air in the area has no more than 3,520,000 particles per cubic meter of air
0.5 microns and larger. This is equivalent to a Class 100,000 area.
Primary engineering control (PEC): a device such as a laminar air flown workbench (LAFW),
biological safety cabinet (BSC), or compounding aseptic isolator (CAI) that provides an ISO
Class 5 environment for the exposure of critical sites when compounding sterile preparations.
Unidirectional flow: air flow moving in a single direction, in a robust and uniform manner, and
at sufficient speed to reproducibly sweep particles away from the critical processing area.
Piggyback: A vial of medication is added to an IV medication by removing the contents of the
vial via a syringe and injecting it into the IV bag of medication.
Sanitization: A process of cleansing to remove undesirable debris.
Sterilization: Complete destruction of all forms of microbial life.
Validation/verification: establishing documented evidence that provides a high degree of
assurance that a specific process will consistently produce a product meeting predetermined
specifications and quality attributes.

Steps of aseptic production

Dosage form selection
There are many different forms into which a medicinal agent may be placed for the convenient
and efficacious treatment of disease. Most commonly, a manufacturer prepare a drug substance
in several dosage forms and strengths for the efficacious and convenient treatment of disease.
In most cases, the prescriber specifies a particular dosage form, such as a topical ointment, oral
solution or rectal suppository. Sometimes, however, the prescriber relies on the pharmacist to
decide on an appropriate form. Irrespective of how the drug order is written, the pharmacist
should evaluate the appropriateness of ingredients and the drug delivery system recommended.
Factors to consider in selecting the dosage form include:
 physical and chemical characteristics of the active ingredient,
 possible routes of administration that will produce the desired therapeutic effect (e.g.,
oral or topical),
 patient characteristics (e.g., age, level of consciousness, ability to swallow a solid dosage
form),
 specific characteristics of the disease being treated,
 comfort for the patient, and
 Ease or convenience of administration.
Client need
 The age of the intended patient also plays a role in dosage form design. For infants and
children younger than 5 years of age, pharmaceutical liquids rather than solid forms are
preferred for oral administration.
 These liquids, which are flavored aqueous solutions, syrups, or suspensions, are usually
administered directly into the infant’s or child’s mouth by drop, spoon, or oral dispenser
or incorporated into the child’s food.
 A single liquid pediatric preparation may be used for infants and children of all ages, with
the dose of the drug varied by the volume administered.
 When a young patient has a productive cough or is vomiting, gagging, or simply
rebellious, there may be some question as to how much of the medicine administered is
actually swallowed and how much is expectorated. In such instances, injections may be
required.
 During childhood and even adulthood, a person may have difficulty swallowing solid
dosage forms, especially uncoated tablets. For this reason, some medications are
formulated as chewable tablets.
 If a person has difficulty swallowing a capsule, the contents may be emptied into a spoon,
 mixed with jam, honey, or other similar food to mask the taste of the medication and
swallowed.
 Medications intended for the elderly are commonly formulated into oral liquids or may
be extemporaneously prepared into an oral liquid by the pharmacist.
 However, certain tablets and capsules that are designed for controlled release should not
be crushed or chewed, because that would interfere with their integrity and intended
performance.
 Dosage forms that allow reduced frequency of administration without sacrifice of
efficiency are particularly advantageous.
Application of the drug
 If the medication is intended for systemic use and oral administration is desired, tablets
and/or capsules are usually prepared because they are easily handled by the patient and
are most convenient in the self-administration of medication.
 If a drug substance has application in an emergency in which the patient may be
comatose or unable to take oral medication, an injectable form of the medication may
also be prepared.
 If a drug substance has application in local hairy area for example scalp lotion is desired
the cream or ointment. Many other examples of therapeutic situations affecting dosage
form design could be cited, including motion sickness, nausea, and vomiting, for which
skin patches, suppositories or injections are used for treatment.
 The formulation that best meets the goals for the product is selected to be its master
formula. Each batch of product subsequently prepared must meet the specifications
established in the master formula.
1.3 Source of information to source formulae for the required product
 Consistency of the compounded product is important. Formulas should be developed or
obtained and tried to assure that each time an extemporaneous product is prepared, the
methods used, ingredients added, and the order of steps is documented.
This accomplishes three things.
First, it provides the methodology for each person involved or requested to provide such service
the information necessary to do so properly.
Second, it provides consistency from batch to batch.
Third, if the product does not turn out the way expected, a stepwise methodology exists for
reviewing and determining what happened and if revisions and improvements are needed.
 When a pharmaceutical product is to be prepared extemporaneously, a reference formula
is usually required.
 These formulae can be found in the pharmaceutical reference sources, such as the
Pharmacopoeia or the Pharmaceutical Codex or developed.
 A reference formula lists the ingredients of the preparation and the quantities of each
ingredient required to make a certain weight or volume of the preparation, depending on
whether the preparation is a solid or a liquid. Frequently, the weight or volume of the
 preparation given in the reference formula will not be the same as that which must be
prepared, in which case the quantities of each ingredient must be increased or reduced.
1.3 consolidates and makes relevant information available and resource
1.3.1. Raw drug materials list
Are all of the ingredients appropriate for the condition being treated?
Are the concentrations of the ingredients in the drug order reasonable?
Selection of ingredients may also depend on the dosage form to be compounded.Care must be
exercised when using commercial drug products as a source of active ingredients. For example,
extended-release or delayed-release products should not be crushed.
1.3.2. Equipment required
The equipment needed to compound a drug product depends upon the particular dosage form
requested. Although boards of pharmacy publish lists of required equipment and accessories,
these lists are not intended to limit the equipment available to pharmacists for compounding.
Equipment should be maintained in good working order. Pharmacists are responsible for
obtaining the required equipment and accessories and ensuring that equipment is properly
maintained and maintenance is documented.
1.3.3. Preparation instructions
Availability of Preparation instructions for batch compounding
It is suitable to the current setting of our lab or compounding facility
Is there any missed instruction
Is there any unclear instruction
1.3.4. Storage and stability data
Are the physical, chemical and therapeutic properties of the individual ingredients consistent
with the expected properties of the ordered drug product?
Stability is the extent to which a product retains within specified limits and throughout its period
of storage and use the same properties and characteristics that it possessed at the time of its
manufacture.
Five types of stability concern pharmacists:
1. Chemical: Each active ingredient retains its chemical integrity and labeled potency within the
specified limits.
2. Physical: The original physical properties, including appearance, palatability, uniformity,
dissolution, and suspend ability are retained.
3. Microbiologic: Sterility or resistance to microbial growth is retained according to the specified
requirements. Antimicrobial agents retain effectiveness within specified limits.
4. Therapeutic: The therapeutic effect remains unchanged.
5. Toxicological: No significant increase in toxicity occurs.
Chemical stability
 is important for selecting storage conditions (temperature, light, humidity), selecting the
proper container for dispensing (glass vs. plastic, clear vs. amber or opaque), and
anticipating interactions when mixing drugs and dosage forms.
 1.3.5. Packaging and label requirements
 The packaging of extemporaneously compounded products for ambulatory patients
should comply with regulations pertaining to the Poison Prevention Packaging Act.
 Containers for compounded products should be appropriate for the dosage form
compounded. For example, to minimize administration errors, oral liquids should never
be packaged in syringes intended to be used for injection.
Packaging is essential to protect the preparation from adverse environmental influences. In daily
practice however the optimum is not always possible. When suboptimal packaging is used the
shelf life is shorter.
The drug product container should not interact physically or chemically with the product so as to
alter the strength, quality, or purity of the compounded product.
In general the following packaging is suitable for dermatological preparations:
Glass or polyethylene bottles for fluids
Polyethylene jars for semisolids (creams, ointments).
Jars made of glass are also suitable containers but are a little more expensive, heavier, and more
fragile. Jars with a wide opening are practical to allow stirring when the preparation has become
inhomogeneous. Such jars are also easily cleaned for reuse. A deposit system can be set up for
return of empty jars and bottles.
Primarily two types of containers are used for packaging:
1. Glass Containers
2. Plastic Containers
 Confirm suitability of chosen formula
Evaluating the Feasibility of Batch Compounding
The following questions may be considered prior to batch compounding activities:
 Will the processes, procedures, compounding environment, and equipment used to
prepare this batch produce the expected qualities in the finished product?
 Will all the critical processes and procedures be carried out as exactly as intended for
every batch of the prepared products to produce the same high-quality product in every
batch
3. Will the finished product have all the qualities as specified, on completion of the
preparation and packaging of each batch?
4. Will each batch retain all the qualities with in the specified limits until the end of the
labeled beyond-used date!
5. Can I monitored trace the history of each batch, identify potential sources of problems
and institute appropriate corrective measures to minimize with the likelihood of their
occurrence?

Unit two Designing master batch/work sheet and labels

 2.1 Characteristics of master batch/work

 Master production forms need to be developed for each preparation that will be made.
 The forms should be fairly detailed, and Contain all required information, clearly written
in logical order and no contain ambiguous directions, always adjusted to the specific local
situation, taking into account the usual batch size, preparation method, available
apparatus, etc.
 For each stock preparation a batch production form needs to be filled in and kept in file.
A practical method is to make a print or copy of the master production form prior to
starting the manufacturing of a new batch.
 All production details for that specific batch are written down on the form and checked
before releasing the batch for stock or dispensing.
 The master production forms also provide models of labels for stock storage, as well as
models of labels for the patient. Preparations that are directly dispensed to the patient on
doctor’s prescriptions also require recording and filing.
 All production details for that specific preparation are written down on the form and
checked before releasing and dispensing.
2.2 Using template
Below is an example of how to complete the Compounding template for a product, Resorcinol
and Sulphur Ointment Compound that you have been asked to prepare.

Name of product: Resorcinol and Sulphur Ointment Compound

Date prepared: 10 September 2011E.C

Source of Formula: NF 17th edition

Prescription Number: 692462

Product Expiry Date: 19 April 2009

Ingredient Quantity Quantity Student Pharmacist Batch Expiry

in used To sign to sign Number date
formula when when
measured checked
or
weighed
Resorcinol 2 4grams SI26RA 9/2018
SulphurPrecip 3 6grams AJ30947 9/2018
.
 Salicylic Acid 1 2grams FHF278DG6 10/2018
White Simple 94 188grams FHF7828364 9/2018
Ointment R

2.2 Using existing institutional format

Product name: Calamine lotion Batch quantity:1000mlMaster manufacturing formula

Approved by:------------------.
Prepared by: .......................... Source master manufacturing:..............
Preparation date: ................... formula: ------------------------
Batch number: ------------------
Example 1
The preparation of Calamine and Coal Tar Ointment BP
You receive a prescription in your pharmacy with the following details:
Patient: Mr Abush Dina
Age:48
Prescription: Calamine and Coal Tar Ointment BP
Directions: Apply once daily
Mitte:20g
Product formula
(From the British Pharmacopoeia2004, p 2233):
Master 100 g 10 g 30 g
Calamine BP 125 g 12.5 g 1.25 g 3.75 g

Strong Coal Tar Solution BP 25 g 2.5 g 0.25 g

0.75g
Zinc Oxide BP 125 g 12.5g 1.25g ?
Hydrous Wool Fat BP 250 g ? ? ?
White Soft Paraffin BP 475 g ? 4.75 g 14.25 g

Method of preparation
The following method would be used to prepare 30 g of Calamine and Coal Tar Ointment BP
from the formula above:
Noting that the melting points of the ingredients are as follows:
Hydrous Wool Fat BP: 38–44°C (British Pharmacopoeia 1988, p 602). White/Yellow Soft
Paraffin BP: 38–56°C (British Pharmacopoeia1988, p 416).
1. Weigh 3.75 g Calamine BP on a Class II or electronic balance.
2. Weigh 3.75 g Zinc Oxide BP on a Class II or electronic balance.
3. Transfer the Calamine BP and the Zinc Oxide BP to a porcelain mortar and triturate together
with a pestle.
4. Weigh 14.25 g White Soft Paraffin BP on a Class II or electronic balance.
5. Weigh 7.5 g Hydrous Wool Fat BP on a Class II or electronic balance.
6. Place the White Soft Paraffin BP into an evaporating dish and melt over a water bath.
7. Remove from the heat and add the Hydrous Wool Fat BP. Stir until melted to ensure an even
well-mixed base.
8. Transfer the powders to a glass tile and levigate with some of the molten base.
9. Transfer the powder/base mix to the rest of the molten base and stir until homogeneous.
10. Weigh 0.75 g Strong Coal Tar Solution BP on a Class II or electronic balance.
11. Allow the base/powder mixture to cool and add the Strong Coal Tar Solution BP and stir
until homogeneous.
12. Weigh 20 g of the product and pack into a collapsible tube or amber glass jar.
5. Choice of container
A collapsible tube or plain amber jar would be most suitable.
6. Labelling considerations
a. Title
The product is official therefore the following title would be suitable: ‘Calamine and Coal Tar
Ointment BP’.
b. Quantitative particulars
Quantitative particulars are not required as the product is official.
c. Product-specific cautions (or additional labelling requirements) ‘For external use only’ will
need to be added to the label as the product is an ointment for external use. In addition, the
product contains coal tar and so the following warning should be added to the label: ‘Caution:
may stain hair, skin and fabrics’.
d. Directions to patient – interpretation of Latin abbreviations where necessary
‘Apply ONCE or TWICE a day.’
e. Recommended British National Formulary cautions when suitable
Not applicable.
f. Discard date
The product is an ointment and so will attract a 3-month discard date.
g. Sample label (you can assume that the name and address of the pharmacy and the words ‘Keep
out of the reach of children’ are pre-printed on the label):
Use and contents of Master production instructions
 To ensure uniformity from batch to batch, master production instructions for each
intermediate or API/ finished product should be prepared, dated, and signed by one
person and independently checked, dated, and signed by a second person in the quality
unit(s).
 Competent persons experienced in production and quality control should be responsible
for the content and distribution within the firm of instructions and master formulae.
Master production instructions should include:
  The name of the intermediate/API/formulation being manufactured and an identifying
document reference code, if applicable
 A complete list of raw materials and intermediates (designated by names or codes
sufficiently specific to identify any special quality characteristics)
 An accurate statement of the quantity or ratio of each raw material or intermediate to
be used, including the unit of measure. Where the quantity is not fixed, the calculation for
each batch size or rate of production should be included. Variations to quantities should
be included wherever justified
 The production location and major production equipment to be used
 Detailed production instructions, including the:
 Sequences to be followed
 Ranges of process parameters to be used
 The methods, or reference to the methods, to be used for preparing the critical
equipment (e.g. cleaning, assembling)
 Sampling instructions and in-process controls, with their acceptance criteria,
where appropriate
 Time limits for completion of individual processing steps and/or the total process,
where appropriate
 Expected yield ranges at appropriate phases of processing or time.
 Where appropriate, special notations and precautions to be followed, or cross-references
to these
 Instructions for storage of the intermediate or API/ semi-finished formulations to assure
its suitability for use; instructions should cover the labeling (specimen labels and
packaging materials and special storage conditions with time limits, where appropriate).
 Master label

Labeling should be done according to state and federal regulations. Usually, labeling information
includes the following:
 generic or chemical names of the active ingredients,
 strength or quantity,
 pharmacy lot number,
 beyond-use date, and
 Any special storage requirements.
 When a commercial drug product has been used as a source of the drug, the generic
name of the drug product, not the proprietary name, should be placed on the label.
Inactive ingredients and vehicles should also be listed on the label. If no expiration date is
provided on the chemicals or materials that are used, a system of monitoring should be
established (e.g., placing the date of receipt of the materials on the label of the container,
or whatever the state board of pharmacy requires).
  Monitoring expiration dates will ensure that materials, ingredients, and supplies are
rotated so that the oldest stock is used first. The use of specially coined names or short
names for convenience should be discouraged.Such names can cause difficulty in
emergency departments if an overdose or accidental poisoning has occurred or if health
professionals treating the patient need to know what the patient has been taking.
 If batch quantities of a preparation are compounded, a lot number should be assigned and
placed on the labels. Surplus prepared labels should be destroyed.
 If excess preparation is compounded or additional quantities are prepared in anticipation
of future requests for the preparation, the pharmacist should have written procedures for
the proper labeling of the excess preparation.
Labeling should include the;
 complete list of ingredients,
 preparation date,
 assigned beyond-use date,
 appropriate testing/published data, and
 control numbers
 The preparation should then be entered into the inventory and stored appropriately to help
ensure its strength, quality, and purity.
 When the compounding process is completed, the excess preparation should be re-
examined for correct labeling and contents.
Recommendations for labeling of Compounded preparations
 The International Academy of Compounding Pharmacists (IACP) has developed
recommendations for labeling preparations compounded in response to a prescription for
a specific patient. The primary label of each compounded medication should include a
statement notifying the patient that the medication has been compounded.
 All important statement should be prominently displayed in the medication labeling.
IACP recommends the following statement: “This medicine was specially compounded
in our pharmacy for you at the direction of your prescriber.” Alternative language that
clearly states that the medication has been compounded may be used.
The aim of labeling is to ensure:
 The That the medication is administered properly and
 That the prescriber and the patient are aware that the medication has been compounded:
“This medicine was compounded in our pharmacy for use by a licensed professional
only.”
The regulatory that require the following pieces of information on all prescription labels:
 patient’s name, prescriber’s name
 name, address, and phone number of the pharmacy preparing the medicine,
 Prescription number,
 medication’s established or distinct common name,
 strength, directions for use
 date prescription is filled,
 expiration/beyond-use date,
 storage instructions, and
 any other state labeling requirements

Pharmacopeia specification of Labels

1. All finished drug products should be identified by labeling, as required by the national
legislation, bearing at least the following information:
2(a) The name of the drug product;
2(b) a list of the active ingredients (if applicable, with the International Nonproprietary
Names), showing the amount of each present, and a statement of the net contents, e.g.
number of dosage units, weight or volume;
3(c) The batch number assigned by the manufacturer;
4(d) The expiry date in an encoded form
5(e) Any special storage conditions or handling precautions that may be necessary;
6(f) Directions for use, and warnings and precautions that may be necessary; and
7.(g) The name and address of the manufacturer or the company or the person responsible for
placing the product on the market.

2.3 Be within legislative requirements

  Each compounded product should be appropriately labeled according to state and
federal regulations.
 Labels should include the generic or chemical name of active ingredients,
strength or quantity, pharmacy lot number, beyond-use date, and any special
storage requirements.
 If a commercial product has been used as a source of drug, the generic name of
the product should be used on the label.
 In expressing salt forms of chemicals on a label, it is permissible to use atomic
abbreviations. For example, HCl may be used for hydrochloride, HBr for
hydrobromide, Na for sodium, and K for potassium.
 Vehicles should also be stated on labels, especially if similar products are
prepared with different vehicles. For example, if a pharmacist prepares two
potassium syrups, one using Syrup, USP, as the vehicle and one using a sugar-free
syrup as the vehicle, the name of the vehicle should be included on the labels.
 Liquids and semisolid concentrations may be expressed in terms of percentages.
When the term “percent” or the symbol “%” is used without qualification for
solids and semisolids, percent refers to weight in weight; for solutions or
suspensions, percent refers to weight in volume; for solutions of liquids in liquids,
percent refers to volume in volume.
 Labels for compounded products that are prepared in batches should include a
pharmacy-assigned lot number.
When dispensing a preparation the following information needs to be written on the label:
 name of the patient
 “for external use only”
 name of the preparation
 dose and instructions for use (including: to be stirred, shaken), pictograms can be useful
for patients who cannot read
 dispensing date
 expiry date (“do not use past dd/mm/yyyy”)
 Warnings in case of toxic or hazardous preparations
2.4 Creating batch record sheet
Documentation, written or electronic, enables a compounder, whenever necessary, to
systematically trace, evaluate, and replicate the steps included throughout the preparation process
of a compounded preparation.
Each step of the compounding process should be documented. Pharmacists should maintain at
least four sets of records in the compounding area:
 Compounding formulas and procedures,
 A log of all compounded items, including batch records and sample batch labels
 Equipment-maintenance records, including documentation of checks of balances,
 refrigerators, and freezers, and
 A record of ingredients purchased, including certificates of purity for chemicals
Compounding procedures should be documented in enough detail that preparations can be
replicated and the history of each ingredient can be traced. Documentation should include a
record of who prepared the product (if the compounder is not a pharmacist, the supervising
pharmacist should also sign the compounding record)
Master Formulation Record
This record shall include:
 official or assigned name, strength, and dosage form of the preparation
 calculations needed to determine and verify quantities of components and doses of active
pharmaceutical ingredients
 description of all ingredients and their quantities
 compatibility and stability information, including references when available
 equipment needed to prepare the preparation, when appropriate
 mixing instructions that should include:
 order of mixing
 mixing temperatures or other environmental controls
 duration of mixing
 other factors pertinent to the replication of the preparation as compounded
 sample labeling information, which shall contain, in addition to legally required
information:
 generic name and quantity or concentration of each active ingredient
 assigned BUD
 storage conditions
 prescription or control number, whichever is applicable
 container used in dispensing
 packaging and storage requirements
 description of final preparation
 quality control procedures and expected results
Compounding Record
The Compounding Record shall contain:
 official or assigned name, strength, and dosage of the preparation
 Master Formulation Record reference for the preparation
 names and quantities of all components
 sources, lot numbers, and expiration dates of components
 total quantity compounded
 name of the person who prepared the preparation,
 name of the person who performed the quality control procedures, and
 name of the compounder who approved the preparation
  date of preparation
 assigned control or prescription number
 assigned BUD
 duplicate label as described in the Master Formulation Record
 total quantities of product to be released for use
 description of final preparation
 results of quality control procedures (e.g., weight range of filled capsules, pH of aqueous
liquids)
 Equipment maintenance and calibrations should be documented and the record
maintained in an equipment-maintenance record file. Refrigerator and freezer
thermometers should be checked and documented routinely, as should alarm systems
indicating that temperatures are outside of acceptable limits
Unit three
Seeking approval and release of batch/work sheets for use

Introduction
 A system of approval and release that gives the assurance that the product is of the
intended quality based on information collected during the manufacturing process and on
the compliance with specific GMP requirements related to Parametric Release
 Written procedures should be established and followed for the review and approval of
batch production and laboratory control records, including packaging and labeling, to
determine compliance of the intermediate or API with established specifications before a
batch is released or distributed.
 Batch production and laboratory control records of critical process steps should be
reviewed and approved by the quality unit(s) before an API batch is released or
distributed.
 Production and laboratory control records of non-critical process steps can be reviewed
by qualified production personnel or other units, following procedures approved by the
quality unit(s).
 All deviation identified and investigation of the causes should be reviewed as part of the
batch record review before the batch is released.
 The quality unit(s) can delegate to the production unit the responsibility and authority for
release of intermediates, except for those shipped outside the control of the
manufacturing company.
 Distribution record should be maintained and must include the batch number; quantity
produced; name, address, and contact details of customer; quantity supplied; and date of
supply.
 Good records enable one to track all activities performed during batch manufacture, from
the receipt of raw materials to the final product release; they provide a history of the
 batch and its distribution.
Seeking approval and release of batch/work sheets for use
 Finally when we are prepare the appropriate master work sheet and label for the
batch, presented it to the pharmacist for approval.
 After the pharmacist approve the master work sheet and label we should
documented properly and use it .
Unit four
Preparing for production process
.

4.1 Methods of small-scale compounding

Trituration:
 The trituration process involves direct rubbing or grinding of hard powder in a mortar
with pestle.
 The trituration method is used for both pulverization (size reduction) and mixing of two
powders.
 When grinding a drug (triturating) in a mortar to reduce its particle size is termed
comminution.
 Mortars and pestles are available in three types: glass, Wedgwood, and
porcelain, which is quite similar to Wedgwood in use and appearance
 A Wedge-wood/porcelain mortar is used for pulverization and grinding because of its
rough inner surface. Wedgwood and porcelain mortars and pestles are coarser and best
used when triturating crystals, granules, and powders. They will produce a finer
trituration.
 A glass mortar is used for simple mixing and for mixing of colored materials and dyes.
Glass mortars are preferred for mixing liquids and semisoft dosage forms. Advantages of
glass mortars and pestles are that they are nonporous/no void space within powders/ and
non-staining.
Aggregation: collecting units into a mass.
Dissolution:
 Add the solute into the solvent.
 When a drug is administered orally via tablet, capsule, or suspension, the rate of
absorption often is dictated by the ability of drug particles to dissolve in the surrounding
fluid at the absorption site.
 If the drug particles dissolve slowly, it may take a longer time for the drug to reach the
general circulation and elicit its effects.
 In emergency conditions or when a patient unable to take through oral route of
administration; drugs may be needed to be mixed and dissolved, in aseptic method, and
 administered through parenteral routes of administration to have adequate bioavailability
and fast on set of action. In such cases mixing and dissolving drugs in appropriate
media/solvent/ in correct procedure is crucial activity of the pharmacy personnel.
Mixing:

When two or more powdered substances are to be combined to form a uniform mixture, it is best
to reduce the particle size of each powder individually before weighing and blending.
Depending on the:
 nature of the ingredients, the amount of powder, and the equipment,
powders may be blended by spatulation, trituration, sifting, and tumbling.
Spatulation
is blending small amounts of powders by movement of a spatula through them on a sheet of
paper or an ointment tile. It is not suitable for large quantities of powders or for powders
containing potent substances, because homogeneous blending is not as certain as other methods.
Factors affecting mixing
 Particle size
 Particle shape
 Particle attraction increase surface area

Sifting
 The sifting method is helpful for powders that resist mixing by trituration. Very light
powders, suchas magnesium oxide and charcoal, can be completely mixed by shaking
them through a sieve.
 Standard size prescription sieves are available, but an ordinary house hold flour sifter can
be used effectively for thispurpose.
 This process allows the removal of any large foreign bodies and agglomerates from the
powdermix.
Tumbling
 Tumbling is a process of mixing powders by shaking or rotating them in a closed
container.
 This methodis used when two or more powders have considerable density differences.
This mode of mixing does not yield particle size reduction and compaction.
 The powder mixture should flow freely in the air and avoid sliding the powder through
the side of the container.
 Homogeneity in large-scale mixing is achieved through the use of an appropriate mixer,
which ensures the correct speed and sufficient time for mixing.
 Homogenous mixing is ascertained in a mixture when the concentration of each
component in any region of the mixture is identical.
 
4.2 GMP(Good manufacturing practice)Requirements for Sterile Products
 Good manufacturing practice (GMP) comprises that part of quality assurance that is
aimed at ensuring the product is consistently manufactured to a quality appropriate for its
intended use.
GMP requires that:
(i) The manufacturing process is fully defined before it is commenced.
(ii) The necessary facilities are provided. In practice, this means that:
• Personnel must be adequately trained
• Suitable premises and equipment employed
• Correct materials used
• Approved procedures adopted
• Suitable storage and transport facilities available
Appropriate records made.
GMP Requirements for Sterile Products
GMP-is a system for ensuring that products are consistently produced according to quality
standards.
Premises
 Design
 Avoid unnecessary entry of supervisors and control personnel ,Operations
observed from outside
 In clean areas, all exposed surfaces should be:-
 Smooth, impervious, unbroken
 Minimize shedding and accumulation of particles, microorganisms
 Permit cleaning and disinfection
 No unclean able recesses, ledges, shelves, cupboards, equipment
 Sliding doors undesirable

Equipment
There should be:
 Conveyer belts
 Effective sterilization of equipment
 Maintenance and repairs from outside the clean area
 If taken apart, resterilize before use
 Planned maintenance, validation and monitoring of:
 Equipment, air filtration systems, sterilizers, water treatment systems

Risk of Contamination
  A pharmaceutical product may become contaminated by a number of means and at
several points during manufacture.

 Everything that can come into contact with the product is a potential risk causing
contamination
 active ingredients and excipients
 process water
 primary and secondary packaging material
 rooms, technical installations
 air, personnel
Minimizing risks of contamination
Environmental Monitoring
Microbiological Monitoring by
 Air samples
 Surface swabs
 Personnel swabs
Physical
 Particulate matter
 Differential pressures
 Air changes, airflow patterns
 Clean-up time/recovery
 Filter integrity
 Temperature and relative humidity
 Airflow velocity
Sanitation
 Frequent, thorough cleaning of areas necessary
 Written programme
 Chemical disinfection
 Dilutions
 Clean containers, stored for defined periods of time
 Sterilized before use, when used in Grade A or B area

Risk can be minimized by.

Microbiological

 Microbiological contamination is a critical point in aseptic manufacturing procedures.

 Microorganisms in the air are generally, in combination with particles, but there is no
correlation between the count of particles in the air and the microbiological
contamination, because the microbiological contamination of particles is quite different).
 Therefore, the bacteria count in the air has to be performed by microbiological tests.
Particulate Matter
 Particles are significant because they may enter a product and contaminate it physically
or, by acting as vehicle for microorganisms, biologically.
 Parenteral solutions must be free of particulate matter – mobile, undissolved solids not
intended for sterile preparations.
Examples include , cellulose and cotton fibers, glass, rubber, metals, plastics, undissolved
chemicals.
 Sources of particulate matter are:
 Vehicles and solutions
 Environment
 Containers and closures
 Personnel
 A careful choice of components, containers, and closures can minimize particulate
contamination. Also, filtration can remove particles and bacteria from sterile
preparations.
 To keep unwanted particles out of parenteral products, a number of precautions must be
taken during
- manufacture
- storage,
-use of the products.
During manufacture,
 the parenteral solution is usually filtered just before it goes into the container.
 The containers are carefully selected to be chemically resistant to the solution and of the
highest available quality to minimize the chances of container components leaching into
the solution.
During container filling,
 extreme care must be exercised to prevent the entrance of airborne dust, lint, or other
contaminants.
 Filtered and directed airflow in production areas reduces the likelihood of contamination.
Pyrogen

 Pyrogens are fever-producing endotoxins from bacteria. As large proteins, pyrogens are
not removed by normal sterilization procedures and can exist for years in aqueous
solution or dried form.
 The sources of pyrogens in sterile preparations are:
 Aqueous vehicles
 Equipment
 Containers and closures
  Chemicals used as solutes
 Human touch
 If sterile water for injection is the vehicle, the risk of pyrogens in water is eliminated
 Equipment, containers, and closures can be decontaminated by dry heat or by
washing or soaking with acids and bases.
 Manufacturers of water for injection may employ any suitable method for removal of
pyrogens from their product. Because pyrogens are organic, one of the more common
means of removing them is by oxidizing them to easily eliminated gases or to nonvolatile
solids, both of which are easily separated from water by fractional distillation.

Production in clean areas

 Clean area: An area maintained and controlled to prevent contamination of pharmaceutical
products with microorganisms or foreign substances, in compliance with defined particle
and microbiological cleanliness standards. For the purposes of this document, this term is
synonymous with manufacturing area for aseptic products.
 Cleaning and Disinfection of Processing Areas for Sterile Pharmaceutical Products should
be cleaned and disinfected in accordance with relevant SOPs and results of cleaning and
disinfection should be recorded in writing and retained in an archive.
Cleaning Agents and Disinfectants
 Cleaning agents and disinfectants should be validated for their appropriateness and reliability
in removing contaminants prior to use.
 Cleaning and disinfection efficacy should be assessed and confirmed based on type and count
of microorganisms characterized by periodic environmental monitoring.
 Cleaning agents and disinfectants should be pretreated with filtration or other appropriate
sterilization procedures before use and controlled for the prevention of microbacterial
contamination until use, unless commercial products certified to be sterile are used by
breaking the envelope immediately before use. .
 When cleaned or disinfected, the surfaces of facilities and equipment that may come into
direct contact with pharmaceutical products should be verified by appropriate methods to be
free of cleaning agents or disinfectants after the completion of cleaning or disinfection
procedures.
 Reasonable expiration date should be established for individual disinfectants, and
disinfectants should be used before that date.
 The disinfection of the manufacturing environment should not proceed prior to cleaning, as a
rule. If there are any locations in the environment where cleaning agents may reside after
cleaning, the cleaning agents should be verified not to impair the efficiency of disinfectants.
 The selection and use of disinfectants should take the following matters into account:
 The storage and usage of disinfectants should be in accordance with the supplier’s
instructions.
  The selection of disinfectants should be primarily based on the safety of personnel who
are engaged in disinfection processing.
 If environmental monitoring data indicate or suggest the presence of spore -forming
bacteria or fungi, suitable sporicides or fungicides should be selected for disinfection.
 Chemical properties (e.g. corrosivity) which might damage the surface of facilities and
equipment to be treated should be assessed prior to the selection of cleaning agents and
disinfectants.
 If use of sporicides or fungicides in processing areas for sterile pharmaceutical products
is likely or probable, the type, concentrations, and usage of the agents should be
predetermined and specified in writing.
 Cleaning agents, disinfectants, and utensils for applying these agents should not be
stored in critical areas. Materials needed for operations in the critical area such as
hand sprays to disinfect gloves may be stored in critical areas.
Following correct dress code
Personal protective equipment, or PPE, as defined by the Occupational Safety and Health
Administration, or OSHA, is “specialized clothing or equipment, worn by an employee for
protection against infectious materials.”
Types of PPE Used in compounding area
 Gloves – protect hands
 Gowns/aprons – protect skin and/or clothing
 Masks and respirators– protect mouth/nose
 Respirators – protect respiratory tract from airborne infectious agents
 Goggles – protect eyes
Face Protection
 Masks – protect nose and mouth
 Should fully cover nose and mouth and prevent fluid penetration
 Goggles – protect eyes
 Should fit snuggly over and around eyes
 Personal glasses not a substitute for goggles
 Anti-fog feature improves clarity
Grade D:
 Hair, arms and, where relevant, beard and moustache should be covered.
 A general protective suit and appropriate shoes or overshoes should be worn.
 Appropriate measures should be taken to avoid any contamination coming from outside
the clean area.
Grade C
 Hair, arms and, where relevant, beard and moustache should be covered. A single or two
piece trouser suit, gathered at the wrists and with high neck and appropriate shoes or
overshoes should be worn.
  They should shed virtually no particulate matter.
Grade A and B
 Headgear should totally enclose hair and, where relevant, beard and moustache; it should
be tucked into the neck of the suit; a face-mask should be worn to prevent the shedding of
droplets.
 Appropriate sterilized, non-powdered rubber or plastic gloves and sterilized or
disinfected footwear should be worn.
 Trouser-bottoms should be tucked inside the footwear and garment sleeves into the
gloves. The protective clothing should shed virtually no fibres or particulate matter and
retain particles shed by the body.
 Outdoor clothing should not be brought into changing rooms leading to grade B and C
areas.
 Gloves should be regularly disinfected during operations. Masks and gloves should be
changed at least at every working session.
 It is important to visually check that garments are in good condition and that the seams
are sealed.
 Periodic monitoring of people, clothing and hand, for particles should be considered .
 The justification for the frequency of these periodic tests should be documented.
 The frequency of laundering should be appropriate to the activity undertaken and the use
of biocidal washes or gamma irradiation should be used for grade C and B areas.

Unit five cytotoxic drugs

Learning Outcome
 Upon completion of the Chapter students should be able to define cytotoxic drugs
and list the risk of cytotoxic drugs.
Learning Objectives
At end of the Chapter , student you will be able to:
 Define and describe the various category cytotoxic drugs.
 Discus on preparation of cytotoxic drugs and their transportation and storage
 Discus on package of cytotoxic drugs
Introduction:
Life cycle of a Human cell
All living tissue is made up of cells. Cells grow and reproduce to replace cells lost through injury
or normal “wear and tear.” The cell cycle is the normal life cycle of a cell. It’s a series of steps
that both normal cells and cancer cells go through in order to form new cells.
The cell cycle has 5 phases. Since cell reproduction happens over and over, the cell cycle is
shown as a circle. All the phases lead back to the resting phase (G0), which is the starting point.
  G0 phase (resting stage): The cell has not yet started to divide. Cells spend much of
their lives in this phase. Depending on the type of cell, G0 can last from a few hours to a
few years. When the cell gets a signal to reproduce, it moves into the G1 phase.
 G1 phase: The cell starts making more proteins and growing larger, so the new cells will
be of normal size. This phase lasts about 18 to 30 hours.
 S phase: The chromosomes containing the genetic code (DNA) are copied so that both of
the new cells formed will have matching strands of DNA. This lasts about 18 to 20 hours.
 G2 phase: The cell checks the DNA and gets ready to start splitting into 2 cells. This
phase lasts from 2 to 10 hours.
 M phase (mitosis): The cell actually splits into 2 new cells. This lasts only 30 to 60min.
When a cell goes through the cell cycle, it reproduces 2 new identical cells. Each of the 2 cells
obtain from the first cell can go through this cell cycle again when new cells are needed.
The understanding of cell cycle is important because many chemotherapy drugs affect only on
cells that are actively reproducing (not cells that are in the resting phase, G0). Some drugs
specifically attack cells in a particular phase of the cell cycle (eg. the M or S phases).
Chemotherapy drugs can’t tell the difference between reproducing cells of normal tissues (like
those that are replacing worn-out normal cells) and cancer cells. This means normal cells are
damaged along with the cancer cells, and this causes side effects. Each time chemotherapy is
given, it involves trying to find a balance between destroying the cancer cells (in order to cure or
control the disease) and sparing the normal cells (to lessen unwanted side effects).
According to the World Health Organization (WHO), between now and 2030 the cancer rate is
going to increase by 50% to about 13 million new cases a year, worldwide. The predicted
increase in new cases will mainly be due to the existence of a steadily aging population in both
developed and developing countries, but also to the current prevalence of smoking and the rise in
numbers of those adopting unhealthy lifestyles. One of the most frequently used treatments for
cancer is chemotherapy.
Chemotherapy treatments are utilized in suppressing and/or inhibiting cell growth and division.
It is used as an adjuvant to surgery, and/or treatment of metastatic cells. Unfortunately, it is well
known that cytostatic agents are potentially hazardous for the manipulator (pharmacist, assistant,
nurse, surgeon, pharmacy technicians, etc)
Cytostatic are known to be:
  Mutagenic - induce or increase genetic mutations by causing changes in DNA.
 Carcinogenic - cancer-causing in animal models, in patient population, or both.
 Teratogenic - causing fertility impairment in animal studies or treated patients
5.1 Basic pharmacology of Cytotoxic drugs
WHAT ARE CYTOTOXIC DRUGS?
 These drugs are known to be highly toxic to cells, mainly through their action on cell
reproduction. Many have proved to be carcinogens, mutagens or teratogens.
 Cytotoxic drugs are increasingly being used in a variety of healthcare settings,
laboratories and veterinary clinics for the treatment of cancer and other medical
conditions such as rheumatoid arthritis, multiple sclerosis and auto-immune disorders.
CLASSES OF CYTOTOXIC DRUGS
Traditional antineoplastic drugs, which still constitute most of the anticancer drugs used today,
generally target either the DNA inside the nucleus of a cell directly, inhibit the synthesis of new
DNA strands, or stop the mitotic processes of a cell. In the first case, the objective is to cause
physical changes in the DNA itself, resulting in mutations of the DNA attempting to replicate. In
the second case, these agents usually stop the synthesis of DNA by stopping the synthesis of the
necessary building blocks of DNA. In the third case, the objective is to stop cell replication in
one of the stages of mitosis, often by inhibiting synthesis or breakdown of the cellular structure.
Cytotoxic agents which directly attack DNA in the nucleus:
 Alkylating agents:
These agents directly alkylate or covalently modify the nitrogenous bases of DNA molecules.
This can result in mispairing of bases, or loss of bases, or actual splitting of the DNA backbone.
Examples: Altrtamine (Hexalen), Busulfan (Myleran), Carboplatin (Paraplatin), Chlorambucil
(Leukeran), Cisplatin (Platinol), Cyclophosphamide, Dacarbazine (DTIC), Ifosfamide (Ifex),
Oxiliplatin (Eloxatin), Procarbazene (Matulane),Telomozomide (Temodar)
 Intercalating agents:
These agents bind tightly to the DNA double helix, preventing the unwinding of the double helix
at that point.
Examples: Dactinomycin (Cosmegen), Daunorubicin (Cerubidine), Doxorubicin (Adriamycin) ,
Plicamycin (Mithramycin)

 DNA Topoisomerase inhibitors:

By inhibiting this enzyme involved in supercoiling, these agents somehow cause the actual
scission or breakage of DNA strands in the nucleus. Example: Etoposide (VePesid, VP-16)
Antineoplastic agents which stop the synthesis of DNA precursors:
 Folic Acid antagonists:
These agents stop the formation of tetrahydrofolate, which is necessary for the synthesis of both
purines and pyrimidines. Example: Methotrexate (MTX)
 Purine antagonists:
These agents are competitive inhibitors of enzymes in the purine nucleotide synthetic pathways.
Examples: Mercaptopurine (Purinethol), Thioguanine (Tabloid)
 Pyrimidine antagonists:
These agents are competitive inhibitors of enzymes in the pyrimidine nucleotide synthetic
pathways. Examples: Floxuridine (FUDR), Fluorouracil (5-FU), Cytarabine (Cytosar, ARA-C)
 Ribonucleotide diphosphate reductase inhibitors:
These agents will effectively interfere with DNA construction. These agents damage cells during
S phase. Example: Hydroxyurea (Hydrea)

5.2 POTENTIAL HEALTH EFFECTS OF CYTOTOXIC DRUGS

 Current statistics show that one in three people have a life-long risk of developing cancer.
There is little scientific evidence currently available relating to whether working with
cytotoxic drugs actually increases the risk of developing cancer or not. However, in the
absence of such data, a strategy of prudent avoidance is recommended. In the workplace,
occupational exposure may occur where control measures fail or are not in place.
 Exposure may be through skin contact, skin absorption, inhalation of aerosols and drug
particles, ingestion and needle stick injuries resulting from the following activities:
 drug preparation
 drug administration
 handling patient waste
 Transport and waste disposal, or spills.
Personnel likely to be involved in these activities include:
 nurses and medical officer s
 pharmacists
 laboratory staff, and
 Cleaning, maintenance and waste disposal staff.
 Where control measures are not adequate, adverse health effects may result from
occupational exposure. Health effects attributed to cytotoxic drugs exposure amongst people
preparing and administering cytotoxic drugs include:
 abnormal formation of cells and mutagenic activity
 alterations to normal blood cell count
 fetal loss in pregnant women and malformations in the offspring of pregnant women
 abdominal pain, hair loss, nasal sores and vomiting
 liver damage, and contact dermatitis, local toxic or allergic reaction, which may result
from direct contact with skin or mucous membranes.
RISK CONTROL
 The greatest risk of occupational exposure to cytotoxic drugs is during drug manufacture
 and preparation, because of the concentrations and quantities used. The first priority in
protecting the health of employees is to eliminate or reduce the risks to health so far as is
practicable. This may be implemented through:
 establishment of written policies and protocols to ensure the safe handling of cytotoxic
drugs.
 effective planning and design of the workplace.
 use of best practice control measures and specialized equipment such as
 Cytotoxic drug safety cabinets.
 The implementation of stringent handling procedures.
 Training and education of employees.
 Wearing personal protective equipment.

5.3 PREPARING CYTOTOXIC DRUGS

 Specific handling techniques and procedures incorporating suitable equipment (designed to
reduce the risk of exposure) should be employed, including:
Drug preparation equipment
 Equipment used for preparing drugs should incorporate a closed system, where possible, and
also reduce the potential for generating high pressure. Specific methods of control include:
 Use of Luer-lock syringes and fittings to keep connections together
 Use of Luer-slip syringes (only if Luer-lock connections are incompatible) such as
intrathecal needles.
 use of syringe-to-syringe connectors when transferring solutions from one syringe to
another
 use of wide bore needles to reconstitute and draw-up cytotoxic drugs
 use of filter needles only when the cytotoxic drug has been removed from a glass
ampoule, or if particulate matter is visible, for example if coring of a vial rubber has
occurred
 Use of air-venting devices to equalize pressures. Why?
to prevent the passage of powder, aerosols and liquids.
STANDARD OPERATING PROCEDURES FOR PREPARING CYTOTOXIC DRUGS
 Standard operating procedures for parenteral preparations should be documented, and stress
the need to:
 Avoid using cytotoxic drugs supplied in glass ampoules. If glass ampoules must be
used, open with an ampoule breaker or a low-lining swab.
 Use techniques that avoid the generation of pressure differentials.
 Tablets, capsules and topical creams should be prepared under the same conditions
as parenteral cytotoxic drug preparations. Specific additional standard operating
procedures for non-parenteral preparations. (extemporaneous) include:
  Making mixtures by dispersing tablets in water.
 Not crushing tablets in an open mortar.
 Not counting tablets or capsules by machine.
 Cleaning equipment immediately after use with a strong alkaline deter gent
with p H ≥10.
PACKAGING AND TRANSPORTING CYTOTOXIC DRUGS
 Cytotoxic drugs should be packaged and transported so as to provide adequate physical and
chemical protection for the drug, and protection to handlers in the event of a spill.
Drug packaging
 Cytotoxic drugs should be packaged in a labeled, sealed, leak-proof container, with outer
bags heat-sealed where possible, ensuring the container:
 offers protection from light where required
 protects the drugs from breakage in transit
 contains leakage if breakage occurs.
 Has a childproof lid (if appropriate).
Drug transport
Containers used for transporting prepared cytotoxic drugs should be:
 hard-*-walled and robust
 made from molded foam or other suitable packaging material capable of protecting the
product from a shock equivalent to a drop of one meter onto a concrete surface.
 Securely closed and labeled with cytotoxic warnings.

PERSONAL PROTECTIVE EQUIPMENT

The following personal protective equipment should be provided, in conjunction with other
control measures, to personnel who prepare cytotoxic drugs:
 cover all or gown
 head covering
 closed footwear and over shoes
 protective gloves long enough to cover the elasticized cuffs of gowns or
 cover alls
 protective eyewear
 Respiratory protective device (where an inhalation risk exists, for example, a large
cytotoxic drug spill).
MAINTAINING CONTROLS
Equipment used to prepare cytotoxic drugs, and air-handling facilities, should be maintained
under a planned maintenance schedule. Performance testing and inspection of facilities and
equipment
 Cytotoxic laminar-flow drug safety cabinets and secondary and tertiary barriers should be
assessed and certified by a suitably qualified person,
 An effective equipment maintenance schedule should incorporate the following:
 inspection of cytotoxic drug safety cabinets, isolators and High Efficiency Particulate
Air (HEPA) filters
- At regular intervals (a minimum of every 12 months)
- After relocation or mechanical/electrical maintenance
 keeping test records and a summary of results in a place accessible to employees
 not using a cabinet that has failed, until the fault has been rectified and the cabinet
recertified
 Performing microbial and air-particle testing routinely, and recording the results.
Cleaning drug preparation facilities
 Standard operating procedures should be documented, and stress the need to:
 clean daily
 use a dedicated mop and bucket
 treat all equipment as potentially contaminated
 Provide personal protective equipment.

Unit six

Equipments, Consumables and containers required for manufacturing process

Learning Outcome
 Upon completion of the chapter students should be able to define batch and batch
number and list ophathalmic preparartion
Learning Objectives
At end of the chapter , student you will be able to:
 Define batch ,batch number and describe the various caategory ophathalmic
preparartion.
 Mention pharmaceutical packaging
 Discus methods of disinfection
 Definition of batch number
Batch (or lot)
 A defined quantity of starting material, packaging material, or product processed in a
single process or series of processes so that it is expected to be homogeneous.
 It may sometimes be necessary to divide a batch into a number of sub-batches, which are
later brought together to form a final homogeneous batch. In the case of terminal
sterilization, the batch size determined by the capacity of the autoclave. In continuous
 manufacture, the batch must correspond to a defined fraction of the product ion,
characterized by its intended homogeneity.
 The batch size can be defined either as a fixed quantity or as the amount produced in a
fixed time interval.
Batch number (or lot number)
 A distinctive combination of numbers and/or letters which uniquely identifies a batch on
the labels, its batch records and corresponding certificates of analysis, etc

Small and large volume infusion bags

 There are two types of intravenous administration.
 The first is an intravenous injection
in which the prepared medication is drawn up into a syringe and administered
immediately. The amount of medication is usually a small volume pushed through an IV
line that is already in place on the patient.
 The second type of administration is an IV infusion.
 Infusions are given to overcome dehydration, to build up depleted blood volumes, and
to serve as an aid for the administration of medications.
 Allows a larger volume to be given at a constant rate, depending on the drug to be
administered.
 Can be administered continuously or intermittently. Continuous infusions are used
to administer larger volumes of solutions over several hours at a slow, constant rate.
Intermittent infusions are used to administer a relatively small volume over a shorter time at
specific intervals

IV Bags
 Plastic bags are used for diluting a solution and are the most common way of
administering intravenous medications to patients. Plastic bags are available in many
different sizes, with 50, 100, 250, 500, and 1000 ml being the most common. Special
bags for compounding parenteral nutrition are available in 2,000 ml and 3,000 ml sizes.
 Some IV bags are made of PVC (polyvinyl chloride). But they are more expensive than
plastic bags..
.
 The spike of the administration set is inserted into the port, puncturing the inner
diaphragm to allow the solution to flow from the flexible plastic bag into the
administration set. When the solution has filled the administration set (this process is
called “priming” the set), make sure to clamp the administration set so that the solution
does not leak out. Once the inner diaphragm is punctured, it is not resealable.
 The other port is the medication port. It is covered by a protective rubber tip.
Medication is added to the solution through the medication port by means of a needle and
syringe. The rubber tip is self-sealing, thus preventing solution from leaking when the
 needle punctures the tip. Approximately ½ inch inside this port is a plastic diaphragm
that must be punctured for solution to enter the bag. The inner diaphragm is not self-
sealing when punctured by a needle, so the rubber tip must stay attached to the bag.
 Graduation marks to indicate the volume of solution infused are located on both sides of
the front of some plastic bags at 25-100 ml intervals, depending on their capacity.
 When you place a label on a plastic bag, it does not matter which side of the bag you
place the label; however, many institutions place the label on the printed side of the bag,
beneath the solution name, and offset slightly to one side so that the graduation marks
near the side can still be read. This procedure has the advantage of providing a
convenient cross-check between the actual solution and the name appearing on the
admixture label.
 Some IV solutions, such as 5 percent dextrose injection and 0.9 per cent sodium chloride
injection, are available in minibags, or piggyback bags. These bags typically hold 50 ml
or 100 ml of solution and are used to administer drugs intermittently rather than
continuously.

Ophthalmic Preparations: Types & In-process Controls

 Ophthalmic preparations (eye preparations) are sterile, liquid, semi-solid, or solid
preparations that may contain one or more active pharmaceutical ingredient(s) intended
for application to the conjunctiva, the conjunctival sac or the eyelids.
 The choice of base and any excipients used for the preparation of ophthalmic preparations
must be proven through product development studies not to affect adversely either the
stability of the final product or the availability of the active ingredients at the site of action.
 The addition of coloring agents is not recommended. The different categories of ophthalmic
preparations include drops consisting of emulsions, solutions or suspensions, and
ointments.
Types
 Eye drops
 Eye lotions
  Powders for eye drops and eye lotions
 Semi-solid eye preparations,
 Ophthalmic inserts.
Requirements for specific types of ophthalmic preparations
Ophthalmic drops
 Ophthalmic drops (eye drops) are sterile aqueous or oily solutions, suspensions, or emulsions
intended for instillation into the conjunctiva sac. Ophthalmic drops should be clear and
practically free from particles when examined under suitable conditions of visibility.
 “Water for injections” should be used in the manufacture of aqueous ophthalmic drops. The
preparation of aqueous ophthalmic drops requires careful consideration of the need for
isotonicity, a certain buffering capacity, the desired pH, the addition of
antimicrobial agents and/or antioxidants, the use of viscosity-increasing agents, and the
choice of appropriate packaging.
 Ophthalmic drops are considered isotonic when the tonicity is equal to that of a 0.9%
solution of sodium chloride.
 Ideally, the pH of ophthalmic drops
 Should be equivalent to that of tear fluid, which is however, the decision to add a
buffering agent should be based on stability considerations.
 The pH selected should be the optimum for both stability of the active pharmaceutical
ingredient and physiological tolerance.
 If a buffer system is used, it must not cause precipitation or deterioration of the active
ingredient. The influence on the lachrymal flow should also be taken into account.
Visual inspection
Evidence of physical instability is demonstrated by the cloudiness of aqueous solutions, due to
the formation of a precipitate.
Containers
 Ophthalmic drops are normally supplied in suitable multi dose containers that allow
successive drops of the preparation to be administered.
 The container should be fitted with a tamper-evident device. The maximum volume of
the preparation in such a container should be no more than 10 ml, unless otherwise
specified and authorized.
 Multi dose ophthalmic drop preparations may be used for up to 4 weeks after the
container is initially opened.
 Droppers supplied separately should also comply with the “Test for sterility”
 Ophthalmic drops may also be provided in suitable single-dose containers that will
maintain the sterility of the contents and the applicator up to the time of use.
 It is recommended that single-dose containers for surgical use should not
include any antimicrobial agents.
Ophthalmic emulsions
  Ophthalmic emulsions are generally dispersions of oily droplets in an aqueous phase.
There should be no evidence of breaking or coalescence.
Ophthalmic suspensions
 Ophthalmic suspensions contain solid particles dispersed in a liquid vehicle; they must be
homogeneous when shaken gently and remain sufficiently dispersed to enable the correct
dose to be removed from the container.
Visual inspection
 Evidence of physical instability is demonstrated by the formation of
agglomerates or precipitates in aqueous solutions (suspensions) that do not
disperse when the solution is shaken gently.
Ophthalmic ointments
 Ophthalmic ointments are sterile, homogeneous, semi-solid preparations intended for
application to the conjunctiva or the eyelids.
 They are usually prepared from non-aqueous bases, e.g. soft paraffin (Vaseline),
liquid paraffin, and wool fat.
 They may contain suitable additives, such as antimicrobial agents, antioxidants, and
stabilizing agents.
Organoleptic inspection
 Evidence of physical instability is demonstrated by:
 a noticeable change in consistency, such as excessive “bleeding”
(separation of excessive amounts of liquid) or formation of
agglomerates or grittiness; discoloration; emulsion breakdown; crystal
growth; shrinking due to evaporation of water; or evidence of
microbial growth.
Uniform consistency
 Ophthalmic ointments should be of uniform consistency. When a sample is rubbed on the
back of the hand, no solid components should be noticed.
Containers
 Ophthalmic ointments are normally supplied in small, sterilized, collapsible
tubes fitted with a tamper-evident applicator. The containers or the nozzles of the
tubes are shaped so that the ointment can be applied without contaminating what remains
in the tube.
 The content of such a container is limited to not more than 5g of the preparation. Suitable
single-dose containers may also be used.
 For the formulation of aqueous ophthalmic solutions, many critical factors must be
taken into consideration such as

 Appropriate salt of the drug substance
 Solubility
  Therapeutic concentration required
 Ocular toxicity
 pKa
 Effect of pH on stability and solubility
 Tonicity
 Buffer capacity
 Viscosity
 Compatibility with other formulation ingredients and packaging components
 Choice of preservative
 Ocular comfort
 Ease of manufacturing

In-process control
This comprises any test on a product, the environment or the equipment that is made during the
manufacturing process. An example of this is testing that an autoclave is functioning correctly.

Vials
 Injectable medications usually are supplied in vials or ampuls, each requiring different
techniques for withdrawal of the medication.
 A vial is a plastic or glass container with a rubber closure secured to its top by a metal ring.
 Multidose vials contain preservatives that allow their contents to be used after the rubber
stopper is punctured.
 Therefore, all vials should be swabbed with 70% isopropyl alcohol before needle entry and
left to dry. The correct technique is several firm strokes in the same direction over the
rubber closure, using a clean, unused portion of a swab on each pass.
 The swabbing is effective in two ways:
 The alcohol acts as a disinfecting agent.
 The physical act of swabbing in one direction remove particles from the vial
diaphragm.
 Bottles or trays of isopropyl alcohol should not be used. Because alcohol may harbor
resistant spores, repeated use of non-sterile tray or bottle could promote this problem.
 Individually packaged swabs are sterile from the manufacturer. When vials are pierced
with needles, cores or fragments of the rubber closure can form. To prevent this
problem, the needle should be inserted so that the rubber closure is penetrated at the same
point with both the tip and heel of the bevel. This noncoring technique is accomplished
by first piercing the rubber closure with the bevel tip and then applying lateral (away
from the bevel) and downward pressure to insert the needle. .
 Vials are closed-system containers, since air or fluid cannot pass freely in or out of them.
 Therefore, the volume of fluid to be removed from a vial should be replaced with an
 equal volume of air to avoid creating a vacuum. But this technique should not be used
with drugs that produce gas when they are reconstituted (e.g., ceftazidime).
 If the drug within a vial is in a powered form it must be reconstituted first. The desired
volume of the diluent (e.g., sterile water for injection) is injected into the vial.
Ass

Assigment
syringe and needles

Ampules
 Ampules are composed entirely of glass. Once an ampul is broken, it becomes an open-
system, single-use container. Since air or fluid may now pass freely in and out of them,
the volume of fluid removed does not have to be replaced with air.
 Before an ampule is opened, any solution visible in the top portion (head) should be
moved to the bottom (body) by one of the following methods:
 Swirling the ampule in an upright position.
 Tapping the head with one’s finger
 To open an ampule properly, its neck should be cleansed with an alcohol swab and the
swab should be left in place. This swab can prevent accidental cuts to the fingers as well
as spraying of glass particles and aerosolized drug. The head of the ampule should be
 held between the thumb and index finger of one hand, and the body should be held with
the thumb and index finger of the other hand. Pressure should be exerted on both
thumbs, pushing away

Categorically differentiating pharmaceutical packaging:

1.Primary Packaging:
 This is the first packaging envelope which is in touch with the dosage form or equipment.
The packaging needs to be such that there is no interaction with the drug and will provide
proper containment of
pharmaceuticals. E.g. Blister packages, Strip packages, etc.

2Secondary Packaging:
 This is consecutive covering or package which stores pharmaceuticals packages in it for
their grouping. E.g. Cartons, boxes, etc.
3.Tertiary packaging:
 This is to provide bulk handling and shipping of pharmaceuticals from one place to
another. E.g. Containers, barrels, etc.

 Primarily two types of containers are used for packaging:

1. Glass Containers
2. Plastic Containers
Glass Containers: These need to be chemically inert, impermeable, strong and rigid proving FDA
clearance.

Four types of Glasses are being used in pharmaceutical industry,

1. Type I-Borosilicate glass: Highly resistant and chemically inert glass. Alkali’s and earth
cations of glass are replaced by boron and/or aluminum and zinc. These are used to contain
strong acids and alkalis.

2. Type 2-Treated soda-lime glass: These are more chemically inert than Type I glass. The glass
surface is de-alkalized by “Sulfur treatment” which prevents blooming/weathering from bottles.

3. Type III- Regular soda lime glass: Untreated soda lime glass with average chemical
resistance.

4. Type IV- General Purpose soda lime glass: Glass is not used for parenterals, used only for
products intended to be used orally or topically.

Plastic Containers:
 Plastic containers of high quality can be easily formed with different designs. These
packages are extremely resistant to breakage and leakage.
Primarily plastic containers are made from the following polymers:

1. Polyethylene (PE): Provides good barrier against moisture, relatively poor one against oxygen
and other gases.
High density polyethylene is used with density ranging from 0.91-0.96 leading to four basic
characteristics of container, (1) Stiffness, (2) Moisture vapor transmission, (3)stress cracking
and(4)clarity or translucency based on polymer density used.

2. Polypropylene (PP): Polypropylene has features of polyethylene in addition it does not stress-
crack in any condition.Hot aromatic or halogenated solvents soften the package. It has high
melting point making it suitable for boilable packages and products needed to be sterilized.
Brittleness at low temperature is its major disadvantages.

3.Polyvinyl Chloride (PVC): Can be produced with crystal clear clarity, will provide good
gaseous barrier and stiffness. Reduction in residual vinyl chloride monomers had further
enhanced PVC quality. PVC is used as coating on glass bottles providing shatter resistant
coating.

4.Polystyrene: Rigid and crystal clear plastic. Not useful for liquid products. Polystyrene has
high water and gaseous permeability also these are easily stretchable and breakable. To increase
their strength and quality for permeability polystyrene is combined with rubber and acrylic
compounds. Base on the composition these are classified as intermediate impact, high impact
and super impact packages.

5. Nylon (polyamide): Many dibasic acids and amines combine to provide numerous varieties of
nylon. Nylon is extremely strong and is quite difficult to be destroyed by mechanical means.
Nylon provides resistance to wide range of acids and alkali only disadvantage of it is being
permeable to water vapor for some amount this can also be dealt with coating of PE over the
container. Not used for long term storage of products.

6. Polycarbonate: Has an ability to be sterilized repeatedly. It has immense rigidity and is a

possible replacement for glass, vials and syringes. It has qualities like high dimensional stability,
high impact strength, resistance to strain, low water absorption, transparency, and resistance to
heat and flame. Polycarbonates have impact strength five times greater than any other common
packaging plastics.

7. Acrylic multipolymers (Nitrile Polymers): These are polymers of acrylonitrile or

methacrylonitrile monomers. These provide for packaging of those products which are not
packed in usual packages as they provide for high gas barrier, good chemical resistance, and
good strength.

8.Polyethylene terepthalate (PET): Condensation polymer formed by reaction of terepthalic

acid or dimethyl terepthalic acid with ethylene glycol. It has excellent strength and provides
barrier for gas and aroma making it as a useful package for cosmetics, mouth washes and other
products.

Unit seven

Preparing for sterile manufacturing

Disinfect and transfer materials and equipments to production area

Disinfection
 is the process of removing micro-organisms or reducing the number to levels that are no
longer harmful. It is kills viruses, fungi, bacteria but not spores such as tetanus..
The two main disinfection methods are
 boiling
 chemical
 It is important to remember that chemical disinfectants are not suitable for use with needles
and syringes, because traces of chemicals can be toxic, cause irritation and inactivate
vaccines.

Disinfection by boiling
 It is important to remember that boiling provides high level disinfection but not
 sterilisation.
 Boiling is still widely used either because steam sterilisers are not available or because
health staff believe that boiling is the same as sterilisation and guarantees that items are
sterile.
Use the following guidelines for disinfection by boiling:
Preparation of the boiler and the load
• Use a special boiling pan (boiler) or, if not available, a saucepan with a close fitting lid.
• Prepare the items so that they are ready for disinfecting. Make sure they have been thoroughly
cleaned, rinsed and dried.
• Check items for signs of damage and to make sure that, for example, joints are not loose.
Loading the boiler
• Load the boiler so that the water will be able to circulate around each item and each part.
Arrange the items so that they are not touching each other or the sides of the boiler. Do not
overload the boiler.
• Place heavier items at the bottom and smaller, lighter items on top.
• Make sure that hinged instruments are open.
• Do not boil sterilisable needles and syringes unless sterilisation is not possible. Separate the
plunger and barrel of the sterilisable syringes and place the needles in a needle container or stick
into a gauze swab.
• Fill with enough clean water to make sure that all the items are covered. Boiling without
enough water will damage the boiler and the items.
Boiling
• Heat until the water boils, then reduce the heat slightly to save fuel but make sure that the water
remains boiling.
• Start timing. Boiling time starts from when the water boils not from the time the water starts to
be heated. Boil for the required time
• Do not leave the boiler unattended when in use.
• Do not add any items during the boiling cycle. If items are added, you need to start timing from
the beginning again. Similarly, if boiling is stopped at any point, you need to restart again.
Removing the load
• After the required boiling time, shut off the heat source and remove the boiled items. Either
take out the tray with its contents and allow it to drain dry or take out the boiled items using
sterile or disinfected long handled forceps and place them in a sterile or boiled metal container to
dry before using or storing them.
• Allow the boiler to cool down before draining the hot water.
• Do not leave items in the water because it can easily become re-contaminated.
• Do not disinfect by boiling more than 24 hours before you use items. The items may become
contaminated even if they are stored in a closed container.
• Clean the boiler after each day’s use.
Chemical disinfection
  A wide range of chemical disinfectants is available. Each is best suited for a specific
purpose and must be used in a particular way to be effective. Because not all disinfectants
will kill all organisms, a single disinfectant will not fulfil all your requirements, but two
different disinfectants will usually be sufficient.
Choose disinfectants with the following characteristics:
• Wide range of activity
• Not readily inactivated
• Non-corrosive when diluted
• Non-irritant to skin
• Low cost
 It is also important to follow the manufacturer’s instructions for disinfectant handling,
preparation, use and storage.
 Incorrect dilution, poor storage and repeated use of the same working solution reduce the
effectiveness of chemical disinfection.
Raw materials
 Raw materials account for a high proportion of the microorganisms introduced during the
manufacture of pharmaceuticals, and the selection of materials of a good microbiological
quality aids in the control of contamination levels in both products and the environment.
 It is, however, common to have to accept raw materials which have some nonpathogenic
microorganisms present and an assessment must be made as to the risk of their survival to
spoil the finished product by growing in the presence of a preservative system, or the
efficacy of an in-process treatment stage to destroy or remove them..
Disposable equipments

Disposables –
 are items designed for single use. Disposables should only be used once and should not
be re-used.
Containers and packaging
 Packaging material has a dual role and acts both to contain the product and to prevent the
entry of microorganisms or moisture which may result in spoilage, and it is therefore
important that the source of contamination is not the packaging itself.
 Packaging materials that have a smooth, impervious surface, free from crevices or
interstices, such as cellulose acetate, polyethylene, polypropylene, polyvinylchloride, and
metal foils and laminates, all have a low surface microbial count.

Sterile Preparation Facilities and Equipment

The following equipment is essential for sterile compounding:
 Syringes and needles
  Alcohol pads
• Ampoules or vials
• Laminar airflow hoods
• Refrigerators (with thermometers)
• Freezers
• Sinks with hot and cold water
• Automated compounding devices
• Disposable, lint-free towels or wipes
• Disposable gowns, caps, masks, and sterile gloves
• Sharp containers
• Computer systems
• Shelving
• Carts
• Stainless steel furniture
Biological Safety Cabinets
 Since horizontal laminar-airflow hoods blow air toward the operator, vertical laminar
airflow hoods are preferred when working with hazardous substances.
 Vertical flow hoods are part of a family of equipment called biohazard cabinets or
biological safety cabinets.
Three types of biohazard cabinets are available:
 Class I cabinets have a HEPA filters on their exhaust outlet but not for inward airflow. The
protect personnel and the environment but do not prevent contamination of compounded
preparations. This class of hoods has no application in compounding sterile preparations.
 Class II cabinets have HEPA filtered inward air for protection of compounded preparations
and HEPA filtered exhaust air to protect personnel. They are suitable for compounding sterile
preparations. Class II cabinets are further classified according to how their exhaust air is
vented.
 Class III cabinets are totally enclosed, vented, and gastight units. Operations are conducted
through attached rubber gloves, and the cabinet is maintained under negative pressure. These
cabinets have limited applications in the preparation of sterile products and are intended for
the handling of extremely hazardous substances.
A biological safety cabinet functions by having air taken into the unit at the top, where it passes
through a prefilter to remove large contaminants. Air then passes through a HEPA filter and is
directed down toward the work surface, just as with a vertical laminar flow hood. The filter
forms the ceiling of the work area in the biological safety cabinet and removes bacteria to
provide ultra clean air. Unlike the mechanism in a vertical laminar flow hood, however, as air
approaches the work surface, it is pulled through vents at the front, back, and sides of the unit. A
major portion of the contaminated air is recirculated back into the cabinet, and a minor portion is
passed through a HEPA filter before being exhausted into the room.
It is important that biological safety cabinets run continuously. If turned off for any reason, such
as for maintenance or changing the HEPA filter, the biological safety cabinet must be thoroughly
cleaned with a detergent, and the exhaust area must be covered with impermeable plastic and
sealed to prevent any contaminants from escaping the unit.
 Vertical laminar airflow hoods are the preferred choice. These cabinets prevent
cumulative exposure to potentially toxic medications, especially if the staff routinely
compound hazardous preparations for a long time.
 When sterile preparations are compounded, aerosols can form and be blown toward the
operator using a horizontal hood. Long-term exposure to cytotoxic agents as well as
other drugs, especially antibiotics, is a great concern. Vertical airflow hoods minimize
such exposure.
 Class II hoods are more expensive than horizontal hoods and can be very costly to
install due to venting requirements. Furthermore, vertical airflow hoods generally are
more restrictive and may slow workflow.
Laminar Airflow Hood Basics
 A laminar flow hood has three basic functions. The first is to provide clean air in the
working area.
 This is done by passing room air through a bacteria retentive filter to provide a
continuous flow of clean air in the work area. Second, the constant flow of air out of the
laminar flow hood prevents room air from entering the work area. Last, the air flowing
out suspends and removes contaminants introduced in the work area by material (such as
IV bags, syringes, and drug packaging) or personnel. Thus, the laminar flow hood
provides an environment virtually free of airborne contaminants, in which procedures can
be safely performed.
 Laminar flow hoods may be used in the pharmacy to perform the following procedures:
 Preparations of IV admixtures
 Preparations of ophthalmic solutions
 Reconstitution of powdered drugs
 Filling unit dose syringes
 Preparation of miscellaneous sterile products.
 Laminar flow hoods come in various sized and models. One model, called a console
model, sits on the floor. The other common model is called a bench or countertop
model, because it sits on top of the counter, and the space underneath can be used for
storage space. Both the console and bench models are available with vertical rather than
horizontal airflow.
 Laminar airflow hoods are usually kept running continuously. If the hood is turned off,
it is recommended to run for at least 30 minutes before using the work surface area in
order to replace the room air with clean, filtered air. Laminar flow hoods should be
inspected and certified every six months to assure that the HEPA filter is intact,
unclogged, and has no holes in it. The prefilters in the hoods should be changed
monthly.
  It is important for pharmacy technicians to keep their hands within the cleaned area of the
hood as much as possible, and to not touch their hair, face, or clothing. Only materials
essential for preparing the sterile products should be placed in the laminar airflow
workbench or barrier isolator.
Cleaning Laminar Airflow Hoods
 Cleaning the laminar airflow hoods may be done with a non-shedding wipe or sponge
dampened with Water for Injection, with or without mild detergent. This should be
followed by:
 Seventy percent isopropyl alcohol (or another appropriate disinfecting agent) should be
used to clean all interior working surfaces before each use.
 A clean, lint-free cloth should be moved in a side-to-side motion, beginning at the rear and
moving toward the front of the LAH.
 The walls of the LAH also must be cleaned from top to bottom with 70 percent isopropyl
alcohol.
 This procedure should occur often throughout the compounding period and whenever the
work surface becomes dirty.
 Because some materials require water to remove them, these materials may be first
cleaned off with water, followed by the alcohol or other disinfecting agent.

Assigment
Follow appropriate procedures for
Hand washing
Gowning
Gloving

Unit eight
Manufacturing/compounding products using aseptic techniques

Learning Outcome
 Upon completion of the chapte students should be able to define aseptic technique
and terminal sterilization and list the method of steralizations and each use .
Learning Objectives
At end of the chapter , student you will be able to:
 Define define aseptic technique and terminal sterilization and describe the various
category steralizations and each use
 Difereniate different tye of sterile area .
 Discus and define tonicity

Manufacturing/compounding products using aseptic techniques

 Aseptic techniques
Aseptic technique is carrying out a procedure under controlled conditions in a manner that
minimizes the chance of contamination.
Contamination can be caused by the following factors:
 Environment – controlling the air where the compounding is being performed.
 Equipment – all objects that come in contact with the drug(s) must be sterile.
 Personnel – touch contamination is the most frequent cause of contamination.
.
 Aseptic technique refers to the procedures used during preparation that maintains the
sterility of pharmaceutical dosage forms. Sterilization is an essential concept in the
preparation of sterile pharmaceutical products. Its aim is to provide a product that is safe
and that eliminates the possibility of introducing infection.
Sterilization is a process used to destroy or eliminate viable microorganisms that may be present
in or on a particular product or package. The process requires an overall understanding and
control of all parts of the preparation for use of a particular product.
Aseptic technique describes the methods used to manipulate sterile products so that they remain
sterile..
Terminal sterilization
 A process whereby a product is sterilized in its final container or packaging, and
which permit the measurement and evaluation of quantifiable microbial lethality.
 Typically, the sterility assurance level (SAL), should be less than 10-6 i.e. a
probability of not more than one viable microorganism in an amount of 1,000,000
sterilized items of the final product.

SAL-is the measurement of the probability of organisms surviving the sterilization process.
SAL likelihood of surviving organism
10-1 1:10
10-2 1:100
10-3 1:1000
10-4 1:10000
10-5 1:100000
10-6 1:1000000

Who needs to sterilize?

 Manufacturers of
 any product that enters the body, except by ingestion:
  Medical Device
 Pharmaceutical (both human & veterinary)
 Hospitals, Dentists, other health care facilities
Some specialty food product manufacturers
General Requirements for Sterilization Process
 Containers and closures that come into direct contact with pharmaceutical products and the
surfaces of equipment that may come into direct contact with intermediate products after
sterilization should be sterilized by methods appropriate for maintaining the predetermined
sterility assurance level.
 Materials to be sterilized should be handled by techniques appropriate for avoiding mix-ups
of sterilized and unsterilized materials.
 Sterilization processes for sterilizing pharmaceutical products and materials in critical areas
should be individually validated and periodically evaluated at least once a year.

Five general methods are used to sterilize pharmaceutical products:

 Steam
 Dry heat
 Filtration
 Gas
 Ionizing radiation
Steam Sterilization
 Steam sterilization is conducted in an autoclave and employs steam under pressure. It is
usually the method of choice if the product can with-stand it
 Most pharmaceutical products are adversely affected by heat and cannot be heated safely to
the temperature required for dry heat sterilization (about 150°C to 170°C, or 302°F to
338°F). K=C+273 C=F-32

1.8
 When moisture is present, bacteria are coagulated and destroyed at a considerably lower
temperature than when moisture is absent. In fact, bacterial cells with a large percentage of
water are generally killed .
 The mechanism of microbial destruction in moist heat is thought to be by denaturation and
coagulation of some of the organism’s essential protein. It is the hot moisture in the
microbial cell that permits destruction at relatively low temperature.
 Death by dry heat is thought to be by dehydration of the microbial cell followed by slow
oxidation.
 Because it is not possible to raise the temperature of steam above 100°C (212°F) under
atmospheric conditions, pressure is employed to achieve higher temperatures.
 It is the temperature, not the pressure, that destroys the microorganisms, and the application
 of pressure is solely to increase the temperature of the system.
 Time is another important factor in the destruction of microorganisms by heat. Most
modern autoclaves have gauges to indicate to the operator the internal conditions of
temperature and pressure and a timing device to permit the desired exposure time for the
load. The usual steam pressures, the temperatures obtainable under these pressures, and the
approximate length of time required for sterilization after the system reaches the indicated
temperatures are as follows:
 10 lb pressure (115.5°C, or 240°F) for 30 minutes
 15 lb pressure (121.5°C, or 250°F) for 20 minutes
 20 lb pressure (126.5°C, or 260°F) for 15 minutes
 As can be seen, the greater the pressure applied, the higher the temperature obtainable
and the less the time required for sterilization. Most autoclaves routinely operate at 121°C
(250°F), as measured at the steam discharge line running from the autoclave.
 The temperature in the chamber of the autoclave must also be reached by the interior of
the load being sterilized, and this temperature must be maintained for an adequate time.
 In general, steam sterilization is applicable to pharmaceutical preparations and materials
that can withstand the required temperatures and are penetrated by but not adversely
affected by moisture.
 In aqueous solutions, the moisture is already present and all that is required is elevation
of the temperature of the solution for the prescribed period. Thus, solutions in sealed
containers, such as ampoules, are readily sterilized by this method. Sealed empty vials
can be sterilized by autoclaving only if they contain a small quantity of water.
 Steam sterilization is also applicable to bulk solutions, glassware, surgical dressings, and
instruments.
 It is not useful for oils, fats, oleaginous preparations, and other preparations not
penetrated by moisture or for exposed powders that may be damaged by the condensed
moisture

Dry Heat Sterilization

 Dry heat sterilization is generally employed for substances that are not effectively
sterilized by moist heat. Such substances include fixed oils; glycerin; various petroleum
products, such as petrolatum, liquid petrolatum (mineral oil), and paraffin; and various
heat-stable powders, such as zinc oxide.
 Dry heat is also an effective method for sterilizing glassware and surgical instruments.
 Dry heat is the method of choice when dry apparatus or dry containers are required, as in
the handling of packaging of dry chemicals or non-aqueous solutions
 The aim of sterilization is to destroy the ability of microorganisms to survive and
multiply. Depyrogenation seeks to destroy the chemical activity of the by-products: pyro-
 gens or endotoxins (these terms do not mean exactly the same thing, but we will consider
them to be synonymous for the sake of simplicity).
Both processes consist of an oxidation that is almost combustion. However, the temperatures
required to achieve depyrogenation are distinctly higher than those needed to obtain sterilization.
We can summarize the situation as follows:
 If an effective dry heat depyrogenationis performed, Sterilization generally achieved
as well.
 Effective dry heat Sterilization can be performed even without achieving
depyrogenation.
 In moist heat Sterilization (in formal operating conditions) depyrogenation is not
achieved

Sterilization by filtration
 Filtration is the removal of particulate matter from a fluid stream. Sterilizing filtration is a
process that removes, but does not destroy, microorganisms.
 is one of the oldest methods of sterilization, is the method of choice for solutions that are
unstable to other types of sterilizing processes.
 Depends on the physical removal of microorganisms by adsorption on the filter medium or
by a sieving mechanism, is used for heat-sensitive solutions.
 Medicinal preparations sterilized by this method must undergo extensive validation and
monitoring because the effectiveness of the filtered product can be greatly influenced by the
microbial load in the solution being filtered.
 Commercially available filters are produced with a variety of pore size specifications. The
Milli-pore filter is a thin plastic membrane of cellulosic esters with millions of pores per
square inch.
 The pores are made to be uniform in size and occupy approximately 80% of the
membrane’s volume, the remaining 20% being the filter material.

Figure1.Membrane filters act as microporous screens

 Millipore filters are made from a variety of polymers to be suitable for filtration of
almost any liquid or gas system.
  Also, the filters have various pore sizes, 14 to 0.025 μm, to meet the specific
requirements. For comparative purposes, the period that ended the last sentence is
approximately 500 μm.
 The smallest particle visible to the naked eye is about 40μm, a red blood cell is about
6.5 μm, the smallest bacteria, about 0.2 μm, and a poliovirus, about 0.025 μm.
 Although the pore size of a bacterial filter is of prime importance in the removal of
microorganisms from a liquid, other factors, such as the electrical charge on the filter
and that of the microorganism, the pH of the solution, the temperature, and the
pressure or vacuum applied to the system, are also important
 The major advantages of bacterial filtration include
 its speed in the filtration of small quantities of solution
 its ability to sterilize thermo labile materials
 the relatively inexpensive equipment required
 and the complete removal of living and dead microorganisms and other particulate
matter from the solution.

Sterilization by radiation
 Techniques are available for sterilization of some types of pharmaceuticals by gamma rays
and by cathode rays, but application of such techniques are limited because of the highly
specialized equipment required and the effects of irradiation on the products and their
containers.
 Sterilization by radiation is used mainly for heat-sensitive materials and products. Many
pharmaceutical products and some packaging materials are radiation-sensitive, so this
method is permissible only when the absence of deleterious effects on the product has been
confirmed experimentally.

Sterilization by gases and fumigants

 A variety of gases and vapors have shown germicidal properties: chlorine dioxide, ethylene
oxide, propylene oxide, formaldehyde, beta pro -piolactone, ozone (O3), hydrogen peroxide,
per acetic acid, etc.
 Ethylene oxide is currently in wide spread use for medical product sterilization
ETHYLENEOXIDE
 The sterilizing action of ethylene oxide is based on an alkylation reaction: it is, accordingly, a
truly chemical action rather than a physical one. This chemical reaction must be activated by
the presence of water vapor (approximately 60% of RH or relative humidity) and is increased
by temperature and Ethylene oxide concentration.
 The process temperature is limited by the characteristics of the product. Generally, it is
between 40° and 60°C, but it must be remembered that the reaction rate increases by
approximately 2.5 times for each 10 degree centigrade increase in temperature.
 The ethylene oxide must make direct contact with the microorganism for the microbe to be
 inactivated.,
 Generally, it is not possible to use Ethylene oxide to sterilize liquids, solutions, or emulsions.
Powders, too, are difficult to treat unless microbial contamination is only on the outside of
the granules
 These gases are highly flammable when mixed with air but can be employed safely when
properly diluted with an inert gas such as carbon dioxide or a suitable fluorinated
hydrocarbon. Such mixtures are commercially available.
 Sterilization by this process requires specialized equipment resembling an autoclave, and
many combination steam autoclaves and ethylene oxide sterilizers are commercially
available.
 Greater precautions are required for this method of sterilization than for some of the
others, because the variables—for instance, time, temperature, gas concentration and
humidity—are not as firmly quantitated as those of dry heat and steam sterilization.
.
 The great penetrating qualities of ethylene oxide gas make it a useful agent in certain
special applications, such as sterilization of medical and surgical supplies and appliances
such as catheters, needles, and plastic disposable syringes in their final plastic packaging
just prior to shipment. The gas is also used to sterilize certain heat-labile enzyme
preparations, certain antibiotics, and other drugs, after testing to ensure the absence of
chemical reaction and other deleterious effects on the drug substance.
 Unfortunately, ethylene oxide has several drawbacks:
 it is toxic, carcinogenic, teratogenic, inflammable, and explosive when mixed with
more than 3% air by volume.
 These characteristics make the use of ethylene oxide highly controversial, and many
countries have issued regulations or requirements for its use as a sterilizing agent.

Sterile areas
Critical Area (Grade A)
 The critical area is a processing area where sterilized products and materials as well as
their surfaces are directly exposed to the environment.
 The per-cubic-meter content of particle s ≥ 0.5 μm in diameter in the critical area should
be controlled to be below 3,520 under operating and non -operating conditions. This level
of air cleanliness is designated as Grade A, Class 100, or IS O -5 according to domestic
and international standards on air quality.
 The count of airborne particles and microorganisms should be regularly monitored by
appropriate procedures at sites which are critical for ensuring sterility of pharmaceutical
products. It is recommended that airborne particles be continuously counted throughout
aseptic processing, including during critical preparation steps such as assembly of sterile
parts that may contact pharmaceutical products. The location of monitoring should
preferably be as close (≤ 30 cm) as the working place. The frequency and method of
 microbiological monitoring should be carefully selected in order not to break sterility of
products by the monitoring.
 Powder filling operations may generate higher counts of airborne particles than the
specifications. If such a deviation occurs, the count of airborne particles should be
obtained by, for example, sampling air at different locations or monitoring the count in
the same room while no powder filling operation is going, and causes of the deviation
should be identified to maintain air quality in the room at a required level.

Direct Support Area (Grade B)

 The direct support area is defined as a background area of the critical area when aseptic
processing is conducted using an open clean booth or restricted access barrier system
(RABS). The direct support area is a working area for personnel who operate machines
installed in the critical area and for those who supervise the operation of machines.
 The direct support area also serves as a route for the transfer of sterilized products, materials,
and equipment to the critical area or for moving sterilized products from the critical area. In
the latter case, appropriate measures need to be implemented to protect sterilized products or
materials from direct exposure to the environment.
 The per-cubic-meter count of particles (diameter: ≥ 0.5 μm) in the direct support area
should be controlled below 352,000 and 3,520 under operating and non-operating conditions,
respectively. These levels of air cleanliness are designated as Grade B, Class 10,000, or ISO -
7 (under standard operating conditions) according to domestic and international standards on
air quality.
 The count of airborne particles and microorganisms should be regularly monitored by
appropriate procedures in the direct support area.
 The frequency and method of monitoring should be carefully selected based on evaluation
results of product contamination risks in the critical area.

Indirect Support Areas (Grade C or D)

 The indirect support area is an area used for processing materials and products prior to
sterilization processes and hence materials and products are directly exposed to the
environment. Example indirect support areas include an area for preparing drug solution
prior to sterilization and an area for washing and cleaning sterilization equipment and
apparatuses.
 The cleanliness of the indirect support area needs to be controlled by establishing
specifications for acceptable airborne particle count by taking into account the required
level of contamination control and type of works performed in the area.
 Air cleanliness of the indirect support area may be either of the following two grades.
One of the grades specifies that the per -cubic-meter particle content (diameter: ≥ 0.5
μm) should not exceed 3,520,000 and 352,000 under operating and non-operating
 conditions, respectively. These levels of cleanliness are designated as Grade C, Class
100,000, or ISO-8 (standard under operating conditions) according to domestic and
international standards on air quality. The other grade specifies that the per -cubic-meter
particle content (diameter: ≥ 0.5 μm) should not exceed 3,520,000 under non-operating
conditions. This level of cleanliness is designated as Grade D.
 Weighing and preparation processes should preferably be conducted in Grade C or
cleaner areas. If powder handling might elevate the airborne particle count above the
specification, air quality should be maintained below the specification by accurately
determining the particle count that may cause contamination in the area , and for the
determination, air should be sampled, for example, at multiple locations and/or under
powder -free conditions.

Table : Classification of compounding area based on maximum allowable number of airborne

particles
 Examples of operations to be carried out in the various grades
Grade Examples of operations for terminally sterilized products
A Filling of products when unusually at risk
C Preparation of solutions when unusually at risk. Filling of products
D Preparation of solutions and components for subsequent filling

Grade Examples of operations for aseptic preparations

A Aseptic preparation and filling
C Preparation of solutions to be filtered
D Handling of components after washing

Air locks
  A small room that is generally composed of interlocked doors, constructed to
maintain air pressure control between adjoining rooms. The intent of an aseptic
processing airlock is to preclude ingress of particulate matter and microorganism
contamination from a lesser controlled area. The air balance for the bio -safety
facility should be established and maintained to ensure that airflow is from areas of
least- to greater contamination.
Air classification systems
Heating, Ventilating and Air Conditioning System
 Air in clean areas needs to be maintained at appropriate levels by designing, instituting, and
managing a suitable heating, ventilation, and air conditioning (HVAC) system. The integrity
of the system should be ensured with respect to not only temporal variations due to
operational activities, such as door opening and closing and facility equipment operation, but
also sustained variations due to non -operational activities, such as seasonal changes in
outdoor conditions or deterioration of equipment and apparatuses over time.
 The HVAC system and its management program are comprised of the following basic
elements: temperature, relative humidity, air flow volume, air exchange rate, unidirectional
of air flow, pressure difference relative to adjacent rooms, and integrity of HEPA filter,
airborne particle count, and micro bacterial count.
Temperature and Relative Humidity
 Temperature and relative humidity have a direct impact on the comfort of personnel and
potential for microbial contamination in processing areas; therefore, these environmental
parameters should be appropriately defined, controlled, monitored, and maintained at
appropriate levels throughout processing.
Air
 It is critical to secure constant airflow from an area of higher cleanliness level to an area of
lower cleanliness level in order to maintain required environmental conditions of clean areas.
 Pressure difference between the APA and indirect support areas should be adequately
defined, monitored, and controlled.
 Wherever pressure difference is an essential part of sterility assurance, it is recommended
to continuously monitor pressure difference between areas and install an alarm system to
enable prompt detection of abnormal pressure differences.
 Airflow in the critical area (Grade A) should be unidirectional and supplied at velocity
and uniformity sufficient to swiftly remove airborne particles away from the critical area.
 Airflow should also be supplied with sufficient care so as not to create reverse currents
from adjacent areas (direct support areas, Grade B) into the critical area to prevent
contamination.
 In the direct support area, airborne particle count should preferably be returned to the non
-operating count in 15 to 20 minutes.
Laminar flow hoods
How a laminar flow hood functions?
 In a laminar flow hood the air is passed through a HEPA (High Efficiency Particulates Air)
filter which removes all airborne contamination to maintain sterile conditions.

 A laminar flow hood consists of a filter pad, a fan and a HEPA (High Efficiency Particulates
Air) filter. The fan sucks the air through the filter pad where dust is trapped. After that the pre
filtered air has to pass the HEPA filter where contaminating fungi, bacteria, dust etc are
removed. Now the sterile air flows into the working (flasking) area where you can do all your
flasking work without risk of contamination.
 Important parameters to make sure that the hood works efficiently:
 the HEPA filter has to remove all airborne materials
 the air speed in the working area has to be about 0.5 m/s
The two types of laminar flow hoods
 Before you start building your flow hood you have to decide if you prefer a vertical or
horizontal air flow in the flasking area.
 In a vertical flow the air moves from the top of the working area to the bottom and
leaves the flasking area through holes in the base.
  When you use a flow hood with horizontal air flow the air moves from the back of the
working area to the front.

Laminar flow

Premises for manufacture of sterile product

 The manufacture of sterile products shall be carried out in clean areas to which entry
shall be through airlocks.

Cytotoxic drug safety cabinet/isolator

Isolator
A sealed and sterilized enclosure capable of preventing ingress of contaminants by means of total
physical separation of enclosure to the surrounding exterior environment, an isolator’s air supply
is filtered using HEPA or ULPA(ultra low penetration air(filter))grade filters
Physiological VS physical Norms
Physiologic norms: When injectable solutions are formulated, every effort should be made to
mimic the body’s normal serum values for pH and tonicity and to create a pyrogen-free
preparation.
PH: The term pH is used to describe the degree of acidity of a solution. PH values range from 0
to 14, with values below 7 representing greater acidity of the solution, while values above 7
represent less acidity or greater alkalinity. A solution having a pH of 7 is neither acid, nor
alkaline; it is considered neutral. Plasma in our body is about 7.4, and solutions should try to stay
around that number, pH is another characteristic that cannot be seen, but can be tested after it is
prepared. Normal human serum pH, a logarithmic measure of the hydronium ion concentration
in solution, is 7.4. Drugs that are acids or bases or their salts sometimes must be buffered to a pH
near normal (e.g., 3-8) to prevent pain or tissue damage.
Tonicity:
Question: What is the d/c among the following words?
Hypertonic, isotonic & hypotonic
 An isotonic solution has the same concentration as red blood cells.
 Isotonic IV solutions minimize patient discomfort and damage to red blood cells.
Stinging caused by either a hypertonic (shrinking of red blood cells) or hypotonic
(swelling of red blood cells) solution is not experienced with an isotonic solution.
 IV solutions should be as close to isotonic as possible. A good reference point to
remember is that 0.9 percent sodium chloride injection and 5 percent dextrose injection
are both approximately isotonic.
 Any chemical dissolved in water exerts a certain osmotic pressure, which is the pressure
exerted by a solution necessary to prevent osmosis into that solution when it is separated
from the pure solvent (i.e., a solute concentration related to the number of dissolved particles
per unit volume)
 Blood has an osmotic pressure corresponding to sodium chloride 0.9%; thus, its
common name is normal saline.
 Normal saline is said to be “isosmotic” with blood and other physiologic fluids. In the
medical setting, the term “isotonic” is used synonymously with isosmotic.
 A solution is isotonic with a living cell if no net gain or loss of water is experienced
by the cell and no other change is present when the cell contacts that solution.
 Very hypotonic (containing a low concentration of solute relative to another solution)
IV preparations can cause hemolysis (the destruction or dissolution) of red blood
cells.
 Very hypertonic (contains a high concentration of solute relative to another solution)
injections can damage tissue and cause pain on injection.
 The greater the volume of solution to be injected, the closer the parenteral preparation
should be to isotonicity.

Pyrogenicity: Pyrogens are contaminants that are unacceptable in final compounded sterile
preparations. Pyrogens are fever-producing endotoxins from bacteria. As large proteins, pyrogens
are not removed by normal sterilization procedures and can exist for years in aqueous solution or
dried form. The sources of pyrogens in sterile preparations are:
 Aqueous vehicles
 Equipment
 Containers and closures
  Chemicals used as solutes
 Human touch
If sterile water for injection is the vehicle, the risk of pyrogens in water is eliminated.
Equipment, containers, and closures can be decontaminated by dry heat or by washing or soaking
with acids and bases. Touch contamination is most easily prevented with proper aseptic
technique (discussed later).
Physical Norms
Physical Norms: Parenteral solutions must be free of particulate matter, stability problems and
impurities
Stability
 Stability of parenteral preparations must be assured so that patients receive the intended
dose. Hydrolytic (decomposition of a chemical compound) and oxidative degradations
are the most common forms of instability but rarely show as cloudiness or color changes.
 The rate of hydrolysis may be affected by storage temperature or pH of the solution.
 Oxidation is affected by temperature, pH, exposure to light, oxygen concentration of the
solutions, and impurities.
Impurities
 Heavy metals (like lead and mercury) are also to be minimized in sterile preparations.
 Heavy metals can be toxic and can catalyze the degradation of active ingredients and
preservatives. Introduction of these impurities is most likely when non-sterile; raw
materials are used in compounding.
INDUSTRIAL PREPARATION OF PARENTERAL PRODUCTS
Overview of Sterile Compounding and the Role of the Pharmacy Technician.
 When drugs need to be injected, any one of several routes can be used to administer the
drug.
 The most common injectable routes of administration are intravenous (in the vein),
intramuscular (in the muscle), and subcutaneous (in the skin).
 The compounding of sterile preparations is an integral part of any health-system setting.
While the majority of perentral products are prepared using commercially available
medications and diluents solutions, pharmacy departments still perform intravenous
manufacturing. The reasons for this vary greatly, but can include:
 Special patient populations such as pediatrics, geriatrics, or the terminally ill (pain
management). For these patients, the appropriate strengths for certain drugs may
not be available.
 Some patients might be allergic to the diluents and preservatives in commercially
available products.
 Some drugs are unstable and require preparation to be dispensed every few days.
Overview of unique characteristics of parenteral dosage forms
 Parenteral products are unique from any other type of pharmaceutical dosage form for the
following reasons:
  All products must be sterile
 All products must be free from pyrogenic (endotoxin) contamination.
 Injectable solutions must be free from visible particulate matter.This include reconstituted
sterile powder
 Products should be isotonic although strictness of tonicity depends on the route of
administration. Products to be administered into the cerebrospinal fluid must be isotonic.
Products to be administered by bolus injection by routes other than intrnvenous(IV)
essentially should be isotonic or at least very close to isotonicity. IV infusion must be
isotonic.
 All products must be stable (not only chemically and physically like all other dosage
form, but also stable microbiologically, i.e., sterility, freedom from pyrogenic and visible
particulate contamination must be maintained throughout the shelf life of the product).
FORMULATION PRINCIPLES
Parenteral drugs are formulated as solutions, suspensions, emulsions, liposome,
Microspheres , nanosystems and powders to be reconstituted as solutions
Intravenous Administration
 Intravenous administration of drugs has advantages over other routes of administration
because
 it provides the fastest route to the bloodstream. Why?
 There are no barriers like skin or muscle to absorb the drug first, which allow the
most rapid onset of action.
 If someone cannot take medication by mouth because he is unconscious or
vomiting, then intravenous administration is the best route.
 Since the inner lining of a vein is relatively insensitive to pain, drugs that can be
irritating if given by another route can be given intravenously as a slow rate
without causing pain.
 Drugs that can be diluted to reduce irritation can be given only intravenously
because the tissue and skin around the other routes of administration cannot
accommodate large volumes.
The Role of the Pharmacy Technician
Pharmacy technicians must possess the following basic requirements to participate in sterile
compounding:
 A working knowledge of the policy and procedure manuals for compounding,
dispensing, and delivering sterile products.
 Adequate training and adherence to hygienic and aseptic techniques.
 Access to sufficient reference materials about sterile products.
 Knowledge and awareness of the proper methods to store, label, and dispose of drugs
and supplies.
 Awareness of how to conduct sterile compounding in an area separate from other
activities.
  Knowledge of established procedures for assigning beyond-use dates that exceed the
manufacturer labeled expiration dates.
 The level of difficulty of preparing the compounding prescriptions is determined by
 the physical properties of the drug being prescribed
 the dosage form desired either by the prescriber or patient.
 In some cases compounding will be a simple two-step process, whereas in others it will
require extensive knowledge and many steps to perform.
 Sterile compounding is an advanced pharmacy technique that requires proper training of
technicians, in addition to their general education. One point which must always be
remembered, the pharmacist maintains control over all pharmacy activities. The ultimate
responsibility rests with the licensed pharmacist.
 Sterile Preparation Formulations The objective of formulating and
compounding sterile preparations is to provide a dosage form of a labeled drug,
in the stated potency, that is safe to use if administered properly.
Written Procedures
 Any technician who formulates and compounds sterile preparations should develop and
comply with the following written procedures.
 Pharmacies must have a specifically designated and adequate area (space) for the orderly
placement of equipment and materials to be used in compounding. Compounding of
sterile preparations should be in a separate and distinct area from non-sterile
compounding.
 Storing components under the environmental conditions stated in the individual
monographs and/or in the labeling.
 Observing components for evidence of instability. Although chemical degradation
ordinarily cannot be detected by the naked eye, some physical changes not necessarily
related to chemical potency, such as change in color and odor, or formation of a
precipitate, or clouding of solution, may alert the technician of a stability problem. If a
component has undergone a physical change not explained in the labeling, such a
preparation is never to be dispensed.
 Observing components for evidence of lack of sterility. The presence of microbial
contamination in sterile components cannot be detected visually, but color change,
cloudiness, surface film, or gas formation is sufficient reason to suspect possible
contamination. Evidence that the integrity of the seal has been violated should make the
component suspect of microbial contamination.
 Properly handling and labeling preparations that are repackaged, diluted, or mixed with
other products.
 Sterile compounding equipment must be appropriate in design, size, and composition so
that surfaces contacting components are not reactive, additive, or adsorptive. These
surfaces should not alter the required safety, identity, strength, quality, and purity of the
components.
  As a technician, Components
 Components are any ingredient used in compounding, whether or not they appear in the
final preparation (intermediate ingredients). Whenever available, commercially sterile
components should be used. Commercial ingredients should be made in an FDA
approved facility and meet official compendia requirements .If these requirements
cannot be met, an alternative substance must be used.
VEHICLES
WATER
 Since most liquid injections are quite dilute, the component present in the highest
proportion is the vehicle.
 The vehicle of greatest importance for parenteral products is water.
 Water of suitable quality for compounding and rinsing product contact surfaces may be
prepared either by distillation or by re-verse osmosis, to meet United States
Pharmacopeia (USP)
 Specifications for Water for Injection (WFI). Only by these two methods is possible to
separate adequately various liquid, gas, and solid contaminating substances from water.
WATER FOR INJECTION (WFI)
 Water for injection is purified by distillation or reverse osmosis and is free of pyrogens.
Sterile water for injection USP is sterilized and packaged in single-dose containers not
exceeding 1000 ml.
 Bacteriostatic water for injection is sterilized and contains one or more bacteriostatic
agents (benzyl alcohol) in a container no larger than 30 ml.
 Sterile water for inhalation is sterilized and packaged in single-dose containers that are
labeled with the full name. As implied, this component cannot be used to prepare
parenterals. Sterile water for irrigation is sterilized and packaged in single-dose
containers with no added substances. Although this component may be packaged in
containers larger than 1000 ml, it is not intended for parenteral use.
 Vehicles for most liquid sterile preparations have no therapeutic activity or toxicity.
Rather, they serve as solvents or mediums for the administration of therapeutically active
ingredients.
 For parenteral preparations, the most common vehicle is water. Vehicles must meet USP
(United States Pharmacopeia) requirements.
Preparation
 The source water can be expected to be contaminated with natural suspended mineral and
organic substances, dissolved mineral salts, colloidal material, viable bacteria, bacterial
endotoxins, industrial or agricultural chemicals, and other particulate matter.
 The degree of contamination will vary with the source and will be markedly different,
whether obtained from a well or from surface sources, such as a stream or lake. Hence,
the source water usually must be pretreated by one or a combination of the following
treatments:
  chemical softening
 filtration
 deionization
 carbon adsorption, or
 reverse osmosis purification
 The EP (European Pharmacopeia) only permits distillation as the process for producing
WFI. The USP and JP (Japanese Pharmacopeia) allow all these technologies to be
applied.
 Distillation is a process of converting water from a liquid to its gaseous form (steam).
Since steam is pure gaseous water, all other contaminants in the feed water are removed.
 In general, a conventional still consists of
 a boiler (evaporator) containing feed water ;
 a source of heat to vaporize the water in the evaporator;
 a head space above the level of distill and, with condensing surfaces for refluxing
the vapor, thereby returning non volatile impurities to the distill and;
 a means for eliminating volatile impurities before the hot water vapor is
condensed;
 and a condenser for removing the heat of vaporization, thereby converting the
water vapor to a liquid distillate.

Water miscible vehicles

 A number of solvents that are miscible with water have been used as a portion of the vehicle
in the formulation of parenteral. These solvents are used primarily to solubilize certain drugs
in an aqueous vehicle and to reduce hydrolysis.
 The most important solvents in this group are ethyl alcohol, liquid polyethylene glycol, and
propylene glycol
 Ethylalcohol is used particularly in the preparation of solutions of cardiac glycosides and the
glycols in solutions of barbiturates, certain alkaloids, and certain antibiotics. Such
preparations usually are given intramuscularly.
 There are limitations with the amount of these co-solvents that can be administered because
of
 Toxicity concerns, greater potential for hemolysis, and potential for drug precipitation at
the site of injection.
 Aqueous isotonic vehicles are often used in sterile preparations. A common vehicle is
sodium chloride injection, a 0.9% solution (also known as normal saline) that is sterilized
and packaged in single-dose containers no larger than 1000 ml.
 Bacteriostatic sodium chloride injection is a 0.9% sodium chloride injection that contains
one or more bacteriostatic agents in a container no larger than 30 ml.
 Sodium chloride irrigation also is a 0.9% solution; however, it has no preservatives and
 may be packaged in a container larger than 1000 ml.
 Other isotonic vehicles include Ringer’s injection, dextrose injection 5%, and lactated
Ringer’s injection. None of these components is available in containers larger than 1000
ml.
Aqueous isotonic vehicles
are often used in sterile preparations. A common vehicle is sodium chloride injection, a
0.9% solution (also known as normal saline) that is sterilized and packaged in single-
dose containers no larger than 1000 ml.
 Bacteriostatic sodium chloride injection is a 0.9% sodium chloride injection that contains
one or more bacteriostatic agents in a container no larger than 30 ml.
 Sodium chloride irrigation also is a 0.9% solution; however, it has no preservatives and
may be packaged in a container larger than 1000 ml. your work must be checked by a
licensed pharmacist.
 Dispensing pharmacist must inspect and approve or reject all formulas, calculations,
substances, containers, closures, and in-process materials.
 Technicians who compound batches of parenteral preparations must follow a master
formula sheet to reproduce preparations that meet all purported norms.
 Other isotonic vehicles include Ringer’s injection, dextrose injection 5%, and lactated
Ringer’s injection. None of these components is available in containers larger than 1000
ml.
Non-Aqueous Vehicles
 The most important group of non-aqueous vehicles is the fixed oils. The USP provides
specifications for such vehicles, indicating that the fixed oils must be of vegetable origin so
that they will be metabolized, will be liquid at room temperature, and will not become rancid
readily. The USP also specifies limits for the free fatty acid content, iodine value, and
saponification value (oil heated with alkali to produce soap, i.e., alcohol plus acid salt).The
oils most commonly used are corn oil, cottonseed oil, peanut oil, and sesame oil.
 Fixed oils are used particularly as vehicles for certain hormone (eg, progesterone,
testosterone, deoxycorticicosterone) and vitamin (eg, vitamin K, vitamin E) preparations.
Solutes
 A solute is a component of a solution. In a solution, the dissolving substance is called
the solvent, whereas the dissolved substance is called the solute. Solute chemicals
dissolved in vehicles should be USP grade or better since their contaminants can:
 Alter solubility and compatibility of other solutes
 Cause catalytic chemical reactions
 Cause toxicity of patients
 Solutes may be active ingredient or added substances. Added substances can increase
stability or usefulness if they are harmless in their administered amounts and do not
interfere with therapeutic efficacy.
Added substance
  The USP includes in this category all substances added to a preparation to improve or
safe-guard its quality. An added substance may:
 Increase and maintain drug solubility. Examples include complexing agents and
surface active agents. The most commonly used complexing agents are the
cyclodextrins.
 Provide patient comfort by reducing pain and tissue irritation, as do substnnces added
to make a solution isotonic or near physiological pH. Common tonicity adjusters are
sodium chloride, dextrose, and glycerin.
 Enhance the chemical stability of a solution, as do antioxidant. Inert gases, chelating
agents, and buffers.
 Enhance the chemical and physical stability of freeze dried product, as do
cryoprotectant and lyoprotectants.
 Enhance the physical stability of proteins by minimizing self-aggregation or
interfacial induced aggregation. Surface active agents serve nicely in this capacity.
 Minimize protein interaction with inert surfaces such glass, rubber and plastic.
Competitive binders such as albumin and surface active agent are the best examples.
 Protect the preparation against the growth of microorganisms
 sustaining and/or controlling drug release (polymers), maintaining the drug in a
suspension dosage form (suspending agents , usually polymers and surface active
agents), emulsified dosage forms (emulsifying agents, usually amphiphilic polymers
and surface active agents), and preparation of liposomes (hydrated phospholipids).
In-process control of Ophthalmic applications
What is the need for In-process controls?
 It has always been known that facilities and processes involved in pharmaceutical
production impact significantly on the quality of the products.
 The processes include
 Raw material and equipment inspections as well as in-process controls.
 The development of a drug product is a lengthy process involving
drug discovery, laboratory testing, animal studies, clinical trials and
regulatory registration.
 To further enhance the effectiveness and safety of the drug product after
approval, many regulatory agencies such as the United States Food and
Drug Administration (FDA) also require that the drug product be tested for its
identity, strength, quality, purity and stability before it can be released for use.
 For this reason, pharmaceutical validation and process controls are important in spite of
the problems that may be encountered.
 Even after the manufacturing process is validated, current good
manufacturing practice also requires that a well-written procedure for process
controls is established to monitor its performance. Process controls are
mandatory in good manufacturing practice (GMP).
Control of Containers and Closures
General Requirements
 Procedures for receiving, identifying, storing, sampling, and testing containers and closures
should be defined as SOPs for control purposes. Acceptance criteria should also be
established.
 Containers and closures
 should be carefully controlled to avoid contamination from receipt until storage and
use
 Should be washed and cleaned by appropriate and validated procedures. If water is
used for washing, water for injection or water of comparable quality should be used
for final rinsing.
 Transferred into the critical area should be sterilized by appropriate and validated
procedures.
 Should be controlled to meet endotoxin specifications.
 If they are not depyrogenated after transfer into the critical area, their endotoxin
levels should be confirmed prior to transfer to be lower than respective
predetermined levels
 If they are depyrogenated after transfer into the critical area, suitable depyrogenated
procedures should be instituted by taking into account physicochemical properties of
containers and closures.

Unit nine
Completing production process

Learning Outcome
Upon completion of this chapter students should be able to complete production processes of
pharmaceutical products.
Learning Objectives
 Define quarantine area

Completing production process

Place product in quarantine area

 The status of starting or packaging materials, intermediates, or bulk or finished products

isolated physically or by other effective means while a decision is awaited on their
release, rejection or reprocessing.
 All raw materials,components,packaging and labeling materials are held in ‘’quarantine’’
area until they are sampled, tested, and/or examined, and released for use by quality
 control laboratory
 The sampling is performed according to specific procedures by trained personnel.
 The procedures are designed to prevent contamination of raw materials, components, and
packaging materials.
 Every raw material, component, packaging, and labeling material has its own procedure
and specification in documentation.
 When QC laboratory receives the samples, the perspective test procedure is followed and
the results documented and matched against the specifications.
 Up on release each container of each lot number of raw materials, components,
packaging and labeling materials receives a green release sticker.
 Only containers bearing this release sticker are allowed out of quarantine and in to the
main warehouse.
 Quarantined material and Pharmaceutical products should be kept in specified quarantine
areas until approved.
This area should be:
 Well isolated, separated and clearly labeled.
 Restricted only for authorized personnel.
 Any system replacing physical quarantine should provide equivalent security,
isolation and prevention of mixing up, provided that it is validated to demonstrate its
effectiveness and security of access.
Unit ten
Quality control

Environmental monitoring
 Environmental monitoring program: A system to plan, organize and implement all the
activities to achieve and maintain the required levels of air and surface cleanliness in
the manufacturing areas.
 The primary objective of environmental monitoring is to keep manufacturing
environments for sterile pharmaceutical products clean by controlling the levels of
microorganisms and airborne particles within specified limits for individual APAs and
indirect support areas , by monitoring environmental conditions to prevent
environmental deterioration and product contamination, and by continuously
assessing the efficiency of cleaning, disinfection, and decontamination procedures.
Product sample and relevant documentation
Documentation
 Good documentation is an essential part of the quality assurance system and, as such, should
exist for all aspects of GMP.
 Its aims are to define the specifications and procedures for all materials and methods of
manufacture and control; to ensure that all personnel concerned with manufacture know what
to do and when to do it; to ensure that authorized persons have all the information necessary
 to decide whether or not to release a batch of a medicine for sale, to ensure the existence of
documented evidence, traceability, and to provide records and an audit trail that will permit
investigation.
 It ensures the availability of the data needed for validation, review and statistical analysis.
The design and use of documents depend upon the manufacturer. In some cases some or all
of the documents described below may be brought together, but they will usually be separate
Generally
 Documents should
 be designed, prepared, reviewed and distributed with care. They should comply with the
relevant parts of the manufacturing and marketing authorizations.
 Be approved, signed and dated by the appropriate responsible persons. No document should
be changed without authorization and approval.
 Have unambiguous contents: the title, nature and purpose should be clearly stated. They
should be laid out in an orderly fashion and be easy to check. Reproduced documents
should be clear and legible. The reproduction of working documents from master
documents must not allow any error to be introduced through the reproduction process.
 Be regularly reviewed and kept up to date. When a document has been revised, a system
should exist to prevent inadvertent use of the superseded version. Superseded documents
should be retained for a specific period of time.
 Where documents require the entry of data, these entries should
 beclear, legible and indelible.
 Sufficient space should be provided for such entries.
 Any alteration made to a document should
 be signed and dated; the alteration should permit the reading of the original information.
Where appropriate, the reason for the alteration should be recorded.
 Records should be
 Made or completed when any action is taken and in such a way that all significant
activities concerning the manufacture of pharmaceutical products are traceable.
 Retained for at least one year after the expiry date of the finished product.
 By electronic data processing systems or by photographic or other reliable means.

Documents required
Labels
 Labels applied to containers, equipment or premises should be clear, unambiguous and in the
company’s agreed format. It is often helpful in addition to the wording on the labels to use
colors to indicate status (e.g. quarantined, accepted, rejected, and clean).
 All finished medicines products should be identified by labeling, as required by the national
legislation, bearing at least the following information:
 the name of the medicines product ;
  a list of the active ingredients (if applicable, with the INNs), showing the amount of
each present and a statement of the net contents (e.g. number of dosage units, weight,
volume);
 the batch number assigned by the manufacturer;
 the expiry date in an uncoded form ;
 any special storage conditions or handling precautions that may be necessary ;
 directions for use, and warnings and precautions that may be necessary;
 the name and address of the manufacturer or the company or the person responsible for
placing the product on the market .
 For reference standards, the label and/or accompanying document should indicate
potency or concentration, date of manufacture, expiry date, date the closure is first
opened, storage conditions and control number, as appropriate.
Specifications and testing procedures
 Testing procedures described in documents should be validated in the context of available
facilities and equipment before they are adopted for routine testing.
 There should be appropriately authorized and dated specifications, including tests on
identity, content, purity and quality, for starting and packaging materials and for finished
products; where appropriate, they should also be available for intermediate or bulk products.
Specifications for water, solvents and reagents (e.g. acids and bases) used in production
should be included.
 Each specification should be approved, signed and dated, and maintained by the QC, QA
units or documentation center.
 Pharmacopoeias, reference standards, reference spectra and other reference materials should
be available in the QC laboratory.
Specifications for starting and packaging materials
 Specifications for starting, primary and printed packaging materials should provide, if
applicable, a description of the materials, including:
 the designated name ( if applicable, the INN) and internal code reference
 the reference, if any, to a pharmacopoeial monograph ;
 Qualitative and quantitative requirements with acceptance limits.
 Depending on the company’s practice other data may be added to the specification, such as:
 the supplier and the original producer of the materials;
 a specimen of printed materials;
 directions for sampling and testing, or a reference to procedures ;
 storage condition and precautions;
 the maximum period of storage before re-examination.
 Packaging material should conform to specifications, and should be compatible with
the material and/or with the medicines product it
 Documents describing testing procedures should state the required frequency for re-assaying
 each starting material, as determined by its stability.
Discussion Point: What is the difference among the following words:-identity, content, purity
and quality?
Specifications for intermediate and bulk products
 Specifications for intermediate and bulk products should be available. The specifications
should be similar to specifications for starting materials or for finished products, as
appropriate.
Specifications for finished products
 Specifications for finished products should include:
 the designated name of the product and the code reference, where applicable;
 the designated name(s) of the active ingredient(s) ( if applicable, with the INN(s)) ;
 the formula or a reference to the formula;
 a description of the dosage form and package details ;
 directions for sampling and testing or a reference to procedures;
 the qualitative and quantitative requirements, with acceptance limits ;
 the storage conditions and precautions, where applicable;
 the shelf-life .

Methods of quality control of finished product

Visual inspection
 illumination and background
 eyesight checks of operators
 allowed frequent breaks
General Requirements
 Pharmaceutical products should be subjected to the inspection of all products (“100%
inspection”) during the manufacturing process to remove products containing “readily
detectable foreign insoluble matter” or “clearly detectable foreign insoluble matter.” This
100% inspection should be followed by sampling inspection, as appropriate. The sample
size or sampling inspection should be sufficient for statistical analysis with respect to batch
size.
 The test method of visual inspection should be specified in SOPs.
 Light intensity in inspectionposition, light intensity in inspection area or room, and
color of background plate .If all pharmaceutical products are required or planned to
be visually inspected during the manufacturing process, the conditions for inspection
such as the duration of observation and light intensity , should be specified and
optimized for individual products to completely remove “readily detectable foreign
insoluble matter ” and “clearly detectable foreign insoluble matter.” The time required
for visual inspection should be 5 seconds per unit of inspection per background color of
white and black each. The light intensity and duration of observation may be increased,
 as appropriate.
 If visual inspection is conducted using automatic inspection equipment, at least the
following matters should be determined and specified:
 Model of automatic inspection equipment, speed of work, and time
required for inspection per unit of inspection
 Equipment at the beginning and end of inspection operation as well as
periodic verification of the performance using reference standards
 When a boundary sample is to be prepared for use in the interpretation of
inspection results, the quality of the sample should be evaluated and approved by
the quality control department. Since boundary samples deteriorate or decompose
over time, an expiration date should be set or sample quality should be periodically
evaluated.

Endotoxin testing
Pyrogens and PyrogenTesting
Pyrogens
 are products of metabolism of microorganisms. The most potent pyrogenic substances
(endotoxins) are constituents (lipopolysaccharides, LPS) of the cell wall of gram-negative
bacteria (eg, Pseudomonas species, Salmonella species, Escherichia coli).
 are fever producing organic metabolic products arising from microbial contamination and
responsible for many of the febrile reactions in patients following injection. Hence, these
are known synonymously as bacterial endotoxins.
 Endotoxin: Lipopolysaccharide constituting of outer membrane of Gram negative
bacteria and may have pyrogenic reactions and other biological activities to humans
 The causative material is thought to be lipopolysaccharide metabolic products from the
outer cell wall of Gram-negative bacteria. Because the material is thermostable and water
soluble, it may remain in water even after sterilization by autoclaving or by bacterial
filtration.
 Thus, injections are not pyrogen or endotoxin free but are limited.
 The following are examples from the USP
 Dextrose Injection: Contains not more than 0.5 USP EU per mL for injections containing
less than 5% dextrose and not more than 10.0 USP EU per mL for injections containing
between 5% and 70% dextrose.
 Digoxin Injection: Contains not more than 200.0 USP EU per mg of digoxin.
 Gentamicin Injection: Contains not more than 0.71 USP EU per mg of gentamicin.
 Manufacturers of water for injection may employ any suitable method for removal of
pyrogens from their product.
 Because pyrogens are organic, one of the more common means of removing them is by
oxidizing them to easily eliminated gases or to nonvolatile solids, both of which are easily
separated from water by fractional distillation.
  Potassium permanganate is usually employed as the oxidizing agent, with its
efficiency increased by addition of a small amount of barium hydroxide to impart
alkalinity to the solution and to make nonvolatile barium salts of any acidic
compounds that may be present.
 These two reagents are added to water that has been distilled several times, and
distillation is repeated, the chemical-free distillate being collected under strict aseptic
conditions. When properly conducted, this method results in highly pure, sterile, and
pyrogenfree water.
 However, in each instance, the official pyrogen test must be performed to ensure the
absence of these fever-producing materials.
Pyrogen test
Rabbit test
 The USP pyrogen test uses healthy rabbits that have been properly maintained in terms of
environment and diet before the test.
 Normal, or control, temperatures are taken for each animal to be used in the test. These
temperatures are used as the base for the determination of any temperature increase resulting
from injection of a test solution.
 A given test uses rabbits whose temperatures do not differ by more than 1°C from each
other and whose body temperatures are considered not to be elevated. A synopsis of the
procedure of the test is as follows.
 Render the syringes, needles, and glassware free from pyrogens by heating at 250°C
for not less than 30 minutes or by other suitable method.
 Warm the product to be tested to 37°C ± 2°C.Inject into an ear vein of each of three
rabbits 10 mL of the product per kilogram of body weight, completing each injection
within 10 minutes of the start of administration.
 Record the temperature at 30-minute intervals 1 to 3 hours subsequent to the
injection.
 If no rabbit shows an individual rise in temperature of 0.5°C or more, the product meets
the requirements for the absence of pyrogens.
 If any rabbit shows an individual temperature rise of 0.5°C or more, continue the test
using five other rabbits.
 If not more than three of the eight rabbits show individual rises in temperature of 0.5°C
or more and if the sum of the eight individual maximum temperature rises does not
exceed 3.3°C, the material under examination meets the requirements for the absence of
pyrogens.
Limulus amebocyte lysate (LAL) test
 An extract from the blood cells of the horseshoe crab (Limulus Polyphemus) contains an
enzyme and protein system that coagulates in the presence of low levels of
lipopolysaccharides.
 This discovery led to the development of the Limulus amebocyte lysate (LAL) test for the
 presence of bacterial endotoxins.
 The Bacterial Endotoxins Test, USP, uses LAL, and is considered generally more sensitive
to endotoxin than the rabbit test.
 as it also is called, is a biochemical test performed in a test tube and is simpler, more rapid,
and of greater sensitivity than the rabbit test
 The FDA has endorsed it as a replacement for the rabbit test, and it is used for a number of
parenteral products. The USP–NF (National Formulary) has specific allowable has been
distilled several times, and distillation is repeated, the chemical-free distillate being
collected under strict aseptic conditions.

Containers closed by means of validated methods

Containers
 Containers are defined as “that which holds the article and is or may be indirect contact
with the articles. The closure is part of the container.
 All containers for sterile preparations must be sterile, free of both particulate matter and
pyrogens.These containers should not interact physically or chemically with formulations
to alter their required strength, quality, or purity. Containers must also permit inspection
of their contents.
Single or Multiple Dose Containers
 Sterile, single-dose containers are intended for parenteral, inhalation, irrigation, octic, and
ophthalmic administration. Examples are prefilled syringes, cartridges, ampoules, and
vials (when labeled as single-use).
 Multiple-dose containers permit withdrawal of successive portions of their contents
without changing the strength, quality, or purity of the remaining portions. Sterile,
multiple-dose containers may be used for preserved parenterals, ophthalmics, and octics.
Glass
 Glass is the most popular material for sterile preparation containers. USP classifies glass
as Type I (borosilicate glass), Type II (soda-lime-treated glass), Type III (soda-lime
glass), or NP (soda-lime glass unsuitable for parenteral containers). Different glass types
vary in their resistance to attack by water and chemicals. For pharmaceutical containers,
glass must meet the USP test for chemical resistance. Because most pharmacy personnel
do not have the time or facilities to perform glass chemical interaction studies, they
should use only Type I glass to minimize sterile preparation incompatibilities.
Conceptual reading test Question ; what does the "NP glass" mean?
Plastic
 Plastic polymers can be used as sterile preparation containers but present three problems:
 Permeation of vapors and other molecules in either direction through the
container.
  Leaching of constituents from the plastic into the preparation.
 Sorption of drug molecules onto the plastic.
 Plastics must meet USP specifications for biological reactivity and physiochemicals.
 Most plastic containers do not permit ready inspection of their contents because they are
unclear. Most plastics also melt under heat sterilization.
Closures
 Rubber closures must be rendered sterile, free from pyrogens and surface particles. To
meet these specifications, multiple washings and autoclaving are required. An autoclave
heats sterilizing solutions above their boiling point to sterilize medical instruments. But
How?
 Closures are made of natural, neoprene (polychloroprene), or butyl rubber. Thus, the
rubber sealing of a vial or the plug in a syringe is a complex material that can interact
with the ingredients of a formula. Rubber closures also are subject to coring.
Parenteral Formulations
 Pharmacists and technicians will compound a wide variety of sterile formulations in different
settings. These formulations will include products administered by injection, such as:
 Intravenous (IV) – medication is injected directly into the vein
 Intramuscular (IM) – medication is injected directly into a large muscle
 Subcutaneous (SC) – also known as hypodermic injection; medication is injected
into the tissue under the skin
 Intradermal (ID) – medication is injected into the substance of the skin
 Intrathecal – medication is injected into the spinal canal
 Epidural – medication is injected through a catheter placed in the “epidural
space”, which is the outermost part of the spinal canal.
 There are also other sterile products, which may be administered by the following routes:
 Inhalation – medication is inhaled through the mouth
 Intranasal – medication is inhaled through the nose
 Ophthalmic – medication administered through the eye
 Parenteral preparations are classified into six general categories:
 Solutions ready for injection.
 Dry, soluble preparations ready to be combined with solvent before use.
 Suspensions ready for injection.
 Dry, insoluble preparations ready to be combined with a vehicle before use.
 Emulsions.
 Liquid concentrates ready for dilution prior to administration.
 Most compounded sterile parenteral preparations are aqueous solutions (first category).
 Other categories usually require the equipment and expertise of a licensed pharmacist. In
addition to using appropriate vehicle, solvent, and container, you must ensure that the final
aqueous solution maintains the appropriate physiological and physical norms.
Large Volume Parenteral Solutions
 Large-volume parenteral (LVP) solutions are commonly stored in plastic or glass.
 Solutions for injection must be sterile, and contamination must be prevented by using
aseptic techniques. LVP solutions are available in a variety of sizes (250 mL, 500 mL,
and 1000 mL).
Examples of LVP solutions with additives, manufactured in standard concentrations, include:
 Aminophylline
 Dopamine
 Lidocaine
 Nitroglycerin
 Potassium
 In some cases, the preparation of LVPs by the pharmacist or technician depends on the drug
and intended use. The preparation of LVPs in the pharmacy must always follow aseptic
technique. Common examples of LVPs in use include:
 Dextrose Injection, USP
 Dextrose and Sodium Chloride Injection salts sometimes must be buffered to a pH
near normal (e.g., 3-8) to prevent pain or tissue damage.

PACKAGING, LABELING, AND STORAGE OF INJECTIONS

 Containers for injections, including the closures, must not interact physically or
chemically with the preparation so as to alter its strength or efficacy
 If the container is made of glass, it must be clear and colorless or light amber to permit
inspection of its contents. The type of glass suitable for each parenteral preparation is
usually stated in the individual Injections are placed either in single-dose containers or in
multiple-dose containers
 Single-dose container
 A hermetic container holding a quantity of sterile drug intended for parenteral
administration as a single dose; when opened, it cannot be resealed with assurance that
sterility has been maintained.
 Single dose containers may be ampules or single-dose vials
 Multiple-dose container
 A hermetic container that permits withdrawal of successive portions of the contents
without changing the strength, quality, or purity of the remaining portion.
 During manufacturing
 The parenteral solution is usually filtered just before it goes into the container.
 The containers are carefully selected to be chemically resistant to the solution and of the
highest available quality to minimize the chances of container components leaching into
the solution. It has been recognized for some time that some particulate matter in
parenteral products is leached material from the glass or plastic container. Once the
 container is selected, it must be carefully cleaned to be free of all extraneous matter.
 During container filling, extreme care must be exercised to prevent the entrance of
airborne dust, lint, or other contaminants.
 Filtered and directed airflow in production areas reduces the likelihood of contamination.
Laminar flow hoods allow for draft-free flow of clean, filtered air over the work area.
These hoods are commonly found in hospitals for both manufacture and incorporation of
additives into parenteral and ophthalmic products.
Discussion Point: What do by draft-free flow mean?
 The personnel who manufacture parenteral must be made acutely aware of the
importance of cleanliness and aseptic techniques. They are provided with uniforms of
monofilament fabrics that do not shed lint. They wear face hoods, caps, gloves, and
disposable shoe covers.Why?
 to prevent contamination.
Storage and Transport of Sterile Intermediate Products
General Requirements
 Containers used for the storage and transportation of sterile intermediate products
(“containers” in this section refers to cargo transporters, drums, bags, and tanks) should
be capable of isolating the products from the surrounding non-sterile environment and
hence maintaining the sterility of the products.
 The containers should be durable enough to withstand handling and environmental
conditions encountered during storage and transportation.
 Containers used for storage and transportation of intermediate products should be cleaned
and sterilized before being filled with and storing or transporting the products.
 Cleaning and sterilization are not required for sterile single -use containers. However, the
content sterility must be maintained under all circumstances.
 SOPs should be established for pouring intermediate products into and discharging them
from the containers in a closed system, as a rule. If adopting a closed system is difficult,
intervention by personnel should be kept to a minimum. The environment to which
sterile intermediate products are exposed should be a critical area (Grade A) free of
contamination risks.
 Sealing performance (tightness ) of containers should be checked and confirmed, as
required.
Design of Containers for transportation
 The choice of containers for maintaining sterility during storage and transportation of
intermediate products should take the following matters into account:
 The following points should be observed when designing or selecting containers to be used
for isolating contents from the non-sterile environment.
 The structure should ensure hermetic sealing.
 If the container cannot be hermetically sealed, the inside of the container should be
maintained constantly under positive pressure with sterile gas
  If sealing performance of container cannot be ensured because of changes in external
pressure, air vent filters capable of sterile filtration should be installed and their
integrity tested at appropriate intervals.
 Containers should be designed to have a dual structure, as appropriate.
 If the surface of a container needs to be cleaned and sterilized prior to transferring the
container into the APA, the surface should be able to withstand cleaning and disinfection
agents.
 Casters and other parts of transport devices should be protected from generating dust and
particulate matter, if such devices are used in the transportation of containers into the
APA.
 If single-use plastic bags are used for storage and transportation, the potential
extractable/leachable of components out of the bags into drug solution and effects of the
components on product quality should be carefully evaluated and discussed.
Confirmation of Hermeticity
 Whether or not newly designed containers they can be hermetically sealed should be
confirmed.
 Eligibility confirmation at designing, sealing performance of container should be
estimated by taking into account projected use conditions, including worst-case
scenarios.
 Eligibility confirmation at manufacturing (actual use) sealing performance should
be tested after storage or transportation under actual use conditions.
 Sealing performance can be determined by the following example methods:
 Check whether or not leakage occurs in containers on hold status under positive
pressure.
 Check whether or not leakage occurs in containers on hold status under negative
pressure.
 Immerse containers in pigment solution or bacterial suspension and check whether
or not pigment or bacteria are detected in containers.
 Inspect containers with a gas leakage detector.
 Inspect containers with an electric pin hole testing machine.
Charging and Discharging Sterile Intermediate Products in and out of Containers
 When charging and discharging sterile intermediate products in and out of containers
before and after storage or transportation , the following matters should be taken into
account:
1. Automatization. Wherever feasible, automatic charging (including divided charging) and
discharging systems should be instituted to minimize personnel intervention.
2. Minimization of personnel intervention-related risks
If automatic systems cannot be introduced, the following matters should be considered to
manage intervention-related risks:
 Working personnel should not physically block or disrupt airflow directed to the
 charging and discharging ports.
 Charging and discharging operations should be performed in Grade A areas (e.g. clean
booth).
 Certain risk reduction measures such as sterile connections using tubing systems that do
not require opening of containers should be examined and evaluated.
3. Process simulation
A process simulation test should be performed to demonstrate the validity of procedures for
charging and discharging sterile intermediate products in and out of containers.
4. Limitation of working hours
Time is always a critical factor for maintaining sterile conditions; the more time required for
charging and discharging operations, the greater the risk of contamination. A maximum time
limit should preferably be set for these operations, and if more than one container is used per
shift, the containers should be marked with identification numbers or other identifiers to facilitate
a first-in, first-out order of operations.

Unit Eleven
Storage and Transportation Conditions
 Drug storage is among the pharmacist’s most important responsibilities. Therefore,
adequate methods to assure that these responsibilities are met must be developed and
implemented.
 The pharmaceutical are to be stored under conditions that prevent contamination and, as
far as possible, deterioration. The stability of product retain within the specified limit,
throughout it period of storage and use.
 Precautions that should be taken in relation to the effects of the atmosphere, moisture,
heat and light are indicated.
 During storage of the pharmaceutical products is one of the fundamental concerns in
patient care.
 Appropriate conditions of light, humidity, ventilation, temperature and security should be
ensured. All medicinal products must be stored in accordance with the manufacturer’s
directions and within the terms of product authorizations.
 Pharmacy stock should be stored under suitable conditions, appropriate to the nature and
stability of the product concerned.
 Particular attention should be paid to protection from contamination, sunlight, UV rays,
moisture, atmospheric moisture and extreme temperatures.
During storage, medicines should be retained in the manufacturer’s original packaging. Good
storage practice is applicable in all circumstances where pharmaceutical products are stored
throughout distribution process.

The following factors to be taken in consideration for proper storage:

1. Sanitation
2. Temperature
3. Light
4. Moisture
5. Ventilation
6. Segregation

Good storage practice (GSP) is applicable in all circumstances where pharmaceutical

products are stored through the distribution processes.

STORAGE CONDITION ON LABEL

 Storage conditions for pharmaceutical products and materials should be in compliance with
the labelling, which is based on the results of stability testing
 Storage conditions should bedefined and described on the label of the product.
All drugs should be stored according to the conditions described on the label. When specified on
the label, controls for humidity, light, etc., should be in place. Storage areas should be designed
or adapted to ensure good storage conditions6
The label should specify any special storage conditions required for the product.
Written procedures should be available describing the actions to be taken in the event of
temperature excursions outside the labeled storage conditions7
Storage of Tablet
Storage on label:
Store in a cool, protected from light and moisture.
Store in a cool and dark place, protected from light and moisture.
Keep in a dry dark place.
Store in cool dry and dark place.
Storage of Capsule
Storage on label:
Store in a cool and dry place, protected from light.

Storage of Paste
The paste should be stored in well closed container and in a cool place so as to prevent
evaporation of moisture present.
Storage of syrup
The syrup should be stored in well closed and stopper bottle in a cool dark place. The syrup
should be stored at a temperature not exceeding 25 ºC.
Storage on label:
Store in cool, dry and dark place.
Store in a cool and dry place, protected from light.
Store in a cool place, protected from direct sunlight.
Storage of Oral Drop
Storage on label:
Store at temperature not exceeding 30 ºC.
Store in cool, dry place and protected from light.
Store at temperature not exceeding 30 ºC, protect from direct sunlight.
Keep in a dry place, dark place.
Store in a dry place, away from light.
Storage of injection
Storage on label:
Store below 30 ºC, protected from light.
Store below 25 ºC, protected from light.
 Drugs products that must be stored under defined conditions require appropriate storage
instructions. Unless otherwise specified stated deviation may be tolerated only during short
term interruptions. Storage of insulin decreases the potency and hence the pharmacological
action of insulin. Patients should be educated on the proper methods of storage. Insulin is one
such
labile drug, sensitive to extreme temperatures and sunlight and hence needs to be stored
under refrigeration between 2- 8°C.
The uses of the following labeling instructions are given:

On the label Means

Do not store over 30 ºC from +2 ºC to +30 ºC
Do not store over 25 ºC from +2 ºC to +25 ºC
Do not store over 15 ºC from +2 ºC to +15 ºC
Do not store over 8 ºC from +2 ºC to +8 ºC
Do not store below 8 ºC from +8 ºC to +25 º

Potential risks (e.g. temperature, environmental pressure, vibration) that may affect sterility of
intermediate products during storage or transportation should be identified, and acceptable
working conditions or specifications for such risk factors should be specified. Storage and
transportation operations should be conducted with care not to violate established conditions or
specifications.
Reference Manuals and Books
 Ansel; The Science of Dosage form Design, latest edition
 Katzung B. G; Basic and Clinical Pharmacology; 10th or later edition
 Mycek M.J. Harvey R. A; Lippincott’s illustrated Reviews: Pharmacology 2 nd edition or
later edition.
 Remington; The science & practice of pharmacy, volume I and II, latest edition.